Nitrogenous condensed-ring compound and use thereof as hiv integrase inhibitor

专利摘要:
The present invention relates to a nitrogen-containingfused ring compound represented by the following formula [I]
公开号:EP1544199A1
申请号:EP04771830
申请日:2004-08-12
公开日:2005-06-22
发明作者:Susumu c/o Central Pharm. Research MIYAZAKI；Susumu c/o Central Pharmaceutical Research KATOH；Kaoru c/o Central Pharmaceutical Research ADACHI；Hirotaka c/o Central Pharm. Research ISOSHIMA；Satoru c/o Central Pharm. Research KOBAYASHI；Yuji c/o Central Pharm. Research MATSUZAKI；Wataru c/o Central Pharm. Research WATANABE；Kazunobu c/o Central Pharm. Research YAMATAKA；Shinichi c/o Central Pharm. Research KIYONARI；Shuichi Central Pharmaceutical Research WAMAKI
申请人:Japan Tobacco Inc；
IPC主号:A61K-31

专利说明:
[0001] The present invention relates to a novel nitrogen-containingfused ring compound or a pharmaceutically acceptablesalt thereof useful as an anti-HIV agent. Moreover, the presentinvention relates to novel use of a certain kind of nitrogen-containingfused ring compound or a pharmaceutically acceptablesalt thereof as an anti-HIV agent. More specifically, thepresent invention relates to an anti-HIV agent containing anitrogen-containing fused ring compound or a pharmaceuticallyacceptable salt thereof showing an anti-HIV action particularlybased on an integrase inhibitory activity. Background Art
[0002] HIV (Human Immunodeficiency Virus (type 1)) belonging toretrovirus is a causative virus of AIDS (AcquiredImmunodeficiency Syndrome).
[0003] HIV targets CD4 positive cell groups such as helper Tcell, macrophage and dendritic cell and destroys theseimmunocompetent cells to cause immunodeficiency.
[0004] Accordingly, a pharmaceutical agent that eradicates HIV ina living organism or suppresses its growth is effective for thetreatment or prophylaxis of AIDS.
[0005] HIV possesses a bimolecular RNA gene in a shell, and whichis covered with an envelope protein. The RNA codes for severalenzymes (protease, reverse transcriptase, integrase etc.)characteristic of the virus and the like, and has translatedreverse transcriptase and integrase in the core, as well asprotease inside and outside the core.
[0006] HIV contacts and invades a host cell, causes uncoating,and releases a complex of RNA and integrase, and the like intothe cytoplasm. From the RNA, DNA is transcribed by reversetranscriptase, and a full length double stranded DNA isproduced. The DNA moves into the core of the host cell and is incorporated by integrase into the DNA of the host cell. Theincorporated DNA is converted to an mRNA by polymerase of thehost cell, from which mRNA various proteins necessary forforming a virus are synthesized by HIV protease and the like,and a virus particle is finally formed, which then undergoesbudding and its release.
[0007] These virus specific enzymes are considered to beessential for the growth of HIV. These enzymes are drawingattention as the target of the development of antiviral agents,and several anti-HIV agents have been already developed.
[0008] For example, zidovudine, didanosine, lamivudine and thelike have been already on the market as reverse transcriptaseinhibitors, and indinavir, nelfinavir and the like as proteaseinhibitors.
[0009] In addition, a multiple drug combination therapyconcurrently using these pharmaceutical agents has beenemployed. For example, a combined use of two reversetranscriptase inhibitors (zidovudine and didanosine), and acombined use of three agents of reverse transcriptase inhibitors(zidovudine and lamivudine) and a protease inhibitor(nelfinavir) have been clinically applied. Such multiple drugcombination therapy is becoming a mainstream of AIDS therapy(Folia Pharmacologica Japonica, 118, 131-134, 2001).
[0010] However, some of these pharmaceutical agents are known tocause side effects such as liver function failure, centralnervous disorders (e.g., vertigo), and the like. In addition,acquisition of resistance to a pharmaceutical agent causes aproblem. Even worse, emergence of an HIV that shows multipledrug resistance in a multiple drug combination therapy has beenknown.
[0011] Under the circumstances, a further development of a novelpharmaceutical agent, particularly a development of an anti-HIVagent based on a new mechanism, has been desired, wherein adevelopment of an anti-HIV agent having an integrase inhibitory activity is expected, because an integrase characteristic ofretrovirus is an essential enzyme for the growth of HIV.
[0012] Nevertheless, an effective integrase inhibitor has notbeen found as yet.
[0013] Known compounds comparatively similar to the anti-HIVagent of the present invention are described in the following.
[0014] WO01/96283 describes, as an anti-HIV agent having anintegrase inhibitory activity, the following compound [A] (seeWO01/96283, p. 176, compound 70).
[0015] WO03/016266 describes the following compound [B] and thelike having an integrase inhibitory activity (see WO03/016266, p.159, Example No. 3-17).
[0016] WO01/95905 describes the following compound [C] and thelike, as an anti-HIV agent having an integrase inhibitoryactivity (see WO01/95905, p. 109, Example E-2).
[0017] In addition, WO03/047564 describes the following compound[D] and the like, as an anti-HIV agent having an integraseinhibitory activity (see WO03/047564, p. 73, Example 11).
[0018] Moreover, WO02/30930 and WO02/55079 describe, as an anti-HIVagent having an integrase inhibitory activity, thefollowing compounds [E], [F] and the like, respectively (seeWO02/30930, p. 171, Example 1; WO02/55079, p. 79, Example 1).WO02/30426, WO02/30931 and WO02/36734 also disclose similarcompounds.
[0019] In addition, WO03/031413 describes, as an anti-HIV agenthaving an integrase inhibitory activity, the following compound[G] and the like (see WO03/031413, p. 21, compound 8).
[0020] Moreover, WO03/035076 and WO03/035077 describe, as ananti-HIV agent having an integrase inhibitory activity, thefollowing compounds [H], [i] and the like (WO03/035076, p. 188,Example 1; WO03/035077, p. 146, Example 22).
[0021] However, these publications do not disclose nitrogen-containingfused ring compound encompassed in the present invention, or a description suggestive thereof.
[0022] Furthermore, WO2004/24078 describe, as an anti-HIV agenthaving an integrase inhibitory activity, the following compound[J] and the like.
[0023] This publication describes the following formula as theformula (I) of claim 1 and a tautomer thereof. However, thecompound described in this publication is clearly differentfrom the compound of the present invention in that a hydroxylgroup or an oxo group is essential at a position correspondinto the position of R^y1 for Y² in the formula [I] of thenitrogen-containing fused ring compound of the presentinvention. In addition, this publication does not suggest acompound free of a hydroxyl group or an oxo group at saidposition.
[0024] A production method of the compound of the formula (I) isdisclosed in this publication from page 46 to page 113, but theproduction method concretely disclosed here cannot produce anitrogen-containing fused ring compound encompassed in thepresent invention, and a concrete production method of this compound is not referred to at all. Disclosure of the Invention
[0025] From the findings based on the researches and clinicalresults obtained so far, an anti-HIV agent is effective for theprophylaxis of the onset of AIDS and the treatment thereof, andparticularly a compound having an integrase inhibitory actioncan provide an effective anti-HIV agent.
[0026] It is therefore an object of the present invention toprovide a pharmaceutical agent having an anti-HIV action,particularly a pharmaceutical agent having an integraseinhibitory action.
[0027] The present inventors have conducted intensive studies inan attempt to find a compound having an anti-HIV action,particularly a compound having an integrase inhibitory action,and completed the present invention.
[0028] More particularly, the present invention is as shown inthe following [1] to [38]. [1] A nitrogen-containing fused ring compound represented by thefollowing formula [I] or a pharmaceutically acceptable saltthereof:
[0029] The compound of the present invention can be apharmaceutical agent effective for the prophylaxis or treatmentof AIDS, as an anti-HIV agent having an HIV integrase inhibitoryactivity. In addition, by a combined use with other anti-HIVagents such as protease inhibitors, reverse transcriptaseinhibitors and the like, the compound can be a more effectiveanti-HIV agent. Moreover, since the compound has an integrase-specific high inhibitory activity, it can be a pharmaceuticalagent safe on the human body, which is associated with a fewerside effects. Best Mode for Embodying the Invention
[0030] The "bond" means a direct connection and in the case of N-Z-Ph,for example, when Z is a "bond", it means N-Ph.
[0031] The "halogen atom" is a fluorine atom, a chlorine atom, abromine atom or an iodine atom, and is preferably a fluorineatom, a chlorine atom or a bromine atom.
[0032] For group A, it is more preferably a fluorine atom, forgroup B, it is more preferably a fluorine atom or a chlorineatom, and for group C, it is more preferably a bromine atom.
[0033] The "C1-6 alkyl group" is a linear or branched chain alkylgroup having 1 to 6 carbon atoms, and preferably a linear orbranched chain alkyl group having 1 to 4 carbon atoms.Specifically, methyl group, ethyl group, propyl group, isopropylgroup, butyl group, isobutyl group, sec-butyl group, tert-butylgroup, pentyl group, isopentyl group, tert-pentyl group, hexylgroup and the like can be mentioned.
[0034] It is preferably a methyl group for R⁶, R^b2, R^b3, R^b4, R^b5 orR^b6, preferably a methyl group, a propyl group or an isopropylgroup for R^b1, and preferably a methyl group, an ethyl group or atert-butyl group for group B.
[0035] The "C1-7 alkyl group" is a linear or branched chain alkylgroup having 1 to 7 carbon atoms, and is preferably a linear orbranched chain alkyl group having 1 to 4 carbon atoms.Specifically, methyl group, ethyl group, propyl group, isopropylgroup, butyl group, isobutyl group, sec-butyl group, tert-butylgroup, pentyl group, isopentyl group, tert-pentyl group, hexylgroup, 1-isopropyl-2-methylpropyl group and the like can bementioned.
[0036] The "C2-6 alkenyl group" is a linear or branched chainalkenyl group having 2 to 6 carbon atoms. Specifically, vinylgroup, allyl group, 1-propenyl group, isopropenyl group, 2-methyl-1-propenylgroup, 1-butenyl group, 2-butenyl group, 1,3-butadienyl group, 3-methyl-2-butenyl group, 4-methyl-2-pentenylgroup, 4-methyl-3-pentenyl group, 1-methyl-2-butenyl group andthe like can be mentioned.
[0037] The "C2-6 alkynyl group" is a linear or branched chainalkynyl group having 2 to 6 carbon atoms. Specifically, ethynylgroup, 1-propynyl group, 2-propynyl group, 3-butynyl group andthe like can be mentioned.
[0038] The "C1-6 alkylene" is a linear or branched chain alkylenehaving 1 to 6 carbon atoms and methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, propylene,-CH(CH₃)-, C(CH₃)₂-, -CH(CH₃)-(CH₂)₂- and the like can be mentioned.
[0039] Preferably, it is methylene, ethylene, trimethylene ortetramethylene, and more preferably methylene.
[0040] The "C2-6 alkenylene" is a linear or branched chainalkenylene having 2 to 6 carbon atoms and vinylene, propenylene,1-butenylene, 1,3-butadienylene, -CH(CH₃)-CH=CH- and the like canbe mentioned. Preferably, it is propenylene.
[0041] The "haloC1-6 alkyl group" is the above-defined "C1-6alkyl group" substituted by the above-defined "halogen atom",and preferably it is a haloalkyl group wherein its alkyl moietyis a linear or branched chain alkyl group having 1 to 4 carbonatoms. Specifically, fluoromethyl group, difluoromethyl group,trifluoromethyl group, bromomethyl group, chloromethyl group,1,2-dichloroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethylgroup and the like can be mentioned. Preferably,it is trifluoromethyl group.
[0042] The "C1-6 alkyloxy group" is an alkyl-oxy group whereinits alkyl moiety is the above-defined "C1-6 alkyl group", andpreferably an alkyl-oxy group wherein its alkyl moiety is alinear or branched chain alkyl group having 1 to 4 carbon atoms.Specifically, methoxy group, ethoxy group, propoxy group,isopropyloxy group, butoxy group, isobutyloxy group, tert-butyloxygroup, pentyloxy group, hexyloxy group and the like canbe mentioned.
[0043] The "C6-14 aryl group" is an aromatic hydrocarbon group having 6 to 14 carbon atoms. Specifically, phenyl group,naphthyl group, anthryl group, indenyl group, azulenyl group,fluorenyl group, phenanthryl group and the like can be mentioned,with preference given to phenyl group.
[0044] The "C6-14 aryloxy group" is an aryl-oxy group wherein itsaryl moiety is the above-defined "C6-14 aryl group".Specifically, phenoxy group, naphthyloxy group, anthryloxy group,indenyloxy group, azulenyloxy group, fluorenyloxy group,phenanthryloxy group and the like can be mentioned, withpreference given to phenoxy group.
[0045] The "C6-14 aryl C1-6 alkyl group" is an aryl-alkyl groupwherein its alkyl moiety is the above-defined "C1-6 alkyl group"and its aryl moiety is the above-defined "C6-14 aryl group".Preferably, it is an aryl-alkyl group wherein its alkyl moietyis a linear or branched chain alkyl group having 1 to 4 carbonatoms and its aryl moiety is phenyl group. Specifically, benzylgroup, phenethyl group, 3-phenylpropyl group, 2-phenylpropylgroup, 4-phenylbutyl group and the like can be mentioned.
[0046] It is particularly preferably benzyl group for R².
[0047] The "C6-14 aryl C1-6 alkyloxy group" is an aryl-alkyl-oxygroup wherein its C6-14 aryl C1-6 alkyl moiety is the above-defined"C6-14 aryl C1-6 alkyl group". Preferably, it is anaryl-alkyl-oxy group wherein its alkyl moiety is a linear orbranched chain alkyl group having 1 to 4 carbon atoms and itsaryl moiety is phenyl group. Specifically, benzyloxy group,phenethyloxy group, 3-phenylpropyloxy group, 2-phenylpropyloxygroup, 4-phenylbutyloxy group and the like can be mentioned.
[0048] The "C6-14 aryl C1-6 alkyloxycarbonyl group" is an aryl-alkyl-oxy-carbonylgroup wherein its C6-14 aryl C1-6 alkylmoiety is the above-defined "C6-14 aryl C1-6 alkyl group".Preferably, it is an aryl-alkyl-oxy-carbonyl group wherein itsalkyl moiety is a linear or branched chain alkyl group having 1to 4 carbon atoms and its aryl moiety is phenyl group.Specifically, benzyloxycarbonyl group, phenethyloxycarbonylgroup, 3-phenylpropyloxycarbonyl group, 2-phenylpropyloxycarbonyl group, 4-phenylbutyloxycarbonyl groupand the like can be mentioned.
[0049] It is preferably benzyloxycarbonyl group.
[0050] The "C6-14 arylcarbonyl group" is an aryl-carbonyl groupwherein its aryl moiety is the above-defined "C6-14 aryl group".Specifically, benzoyl group, 1-naphthoyl group, 2-naphthoylgroup, anthrylcarbonyl group, indenylcarbonyl group,azulenylcarbonyl group, fluorenylcarbonyl group,phenanthrylcarbonyl group and the like can be mentioned, withpreference given to benzoyl group.
[0051] The "C3-10 carbon ring group" is a saturated orunsaturated cyclic hydrocarbon group having 3 to 10 carbon atomsand means aryl group, cycloalkyl group, cycloalkenyl group, or afused ring thereof.
[0052] As the "aryl group", phenyl group, naphthyl group,pentalenyl group, azulenyl group and the like can bespecifically mentioned. It is preferably phenyl group ornaphthyl group, and more preferably phenyl group.
[0053] As the "cycloalkyl group", cyclopropyl group, cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group,cyclooctyl group, adamantyl group, norbornanyl group and thelike can be specifically mentioned. It preferably includescyclopentyl group, cyclohexyl group and cycloheptyl group, andparticularly preferably includes cyclopentyl group andcyclohexyl group.
[0054] The "cycloalkenyl group" contains at least one, preferably1 or 2, double bonds. Specifically, cyclopropenyl group,cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group,cyclohexenyl group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadien-1-ylgroup etc.), cycloheptenyl group andcyclooctenyl group and the like can be mentioned.
[0055] As a fused ring of these "aryl group", "cycloalkyl group"and "cycloalkenyl group", indenyl group, indanyl group, 1,4-dihydronaphthylgroup, 1,2,3,4-tetrahydronaphthyl group(1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group etc.), perhydronaphthyl group and the like can bespecifically mentioned. Preferably, it is a fused ring ofphenyl group and other ring, such as indenyl group, indanylgroup, 1,4-dihydronaphthyl group, 1,2,3,4-tetrahydronaphthylgroup and the like.
[0056] The "heteroaryl group" is a 5 or 6-membered heteroarylgroup containing, as a ring-constituting atom, besides thecarbon atom, at least one hetero atom selected from nitrogenatom, oxygen atom and sulfur atom.
[0057] Specifically, pyridyl group, pyrazinyl group, pyrimidinylgroup, pyridazinyl group, 1,3,5-triazinyl group, pyrrolyl group,pyrazolyl group, imidazolyl group, triazolyl group (1,2,3-triazolylgroup, 1,2,4-triazolyl group), tetrazolyl group,thienyl group, furyl group, oxazolyl group, isoxazolyl group,thiazolyl group, isothiazolyl group, oxadiazolyl group (1,2,4-oxadiazolylgroup, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolylgroup), thiadiazolyl group (1,2,4-thiadiazolyl group, 1,3,4-thiadiazolylgroup, 1,2,5-thiadiazolyl group) and the like canbe mentioned.
[0058] The "heterocyclic group" is a saturated or unsaturated(including partially unsaturated and completely unsaturated)monocyclic 5-membered or 6-membered heterocycle containing,besides carbon atom, at least 1, preferably 1 to 4, hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom, or afused ring of such heterocycles, or a fused ring of a carbonring selected from benzene, cyclopentane and cyclohexane and theabove-defined heterocycle.
[0059] As the "saturated monocyclic heterocyclic group",pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienylgroup, imidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanylgroup, 1,3-oxathiolanyl group, oxazolidinyl group, thiazolidinylgroup, piperidinyl group, piperazinyl group, tetrahydropyranylgroup, tetrahydrothiopyranyl group, dioxanyl group, morpholinylgroup, thiomorpholinyl group, 3-hydroxypyrrolidinyl group, 2-oxopyrrolidinylgroup, 3-oxopyrrolidinyl group, 2-oxopiperidinyl group, 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group andthe like can be mentioned. Preferably, it is pyrrolidinyl group,piperidinyl group or morpholinyl group.
[0060] As the "unsaturated monocyclic heterocyclic group",pyrrolyl group, furyl group, thienyl group, imidazolyl group,1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, oxazolylgroup, isoxazolyl group, thiazolyl group, isothiazolyl group,1,2,4-triazolyl group, 1,2,3-triazolyl group, tetrazolyl group,1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-thiadiazolylgroup, 1,2,4-thiadiazolyl group, furazanyl group,pyridyl group, pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinylgroup, pyridazinyl group, pyrazinyl group, 1,3,5-triazinyl group,imidazolinyl group, pyrazolinyl group, oxazolinyl group (2-oxazolinylgroup, 3-oxazolinyl group, 4-oxazolinyl group),isoxazolinyl group, thiazolinyl group, isothiazolinyl group,pyranyl group, 2-oxopyranyl group and the like can be mentioned.It is preferably imidazolyl group, pyrazolyl group, isoxazolylgroup, thiazolyl group, 1,2,4-triazolyl group, tetrazolyl group,1,3,4-oxadiazolyl group, pyridyl group, pyrimidinyl group,pyridazinyl group, pyrazinyl group or oxazolinyl group.
[0061] As the "fused heterocyclic group", indolyl group,isoindolyl group, 1,3-dihydro-1,3-dioxoisoindolyl group,benzimidazolyl group, indazolyl group, benzothiazolyl group,benzofuranyl group, isobenzofuranyl group, indolizinyl group,quinolyl group, isoquinolyl group, 1,2-dihydro-2-oxoquinolylgroup, quinazolinyl group, quinoxalinyl group, cinnolinyl group,phthalazinyl group, quinolizinyl group, pyrinyl group,pteridinyl group, indolinyl group, isoindolinyl group, 5,6,7,8-tetrahydroquinolylgroup, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolylgroup, 1,3-benzodioxolyl group,3,4-methylenedioxypyridyl group, 4,5-ethylenedioxypyrimidinylgroup, chromenyl group, chromanyl group, isochromanyl group,1,2,4-benzotriazinyl group and the like can be mentioned.Preferably, it is indolyl group, benzofuranyl group, quinolylgroup, benzothiazolyl group, 1,2,3,4-tetrahydroquinolyl group, 1,3-benzodioxolyl group or 1,2,4-benzotriazinyl group.
[0062] The "heterocyclic group" that substitutes C1-7 alkyl group,C1-6 alkyl moiety, C2-6 alkenyl group and C2-6 alkynyl group ofgroup C is preferably a 2-oxopyrrolidin-1-yl group.
[0063] The "C3-8 cycloalkyl group" is a cycloalkyl group having 3to 8 carbon atoms, and is specifically cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group,cycloheptyl group or cyclooctyl group.
[0064] As R^c7 in group C, preferred is a cyclopentyl group.
[0065] The "C3-8 cycloalkyl C1-6 alkyl group" is a cycloalkylalkylgroup wherein the above-defined "C1-6 alkyl group" issubstituted by the above-defined "C3-8 cycloalkyl group". TheC1-6 alkyl moiety is preferably a linear alkyl group having 1 to4 carbon atoms, and as C3-8 cycloalkyl, preferred arecyclopropyl group, cyclobutyl group, cyclopentyl group andcyclohexyl group.
[0066] As the "C3-8 cycloalkyl C1-6 alkyl group",cyclopropylmethyl group, cyclobutylmethyl group,cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethylgroup, 3-cyclohexylpropyl group and the like canbe specifically mentioned.
[0067] It is preferably a cyclohexylmethyl group for group C.
[0068] The "C1-6 alkylsulfonyl group" is an alkyl-sulfonyl groupwherein its C1-6 alkyl moiety is the above-defined "C1-6 alkylgroup", preferably a linear or branched chain alkyl group having1 to 4 carbon atoms.
[0069] Specifically, methylsulfonyl group, ethylsulfonyl group,propylsulfonyl group, isopropylsulfonyl group, butylsulfonylgroup, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonylgroup, pentylsulfonyl group, isopentylsulfonylgroup, tert-pentylsulfonyl group, hexylsulfonyl group and thelike can be mentioned.
[0070] It is preferably a methylsulfonyl group for group A.
[0071] The "di(C1-6 alkyl)amino group" is a di(alkyl)-amino groupwherein its C1-6 alkyl moiety is the above-defined "C1-6 alkyl group", preferably a linear or branched chain alkyl group having1 to 4 carbon atoms.
[0072] Specifically, dimethylamino group, diethylamino group,dipropylamino group, diisopropylamino group, N-ethyl-N-methylaminogroup, N-isopropyl-N-methylamino group and the likecan be mentioned.
[0073] It is preferably a dimethylamino group for group A.
[0074] The "C1-6 alkylcarbonylamino group" is an alkyl-carbonylaminogroup wherein its C1-6 alkyl moiety is the above-defined"C1-6 alkyl group", and preferably a linear or branched chainalkyl group having 1 to 4 carbon atoms.
[0075] Specifically, acetylamino group, propionylamino group,butyrylamino group, isobutyrylamino group, pivaloylamino groupand the like can be mentioned.
[0076] It is preferably an acetylamino group for group A.
[0077] The "C1-6 alkylcarbonyloxy group optionally substituted byhalogen atom(s)" is an alkyl-carbonyl-oxy group wherein its C1-6alkyl moiety is the above-defined "C1-6 alkyl group", which isoptionally substituted by the above-defined "halogen atom". Itincludes unsubstituted C1-6 alkylcarbonyloxy group, and ispreferably one wherein its alkyl moiety is a linear or branchedchain alkyl group having 1 to 4 carbon atoms. Here, the halogenatom is preferably a fluorine atom.
[0078] Specifically, acetyloxy group, propionyloxy group,butyryloxy group, isobutyryloxy group, pivaloyloxy group,fluoromethylcarbonyloxy group, trifluoromethylcarbonyloxy group,2,2,2-trifluoroethylcarbonyloxy group can be mentioned.
[0079] It is preferably an acetyloxy group or atrifluoromethylcarbonyloxy group for group A.
[0080] The "C6-14 aryl group optionally substituted by 1 to 3substituent(s) selected from the group consisting of halogenatom, C1-6 alkyl group, C1-6 alkylsulfonyl group, di(C1-6alkyl)amino group and C1-6 alkylcarbonylamino group" is theabove-defined "C6-14 aryl group", preferably a phenyl group,which is optionally substituted by 1 to 3 substituent(s) selected from the group consisting of the above-defined "halogenatom", the above-defined "C1-6 alkyl group", the above-defined"C1-6 alkylsulfonyl group", the above-defined "di(C1-6alkyl)amino group" and the above-defined "C1-6alkylcarbonylamino group", and includes unsubstituted aryl group.
[0081] As the "C6-14 aryl group optionally substituted by 1 to 3substituent(s) selected from the group consisting of halogenatom, C1-6 alkyl group, C1-6 alkylsulfonyl group, di(C1-6alkyl)amino group and C1-6 alkylcarbonylamino group", phenylgroup, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenylgroup, 4-chlorophenyl group, 4-bromophenyl group,2,4-difluorophenyl group, 3,5-dichlorophenyl group, 4-methylphenylgroup, 4-isopropylphenyl group, 4-tert-butylphenylgroup, 4-dimethylaminophenyl group, 4-methylsulfonylphenyl group,4-acetylaminophenyl group and the like can be specificallymentioned.
[0082] It is preferably phenyl group, 2-fluorophenyl group, 4-fluorophenylgroup, 4-tert-butylphenyl group, 4-dimethylaminophenylgroup, 4-methylsulfonylphenyl group or 4-acetylaminophenylgroup for group A.
[0083] The "heterocyclic group optionally substituted by C1-6alkyloxy group" is the above-defined "heterocyclic group", whichis optionally substituted by the above-defined "C1-6 alkyloxygroup", and includes unsubstituted heterocyclic group.
[0084] It is preferably a 5-membered or 6-membered monocyclicheterocyclic group.
[0085] As the "heterocyclic group optionally substituted by C1-6alkyloxy group", pyrrolidinyl group, piperidinyl group,piperazinyl group, morpholinyl group, pyrrolyl group, furylgroup, imidazolyl group, pyrazolyl group, 1,2,4-triazolyl group,tetrazolyl group, pyridyl group, pyrimidinyl group, pyrazinylgroup, pyridazinyl group, 3-methoxypyridin-2-yl group, 6-methoxypyridin-2-ylgroup, 5-isopropyloxypyridin-3-yl group and4-methoxypyrimidin-2-yl group and the like can be specificallymentioned.
[0086] It is preferably 2-pyridyl group, 3-pyridyl group, 2-furylgroup, 6-methoxypyridin-2-yl group or 4-methoxypyrimidin-2-ylgroup for group A.
[0087] The "group A" is the following substituent group, in whichR^a1, R^a2, R^a3 and R^a4 are each independently a hydrogen atom or theabove-defined "C1-6 alkyl group": the above-defined "halogen atom",cyano group, -OR^a1 (e.g., hydroxyl group, methoxy group, ethoxy group, propoxygroup, isopropyloxy group, butoxy group, isobutyloxy group,tert-butyloxy group etc.), -SR^a1 (e.g., mercapto group, methylsulfanyl group, ethylsulfanylgroup, isopropylsulfanyl group etc.), -CO₂R^a1 (e.g., carboxyl group, methoxycarbonyl group,ethoxycarbonyl group, isopropyloxycarbonyl group, tert-butoxycarbonylgroup etc.), -CONR^a2R^a3 (e.g., carbamoyl group, methylcarbamoyl group,ethylcarbamoyl group, isopropylcarbamoyl group,dimethylcarbamoyl group, diethylcarbamoyl group,diisopropylcarbamoyl group, di-tert-butylcarbamoyl group, N-ethyl-N-methylcarbamoylgroup, N-isopropyl-N-methylcarbamoylgroup etc.), -COR^a4 (e.g., formyl group, acetyl group, propionyl group,butyryl group, isobutyryl group, pivaloyl group etc.), -SO₂NR^a2R^a3 (e.g., sulfamoyl group, methylsulfamoyl group,ethylsulfamoyl group, isopropylsulfamoyl group,dimethylsulfamoyl group, diethylsulfamoyl group,diisopropylsulfamoyl group, di-tert-butylsulfamoyl group, N-ethyl-N-methylsulfamoylgroup, N-isopropyl-N-methylsulfamoylgroup etc.), -SO₂R^a4 (e.g., methylsulfonyl group, ethylsulfonyl group,isopropylsulfonyl group, tert-butylsulfonyl group etc.), the above-defined "C6-14 aryloxy group", the above-defined "C6-14 aryl C1-6 alkyloxycarbonyl group", the above-defined "C1-6 alkylcarbonyloxy group optionally substituted by halogen atom", the above-defined "C6-14 aryl group optionally substituted by 1to 3 substituent(s) selected from the group consisting ofhalogen atom, C1-6 alkyl group, C1-6 alkylsulfonyl group, di(C1-6alkyl)amino group and C1-6 alkylcarbonylamino group" and the above-defined "heterocyclic group optionally substituted byC1-6 alkyloxy group".
[0088] The "C1-6 alkyl group optionally substituted by 1 to 3substituent(s) selected from group A" is the above-defined "C1-6alkyl group", which is optionally substituted by 1 to 3substituent(s) selected from the above-defined "group A", andincludes unsubstituted alkyl group.
[0089] Specifically, methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, sec-butyl group,tert-butyl group, pentyl group, isopentyl group, tert-pentylgroup, neopentyl group, 1-ethylpropyl group, hexyl group,trifluoromethyl group, cyanomethyl group, 2-cyanoethyl group,hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group,3-hydroxypropyl group, 4-hydroxybutyl group, 1-hydroxy-1-methylethylgroup, 1-hydroxypropan-2-yl group, 1,3-dihydroxypropan-2-ylgroup, 1-hydroxy-2-methylpropan-2-yl group,1-hydroxy-2-methylpropyl group, 1-hydroxy-2,2-dimethylpropylgroup, methoxymethyl group, 2-methoxyethyl group,isopropyloxymethyl group, isobutyloxymethyl group,mercaptomethyl group, methylsulfanylmethyl group,isopropylsulfanylmethyl group, 2-methylsulfanylethyl group,carboxymethyl group, ethoxycarbonylmethyl group, 2-carboxyethylgroup, 2-ethoxycarbonylethyl group, carbamoylmethyl group,methylcarbamoylmethyl group, formylmethyl group, acetylmethylgroup, isobutyrylmethyl group, pivaloylmethyl group,sulfamoylmethyl group, 2-sulfamoylethyl group,methylsulfamoylmethyl group, methylsulfonylmethyl group,isopropylsulfonylmethyl group, 2-methylsulfonylethyl group,phenoxymethyl group, benzyloxycarbonylmethyl group and the likecan be mentioned.
[0090] It is preferably methyl group, ethyl group, propyl groupor pentyl group, particularly preferably methyl group or pentylgroup, for R¹.
[0091] The "C1-7 alkyl group optionally substituted by 1 to 3substituent(s) selected from group A" is the above-defined "C1-7alkyl group", which is optionally substituted by 1 to 3substituent(s) selected from "group A", and includesunsubstituted alkyl group.
[0092] Specifically, the substituents for the "C1-6 alkyl groupoptionally substituted by 1 to 3 substituent(s) selected fromgroup A" can be mentioned.
[0093] It is preferably a methyl group for R². As group C,preferred are methyl group, ethyl group, propyl group, isobutylgroup, isopropyl group, butyl group, isobutyl group, tert-butylgroup, cyanomethyl group, hydroxymethyl group, 2-hydroxyethylgroup, 1-hydroxyethyl group, 3-hydroxypropyl group, 1-hydroxypropylgroup, 1-hydroxy-2-methylpropyl group,methoxymethyl group, isopropyloxymethyl group, isobutyloxymethylgroup, 2,2-dimethylpropyl group, 2,2-dimethyl-1-hydroxypropylgroup, 3,3-dimethyl-2-hydroxybutyl group, carboxymethyl group,methoxycarbonylmethyl group, methylcarbamoylmethyl group,dimethylcarbamoylmethyl group, methylsulfanylmethyl group, 2-(methylsulfanyl)ethylgroup, methylsulfonylmethyl group,isopropylsulfonylmethyl group, 2-(methylsulfonyl)ethyl group,isopropylsulfanylmethyl group, pivaloylmethyl group, benzylgroup, phenethyl group, 3-phenylpropyl group, phenoxymethylgroup and benzyloxycarbonylmethyl group.
[0094] The "C2-6 alkenyl group optionally substituted by 1 to 3substituent(s) selected from group A" is the above-defined "C2-6alkenyl group", which is optionally substituted by 1 to 3substituent(s) selected from "group A", and includesunsubstituted alkenyl group.
[0095] Specifically, vinyl group, allyl group, 1-propenyl group,isopropenyl group, 2-methyl-1-propenyl group, 1-butenyl group,2-butenyl group, 1,3-butadienyl group, 3-methyl-2-butenyl group, 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group, 1-methyl-2-butenylgroup, carboxyvinyl group, carbamoylvinyl group andthe like can be mentioned.
[0096] The "C2-6 alkynyl group optionally substituted by 1 to 3substituent(s) selected from group A" is the above-defined "C2-6alkynyl group", which is optionally substituted by 1 to 3substituent(s) selected from "group A", and includesunsubstituted alkynyl group.
[0097] Specifically, ethynyl group, 1-propynyl group, 2-propynylgroup, 3-butynyl group, carboxyethynyl group, carbamoylethynylgroup and the like can be mentioned.
[0098] The "group B" is a group selected from the followingsubstituent group, in which R^b1, R^b2, R^b3, R^b4, R^b5 and R^b6 are eachindependently a hydrogen atom or the above-defined "C1-6 alkylgroup": the above-defined "halogen atom", cyano group, the above-defined "C1-6 alkyl group", the above-defined "haloC1-6 alkyl group", -OR^b1 (e.g., hydroxyl group, methoxy group, ethoxy group, propoxygroup, isopropyloxy group, butoxy group, isobutyloxy group,tert-butyloxy group etc.), -SR^b1 (e.g., mercapto group, methylsulfanyl group, ethylsulfanylgroup, isopropylsulfanyl group etc.), -CO₂R^b1 (e.g., carboxyl group, methoxycarbonyl group,ethoxycarbonyl group, isopropyloxycarbonyl group, tert-butoxycarbonylgroup etc.), -CONR^b2R^b3 (e.g., carbamoyl group, methylcarbamoyl group,ethylcarbamoyl group, isopropylcarbamoyl group,dimethylcarbamoyl group, diethylcarbamoyl group,diisopropylcarbamoyl group, di-tert-butylcarbamoyl group, N-ethyl-N-methylcarbamoylgroup, N-isopropyl-N-methylcarbamoylgroup etc.), -COR^b4 (e.g., formyl group, acetyl group, propionyl group,butyryl group, isobutyryl group, pivaloyl group etc.), -SO₂NR^b2R^b3 (e.g., sulfamoyl group, methylsulfamoyl group,ethylsulfamoyl group, isopropylsulfamoyl group,dimethylsulfamoyl group, diethylsulfamoyl group,diisopropylsulfamoyl group, di-tert-butylsulfamoyl group, N-ethyl-N-methylsulfamoylgroup, N-isopropyl-N-methylsulfamoylgroup etc.), -SO₂R^b4 (e.g., methylsulfonyl group, ethylsulfonyl group,isopropylsulfonyl group, tert-butylsulfonyl group etc.), the above-defined "C6-14 aryloxy group" and the above-defined "C6-14 aryl C1-6 alkyloxycarbonyl group" -NR^b5COR^b6 (e.g., acetylamino group, propionylamino group,butyrylamino group, isobutyrylamino group, pivaloylamino groupand the like.
[0099] The "C3-10 carbon ring group optionally substituted by 1to 3 substituent(s) selected from group B" is the above-defined"C3-10 carbon ring group", preferably a phenyl group, which isoptionally substituted by 1 to 3 substituent(s) selected fromthe above-defined "group B", and includes unsubstituted C3-10carbon ring group.
[0100] Specifically, phenyl group, 2-fluorophenyl group, 3-fluorophenylgroup, 4-fluorophenyl group, 2,4-difluorophenylgroup, 3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenylgroup, 4-chlorophenyl group, 2-bromophenyl group,3-bromophenyl group, 4-bromophenyl group, 2,3-dichlorophenylgroup, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4-dichlorophenylgroup, 3,5-dichlorophenyl group, 3,4-dibromophenylgroup, 3-chloro-2-fluorophenyl group, 2-chloro-3-fluorophenylgroup, 4-chloro-3-fluorophenyl group, 3-chloro-4-fluorophenylgroup, 2-chloro-6-fluorophenyl group, 2-methylphenylgroup, 3-methylphenyl group, 4-methylphenyl group,4-ethylphenyl group, 4-propylphenyl group, 3-isopropylphenylgroup, 4-isopropylphenyl group, 3-butylphenyl group, 3-isobutylphenylgroup, 4-isobutylphenyl group, 3-(2-methyl-1-propenyl)phenylgroup, 2-trifluoromethylphenyl group, 3-trifluoromethylphenylgroup, 4-trifluoromethylphenyl group, 3,5-bistrifluoromethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenylgroup, 4-methoxyphenyl group, 2-ethoxyphenyl group,3-ethoxyphenyl group, 4-ethoxyphenyl group, 2-isopropyloxyphenylgroup, 3-isopropyloxyphenyl group, 4-isopropyloxyphenyl group,3-phenoxyphenyl group, 4-phenoxyphenyl group, 3-methylthiophenylgroup, 4-methylthiophenyl group, 3-carboxyphenyl group, 4-carboxyphenylgroup, 3-cyanophenyl group, 4-cyanophenyl group,3-acetylphenyl group, 4-acetylphenyl group, 3-isobutyrylphenylgroup, 4-isobutyrylphenyl group, 3-carbamoylphenyl group, 4-carbamoylphenylgroup, 3-(methylcarbamoyl)phenyl group, 4-(methylcarbamoyl)phenylgroup, 3-(isopropylcarbamoyl)phenylgroup, 4-(isopropylcarbamoyl)phenyl group, 3-(butylcarbamoyl)phenylgroup, 3-(N-ethyl-N-methylcarbamoyl)phenylgroup, 3-(dimethylcarbamoyl)phenyl group,4-(dimethylcarbamoyl)phenyl group, 3-(diethylcarbamoyl)phenylgroup, 4-(diethylcarbamoyl)phenyl group, 3-{N-methyl-N-(3-methylbutyl)carbamoyl}phenylgroup, 4-{N-methyl-N-(3-methylbutyl)carbamoyl}phenylgroup, 3-sulfamoylphenyl group, 4-sulfamoylphenylgroup, 3-(methylsulfamoyl)phenyl group, 4-(methylsulfamoyl)phenylgroup, 3-(ethylsulfamoyl)phenyl group,4-(ethylsulfamoyl)phenyl group, 3-(isopropylsulfamoyl)phenylgroup, 3-(butylsulfamoyl)phenyl group, 3-(dimethylsulfamoyl)phenylgroup, 4-(dimethylsulfamoyl)phenylgroup, 3-(diethylsulfamoyl)phenyl group, 4-(diethylsulfamoyl)phenylgroup, 3-(N-ethyl-N-methylsulfamoyl)phenylgroup, 3-(methylsulfonyl)phenyl group, 4-(methylsulfonyl)phenylgroup, 3-(ethylsulfonyl)phenyl group, 4-(ethylsulfonyl)phenylgroup, 3-(isopropylsulfonyl)phenyl group,4-(isopropylsulfonyl)phenyl group, 4-chloro-3-carboxyphenylgroup, 4-chloro-3-dimethylcarbamoylphenyl group, 3-chloro-4-methylphenylgroup, 3-chloro-2-hydroxyphenyl group, 3-chloro-4-hydroxyphenylgroup, 3-chloro-2-methoxyphenyl group, 3-chloro-4-methoxyphenylgroup, 3-chloro-4-propyloxyphenyl group, 3-chloro-4-isopropyloxyphenylgroup, 3-chloro-4-benzyloxyphenyl group, 3-chloro-5-methoxyphenylgroup, 3-chloro-6-methoxyphenyl group, 3-chloro-4-ethoxyphenyl group, 3-chloro-4-isopropyloxyphenyl group,4-chloro-2-methoxyphenyl group, 4-chloro-3-methoxyphenyl group,4-chloro-2-hydroxyphenyl group, 4-chloro-2-isopropyloxyphenylgroup, 4-chloro-2-propyloxyphenyl group, 4-chloro-2-benzyloxyphenylgroup, 3-carboxy-5-trifluoromethylphenyl group,3-dimethylcarbamoyl-5-trifluoromethylphenyl group, 4-dimethylcarbamoyl-2-fluorophenylgroup, 4-carboxy-3-chlorophenylgroup, 3-chloro-4-methylcarbamoylphenyl group, 3-chloro-4-dimethylcarbamoylphenylgroup, 3-chloro-4-diethylcarbamoylphenylgroup, 4-carbamoyl-3-chlorophenyl group, 3-chloro-4-acetylphenylgroup, 3-chloro-4-pivaloylphenyl group, 3-chloro-5-dimethylcarbamoylphenylgroup, 3-hydroxy-4-dimethylcarbamoylphenylgroup, 3-hydroxy-5-dimethylcarbamoylphenylgroup, 3-cyano-5-dimethylcarbamoylphenylgroup, 3-carboxy-5-methoxyphenyl group, 3-carboxy-5-ethoxyphenylgroup, 3-carboxy-5-isopropyloxyphenyl group, 3-carboxy-5-cyanophenylgroup, 3,5-dicarboxyphenyl group, 3,4-dicarboxyphenylgroup, 3-carboxy-5-dimethylcarbamoylphenyl group,3-carboxy-4-methoxyphenyl group, 3-carboxy-4-ethoxyphenyl group,3-carboxy-4-isopropyloxyphenyl group, 3-carboxy-4-cyanophenylgroup, 3-carbamoyl-5-dimethylcarbamoylphenyl group, 3-dimethylcarbamoyl-5-methylcarbamoylphenylgroup, 4-carboxy-3-methoxyphenylgroup, 4-carboxy-2-methoxyphenyl group, 4-carboxy-3-ethoxyphenylgroup, 4-carboxy-3-isopropyloxyphenyl group, 4-carboxy-3-cyanophenylgroup, 4-carbamoyl-2-methoxyphenyl group,4-methylcarbamoyl-3-methoxyphenyl group, 4-dimethylcarbamoyl-3-methoxyphenylgroup, 3,5-bis(dimethylcarbamoyl)phenyl group, 3-carbamoyl-5-cyanophenylgroup, 3-carboxy-4-methylphenyl group,3-dimethylcarbamoyl-4-methylphenyl group, 4-methyl-3-methylcarbamoylphenylgroup, 3-dimethylsulfamoyl-4-methylphenylgroup, 4-fluoro-3-chlorophenyl group, 4-fluoro-2-carboxyphenylgroup, 4-fluoro-2-methoxycarbonylphenyl group, 4-fluoro-2-methylcarbamoylphenylgroup, 4-fluoro-2-acetylaminophenyl group,3,5-dichloro-4-hydroxyphenyl group, 3,5-dichloro-4-methoxyphenylgroup, 1-naphthyl group, 2-naphthyl group, 1-bromonaphthalen-2-yl group, 6-bromonaphthalen-2-yl group, 7-cyanonaphthalen-2-ylgroup, 7-methoxynaphthalen-2-yl group, 5-bromo-6-methoxynaphthalen-2-ylgroup, cyclopentyl group, 1-methylcyclopentylgroup, 1-ethylcyclopentyl group, 1-isopropylcyclopentylgroup, 2,5-dimethylcyclopentyl group, 2,2-dimethylcyclopentylgroup, cyclohexyl group, 1-methylcyclohexylgroup, 1-ethylcyclohexyl group, 1-isopropylcyclohexyl group,2,6-dimethylcyclohexyl group, cycloheptyl group, 1-methylcycloheptylgroup, 1-ethylcycloheptyl group, 1-isopropylcycloheptylgroup and the like can be mentioned.
[0101] The ring D for R¹ is preferably phenyl group, 2-fluorophenylgroup, 3-fluorophenyl group, 4-fluorophenyl group,3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenylgroup, 4-chlorophenyl group, 3-bromophenyl group, 4-bromophenylgroup, 2,3-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4-dichlorophenylgroup, 3,5-dichlorophenyl group, 3-chloro-2-fluorophenylgroup, 4-chloro-3-fluorophenyl group, 2-chloro-6-fluorophenylgroup, 3-trifluoromethylphenyl group, 3-methoxyphenylgroup, 3-chloro-2-hydroxyphenyl group, 3-chloro-2-methoxyphenylgroup, 3-chloro-4-methoxyphenyl group, 3-chloro-4-propyloxyphenylgroup, 3-chloro-4-isopropyloxyphenyl group, 3-chloro-4-benzyloxyphenylgroup, 3-chloro-5-methoxyphenyl group,3-chloro-6-methoxyphenyl group, 4-chloro-2-methoxyphenyl group,4-chloro-3-methoxyphenyl group, 4-chloro-2-hydroxyphenyl group,4-chloro-2-isopropyloxyphenyl group, 4-chloro-2-propyloxyphenylgroup, 4-chloro-2-benzyloxyphenyl group, 4-fluoro-3-chlorophenylgroup, 4-fluoro-2-carboxyphenyl group, 4-fluoro-2-methoxycarbonylphenylgroup, 4-fluoro-2-methylcarbamoylphenylgroup, 4-fluoro-2-acetylaminophenyl group or 2-naphthyl group.
[0102] The "heterocyclic group optionally substituted by 1 to 3substituent(s) selected from group B" is the above-defined"heterocyclic group", which is optionally substituted by 1 to 3substituent(s) selected from the above-defined "group B", andincludes unsubstituted heterocyclic group.
[0103] Specifically, 2-imidazolyl group, 5-methylpyrazol-3-yl group, 5-methylisoxazol-3-yl group, 2-furyl group, 2-thiazolylgroup, 4-methylthiazol-2-yl group, 5-methylthiazol-2-yl group,5-thiazolyl group, 2-oxazolyl group, 1-methylimidazol-2-yl group,3-pyrazolyl group, 1,2,4-triazol-3-yl group, 2-methyl-1,2,4-triazol-3-ylgroup, 5-methyl-1,2,4-triazol-3-yl group, 5-ethyl-1,2,4-triazol-3-ylgroup, 1-ethyl-1,2,4-triazol-3-yl group, 1,5-dimethyl-1,2,4-triazol-3-ylgroup, 4-methyl-1,2,4-triazol-3-ylgroup, 4-ethyl-1,2,4-triazol-3-yl group, 5-tetrazolyl group, 5-ethyl-1,2,4-oxadiazol-3-ylgroup, 5-ethyl-1,3,4-oxadiazol-2-ylgroup, 3-methyl-1,2,4-thiadiazol-5-yl group, 2-pyridyl group, 3-pyridylgroup, 4-pyridyl group, 4-methoxypyridin-2-yl group, 6-methylpyridin-2-ylgroup, 2-pyrimidinyl group, 4-pyrimidinylgroup, 4-methylpyrimidin-2-yl group, 4-ethylpyrimidin-2-yl group,4-isopropylpyrimidin-2-yl group, 4-butylpyrimidin-2-yl group, 4-sec-butylpyrimidin-2-ylgroup, 4-carboxypyrimidin-2-yl group, 4-methoxypyrimidin-2-ylgroup, 4-ethoxypyrimidin-2-yl group, 4-isopropyloxypyrimidin-2-ylgroup, 4-tert-butyloxypyrimidin-2-ylgroup, 5-methylpyrimidin-2-yl group, 5-ethylpyrimidin-2-yl group,5-isopropylpyrimidin-2-yl group, 5-butylpyrimidin-2-yl group, 5-sec-butylpyrimidin-2-ylgroup, 5-carboxypyrimidin-2-yl group, 5-methoxypyrimidin-2-ylgroup, 5-ethoxypyrimidin-2-yl group, 5-isopropyloxypyrimidin-2-ylgroup, 5-tert-butyloxypyrimidin-2-ylgroup, 3-pyridazinyl group, 2-pyrazinyl group, 2-quinazolinylgroup, 2-oxazolin-2-yl group, 5-ethyl-2-oxazolin-2-yl group,4,4-dimethyloxazolin-2-yl group, 2-quinolyl group, 6-quinolylgroup, 2-benzothiazolyl group, 1,2,4-triazin-3-yl group, 1,3,5-triazin-2-ylgroup, 1,2,3,4-tetrahydroquinolin-1-yl group, 5-indolylgroup, 1-methylindol-2-yl group, 2-benzimidazolyl group,2-benzofuranyl group, 1,3-benzodioxol-5-yl group, 1,2,4-benzotriazin-3-ylgroup, 4-piperidyl group, 4-methylpiperidin-4-ylgroup, 4-ethylpiperidin-4-yl group, 4-isopropylpiperidin-4-ylgroup, 4-tetrahydropyranyl group, 4-methyltetrahydropyran-4-ylgroup, 4-ethyltetrahydropyran-4-yl group, 4-isopropyltetrahydropyran-4-ylgroup, 3,5-dimethyltetrahydropyran-4-ylgroup, 4-tetrahydrothiopyranyl group, 4-methyltetrahydrothiopyran-4-yl group, 4-ethyltetrahydrothiopyran-4-ylgroup, 4-isopropyltetrahydrothiopyran-4-ylgroup and the like can bementioned.
[0104] It is preferably 2-benzofuranyl group as ring D for R¹.
[0105] It is preferably 2-furyl group, 2-thiazolyl group, 4-methylthiazol-2-ylgroup, 5-methylthiazol-2-yl group, 5-thiazolylgroup, 2-oxazolyl group, 1-methylimidazol-2-yl group,3-pyrazolyl group, 1,2,4-triazol-3-yl group, 2-methyl-1,2,4-triazol-3-ylgroup, 5-tetrazolyl group, 3-methyl-1,2,4-thiadiazol-5-ylgroup, 2-pyridyl group, 3-pyridyl group, 4-pyridylgroup, 2-pyrimidinyl group, 4-pyrimidinyl group, 2-pyrazinylgroup, 3-pyridazinyl group or 2-benzofuranyl group forgroup C.
[0106] The "C6-14 aryl group optionally substituted by 1 to 3substituent(s) selected from group B" is the above-defined "C6-14aryl group", which is optionally substituted by 1 to 3substituent(s) selected from the above-defined "group B", andincludes unsubstituted C6-14 aryl group.
[0107] Specifically, phenyl group, 2-fluorophenyl group, 3-fluorophenylgroup, 4-fluorophenyl group, 2,4-difluorophenylgroup, 3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenylgroup, 4-chlorophenyl group, 2,4-dichlorophenylgroup, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 3,4-dibromophenylgroup, 3-chloro-2-fluorophenyl group, 2-chloro-3-fluorophenylgroup, 4-chloro-3-fluorophenyl group, 3-chloro-4-fluorophenylgroup, 2-methylphenyl group, 3-methylphenyl group,4-methylphenyl group, 2,6-dimethylphenyl group, 2-ethylphenylgroup, 3-ethylphenyl group, 4-ethylphenyl group, 4-propylphenylgroup, 3-isopropylphenyl group, 4-isopropylphenyl group, 3-butylphenylgroup, 3-isobutylphenyl group, 4-isobutylphenylgroup, 3-(2-methyl-1-propenyl)phenyl group, 2-trifluoromethylphenylgroup, 3-trifluoromethylphenyl group, 4-trifluoromethylphenylgroup, 3,5-bistrifluoromethylphenyl group,2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenylgroup, 2-ethoxyphenyl group, 3-ethoxyphenyl group,4-ethoxyphenyl group, 2-isopropyloxyphenyl group, 3-isopropyloxyphenylgroup, 4-isopropyloxyphenyl group, 3-phenoxyphenylgroup, 4-phenoxyphenyl group, 3-methylthiophenylgroup, 4-methylthiophenyl group, 3-carboxyphenyl group, 4-carboxyphenylgroup, 3-cyanophenyl group, 4-cyanophenyl group,3-acetylphenyl group, 4-acetylphenyl group, 3-isobutyrylphenylgroup, 4-isobutyrylphenyl group, 3-carbamoylphenyl group, 4-carbamoylphenylgroup, 3-(methylcarbamoyl)phenyl group, 4-(methylcarbamoyl)phenylgroup, 3-(isopropylcarbamoyl)phenylgroup, 4-(isopropylcarbamoyl)phenyl group, 3-(butylcarbamoyl)phenylgroup, 3-(N-ethyl-N-methylcarbamoyl)phenylgroup, 3-(dimethylcarbamoyl)phenyl group,4-(dimethylcarbamoyl)phenyl group, 3-(diethylcarbamoyl)phenylgroup, 4-(diethylcarbamoyl)phenyl group, 3-{N-methyl-N-(3-methylbutyl)carbamoyl}phenylgroup, 4-{N-methyl-N-(3-methylbutyl)carbamoyl}phenylgroup, 3-sulfamoylphenyl group, 4-sulfamoylphenylgroup, 3-(methylsulfamoyl)phenyl group, 4-(methylsulfamoyl)phenylgroup, 3-(ethylsulfamoyl)phenyl group,4-(ethylsulfamoyl)phenyl group, 3-(isopropylsulfamoyl)phenylgroup, 3-(butylsulfamoyl)phenyl group, 3-(dimethylsulfamoyl)phenylgroup, 4-(dimethylsulfamoyl)phenylgroup, 3-(diethylsulfamoyl)phenyl group, 4-(diethylsulfamoyl)phenylgroup, 3-(N-ethyl-N-methylsulfamoyl)phenylgroup, 3-(methylsulfonyl)phenyl group, 4-(methylsulfonyl)phenylgroup, 3-(ethylsulfonyl)phenyl group, 4-(ethylsulfonyl)phenylgroup, 3-(isopropylsulfonyl)phenyl group,4-(isopropylsulfonyl)phenyl group, 4-chloro-3-carboxyphenylgroup, 4-chloro-3-dimethylcarbamoylphenyl group, 3-chloro-4-methylphenylgroup, 3-chloro-4-hydroxyphenyl group, 3-chloro-4-methoxyphenylgroup, 3-chloro-4-ethoxyphenyl group, 3-chloro-4-isopropyloxyphenylgroup, 3-carboxy-5-trifluoromethylphenylgroup, 3-dimethylcarbamoyl-5-trifluoromethylphenyl group, 4-dimethylcarbamoyl-2-fluorophenylgroup, 4-carboxy-3-chlorophenyl group, 3-chloro-4-methylcarbamoylphenyl group, 3-chloro-4-dimethylcarbamoylphenylgroup, 3-chloro-4-diethylcarbamoylphenylgroup, 4-carbamoyl-3-chlorophenyl group, 3-chloro-4-acetylphenylgroup, 3-chloro-4-pivaloylphenyl group, 3-chloro-5-dimethylcarbamoylphenylgroup, 3-hydroxy-4-dimethylcarbamoylphenylgroup, 3-hydroxy-5-dimethylcarbamoylphenylgroup, 3-cyano-5-dimethylcarbamoylphenylgroup, 3-carboxy-5-methoxyphenyl group, 3-carboxy-5-ethoxyphenylgroup, 3-carboxy-5-isopropyloxyphenyl group, 3-carboxy-5-cyanophenylgroup, 3,5-dicarboxyphenyl group, 3,4-dicarboxyphenylgroup, 3-carboxy-5-dimethylcarbamoylphenyl group,3-carboxy-4-methoxyphenyl group, 3-carboxy-4-ethoxyphenyl group,3-carboxy-4-isopropyloxyphenyl group, 3-carboxy-4-cyanophenylgroup, 3-carbamoyl-5-dimethylcarbamoylphenyl group, 3-dimethylcarbamoyl-5-methylcarbamoylphenylgroup, 4-carboxy-3-methoxyphenylgroup, 4-carboxy-2-methoxyphenyl group, 4-carboxy-3-ethoxyphenylgroup, 4-carboxy-3-isopropyloxyphenyl group, 4-carboxy-3-cyanophenylgroup, 4-carbamoyl-2-methoxyphenyl group,4-methylcarbamoyl-3-methoxyphenyl group, 4-dimethylcarbamoyl-3-methoxyphenylgroup, 3,5-bis(dimethylcarbamoyl)phenyl group, 3-carbamoyl-5-cyanophenylgroup, 3-carboxy-4-methylphenyl group,3-dimethylcarbamoyl-4-methylphenyl group, 4-methyl-3-methylcarbamoylphenylgroup, 3-dimethylsulfamoyl-4-methylphenylgroup, 3,5-dichloro-4-hydroxyphenyl group, 3,5-dichloro-4-methoxyphenylgroup, 1-naphthyl group, 2-naphthyl group, 1-bromonaphthalen-2-ylgroup, 6-bromonaphthalen-2-yl group, 7-cyanonaphthalen-2-ylgroup, 7-methoxynaphthalen-2-yl group, 5-bromo-6-methoxynaphthalen-2-ylgroup and the like can bementioned.
[0108] It is preferably phenyl group, 2-fluorophenyl group, 2-ethylphenylgroup, 2,6-dimethylphenyl group, 2-chlorophenylgroup, 3-chlorophenyl group, 4-chlorophenyl group, 2-methoxyphenylgroup, 3-methoxyphenyl group, 4-methoxyphenylgroup, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenylgroup or 2-trifluoromethylphenyl group for group C.
[0109] The "heteroaryl group optionally substituted by 1 to 3substituent(s) selected from group B" is the above-defined"heteroaryl group", which is optionally substituted by 1 to 3substituent(s) selected from the above-defined "group B", andincludes unsubstituted heteroaryl group.
[0110] Specifically, 2-imidazolyl group, 5-methylpyrazol-3-ylgroup, 5-methylisoxazol-3-yl group, 2-thiazolyl group, 1,2,4-triazol-3-ylgroup, 5-methyl-1,2,4-triazol-3-yl group, 5-ethyl-1,2,4-triazol-3-ylgroup, 1-ethyl-1,2,4-triazol-3-yl group, 1,5-dimethyl-1,2,4-triazol-3-ylgroup, 4-methyl-1,2,4-triazol-3-ylgroup, 4-ethyl-1,2,4-triazol-3-yl group, 5-tetrazolyl group, 5-ethyl-1,2,4-oxadiazol-3-ylgroup, 5-ethyl-1,3,4-oxadiazol-2-ylgroup, 2-pyridyl group, 4-methoxypyridin-2-yl group, 6-methylpyridin-2-ylgroup, 2-pyrimidinyl group, 4-pyrimidinylgroup, 4-methylpyrimidin-2-yl group, 4-ethylpyrimidin-2-yl group,4-isopropylpyrimidin-2-yl group, 4-butylpyrimidin-2-yl group, 4-sec-butylpyrimidin-2-ylgroup, 4-carboxypyrimidin-2-yl group, 4-methoxypyrimidin-2-ylgroup, 4-ethoxypyrimidin-2-yl group, 4-isopropyloxypyrimidin-2-ylgroup, 4-tert-butyloxypyrimidin-2-ylgroup, 5-methylpyrimidin-2-yl group, 5-ethylpyrimidin-2-yl group,5-isopropylpyrimidin-2-yl group, 5-butylpyrimidin-2-yl group, 5-sec-butylpyrimidin-2-ylgroup, 5-carboxypyrimidin-2-yl group, 5-methoxypyrimidin-2-ylgroup, 5-ethoxypyrimidin-2-yl group, 5-isopropyloxypyrimidin-2-ylgroup, 5-tert-butyloxypyrimidin-2-ylgroup, 3-pyridazinyl group, 2-pyrazinyl group and the like canbe mentioned.
[0111] The "group C" is a group selected from the followingsubstituent group: (1) a hydrogen atom, (2) the above-defined "C3-8 cycloalkyl C1-6 alkyl group", (3) a cyano group, (4) the above-defined "halogen atom", (5) the above-defined "C1-6 alkyl group", (6) the above-defined "C2-6 alkenyl group", (7) the above-defined "C2-6 alkynyl group", (8) the above-defined "C6-14 aryl group", (9) a heterocyclic group which is a saturated or unsaturated 5-memberedor 6-membered heteromonocycle containing at least onehetero atom selected from nitrogen atom, oxygen atom and sulfuratom, or a fused ring of such heterocycles, or a fused ring of acarbon ring selected from benzene, cyclopentane and cyclohexaneand the above-defined heterocycle, (10) the above-defined "C1-6 alkyloxy group", (11) the above-defined "C6-14 aryl C1-6 alkyl group", (12) the above-defined "C6-14 aryl C1-6 alkyloxy group", (13) -CO₂R^c1 (e.g., carboxyl group, methoxycarbonyl group,ethoxycarbonyl group, isopropyloxycarbonyl group, tert-butoxycarbonylgroup, 2,2-dimethylpropyloxycarbonyl group,cyclohexyloxycarbonyl etc.), (14) -CONR^c2R^c3 (e.g., carbamoyl group, methylcarbamoyl group,ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoylgroup, butylcarbamoyl group, isobutylcarbamoyl group,dimethylcarbamoyl group, diethylcarbamoyl group,diisopropylcarbamoyl group, di-tert-butylcarbamoyl group, N-ethyl-N-methylcarbamoylgroup, N-isopropyl-N-methylcarbamoylgroup, N-butyl-N-methylcarbamoyl group, 2-fluoroethylcarbamoylgroup, 2-hydroxyethylcarbamoyl group, 2-methoxyethylcarbamoylgroup, N-methyl-N-(2-methoxyethyl)carbamoyl group, 2-oxopropylcarbamoylgroup, 2-hydroxypropylcarbamoyl group,carboxymethylcarbamoyl group, methoxycarbonylmethylcarbamoylgroup, 2,2,2-trifluoroethylcarbamoyl group, 2-(trifluoroacetyloxy)ethylcarbamoylgroup,methylcarbamoylmethylcarbamoyl group,dimethylcarbamoylmethylcarbamoyl group, 2-(methylsulfonyl)ethylcarbamoylgroup, phenylcarbamoyl group,benzylcarbamoyl group, N-benzyl-N-methylcarbamoyl group, 2-fluorobenzylcarbamoylgroup, 4-fluorobenzylcarbamoyl group, 4-tert-butylbenzylcarbamoylgroup, 4-(dimethylamino)benzylcarbamoylgroup, 4-(methylsulfonyl)benzylcarbamoylgroup, 4-(acetylamino)benzylcarbamoyl group, 1-naphthylmethylcarbamoylgroup, diphenylmethylcarbamoyl group, 1,2-diphenylethylcarbamoylgroup, 1,3-diphenylpropylcarbamoyl group, 2-pyridylmethylcarbamoylgroup, 3-pyridylmethylcarbamoyl group, 4-pyridylmethylcarbamoylgroup, 2-furylmethylcarbamoyl group, 4-methoxypyrimidin-2-ylmethylcarbamoylgroup, 2-(2-oxopyrrolidin-1-yl)ethylcarbamoylgroup, 1-pyrrolidinylcarbonyl group, 3-hydroxypyrrolidin-1-ylcarbonylgroup, 3-oxopyrrolidin-1-ylcarbonylgroup, morpholinocarbonyl group etc.), (15) -COR^c4 (e.g., formyl group, acetyl group, propionyl group,butyryl group, isobutyryl group, pivaloyl group, benzoyl group,3-methylbutyryl group, 2,2-dimethylbutyryl group, 2,2-dimethyl-1-hydroxypropionylgroup, 2,2-dimethyl-1-methoxypropionyl group,1-acetyloxy-2,2-dimethylpropionyl group, 2-methyl-2-phenylpropionylgroup etc.), (16) -SO₂NR^c2R^c3 (e.g., sulfamoyl group, methylsulfamoyl group,ethylsulfamoyl group, isopropylsulfamoyl group,dimethylsulfamoyl group, diethylsulfamoyl group,diisopropylsulfamoyl group, di-tert-butylsulfamoyl group, N-ethyl-N-methylsulfamoylgroup, N-isopropyl-N-methylsulfamoylgroup etc.), (17) the above-defined "C6-14 arylcarbonyl group", (18) -NR^c4R^c5 (e.g., amino group, methylamino group, ethylaminogroup, propylamino group, isopropylamino group, butylamino group,isobutylamino group, dimethylamino group, diethylamino group,diisopropylamino group, di-tert-butylamino group, N-ethyl-N-methylaminogroup, N-isopropyl-N-methylamino group etc.), (19) -NR^c6COR^c7 (e.g., acetylamino group, propionylamino group,butyrylamino group, isobutyrylamino group, pivaloylamino group,benzoylamino group, 4-fluorobenzoylamino group, 3-methylbutyrylaminogroup, 3,3-dimethylbutyrylamino group,(methoxyacetyl)amino group, 2-isopropyl-3-methylbutyrylaminogroup, 2,2-dimethyl-1-hydroxypropionylamino group, 2,2-dimethyl-1-methoxypropionylaminogroup, 1-acetyloxy-2,2-dimethylpropionylaminogroup, 2-methyl-2-phenylpropionylamino group, N-acetyl-N-methylamino group, N-acetyl-N-isobutylaminogroup, benzylcarbonylamino group, 4-fluorobenzylcarbonylaminogroup, 3-phenylpropionylamino group, cyclopentylcarbonylaminogroup, 2-pyridylcarbonylamino group, 3-pyridylcarbonylaminogroup, 4-pyridylcarbonylamino group, 2-furylcarbonylamino group,2-thienylcarbonylamino group, 1-methylpyrrol-2-ylcarbonylaminogroup etc.) (20) -NR^c8SO₂R^c9 (e.g., methylsulfonylamino group,ethylsulfonylamino group, isopropylsulfonylamino group,phenylsulfonylamino group, benzylsulfonylamino group, N-methyl-N-(methylsulfonyl)aminogroup, N-methyl-N-(ethylsulfonyl)aminogroup, N-methyl-N-(isopropylsulfonyl)amino group, 4-pyridylsulfonylaminogroup, 2-furylsulfonylamino group, 2-thienylsulfonylaminogroup, 1-methylpyrrol-2-ylsulfonylaminogroup etc.), (21) -SR^c10 (e.g., methylsulfanyl group, ethylsulfanyl group,isopropylsulfanyl group, phenylsulfanyl group etc.), (22) -SOR^c11 (e.g., methylsulfinyl group, ethylsulfinyl group,isopropylsulfinyl group, phenylsulfinyl group etc.), (23) -SO₂R^c12 (e.g., methylsulfonyl group, ethylsulfonyl group,isopropylsulfonyl group, phenylsulfonyl group etc.), (24) -NR^c13CONR^c14R^c15 (e.g., methylcarbamoylamino group,dimethylcarbamoylamino group, diethylcarbamoylamino group,diisopropylcarbamoylamino group, N-ethyl-N-methylcarbamoylaminogroup etc.), (25) -NR^c16CO₂R^c17 (e.g., methoxycarbonylamino group,ethoxycarbonylamino group, isopropyloxycarbonylamino group,phenoxycarbonylamino group etc.) and (26) -NR^c18COCOR^c19 (e.g., 2-oxopropionylamino group, 2-oxobutyrylaminogroup, 3-methyl-2-oxobutyrylamino group, 2-oxo-2-(pyridin-2-yl)acetylaminogroup etc.).
[0112] Here, R^c1, R^c2, R^c3, R^c4, R^c5, R^c6, R^c7, R^c8, R^c9, R^c10, R^c11, R^c12,R^c13, R^c14, R^c15, R^c16, R^c17, R^c18 and R^c19 are each independently (1') a hydrogen atom, (2') a C1-7 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the above-mentioned group A, (3') a C6-14 aryl group optionally substituted by 1 to 3substituent(s) selected from the above-mentioned group B, (4') a heterocyclic group optionally substituted by 1 to 3substituent(s) selected from the above-mentioned group B, or (5') a C3-8 cycloalkyl group, wherein R^c2 and R^c3 may form, together with the adjacent nitrogenatom, a nitrogen-containing heterocycle, and the nitrogen-containingheterocycle may contain an ether moiety or a carbonylmoiety, and are optionally substituted by 1 to 3 substituent(s)selected from the above-mentioned group B .
[0113] The C1-7 alkyl group, C1-6 alkyl moiety, C2-6 alkenylgroup and C2-6 alkynyl group of the above-mentioned group C areoptionally substituted by 1 to 3 substituent(s) selected fromthe above-mentioned group A, or a nitrogen-containingheterocyclic group optionally containing a carbonyl moiety, andspecifically includes the above-defined "C1-7 alkyl groupoptionally substituted by 1 to 3 substituent(s) selected fromgroup A", the above-defined "C2-6 alkenyl group optionallysubstituted by 1 to 3 substituent(s) selected from group A", theabove-defined "C2-6 alkynyl group optionally substituted by 1 to3 substituent(s) selected from group A" and an oxy groupsubstituted by the above-defined "C1-6 alkyl group optionallysubstituted by 1 to 3 substituent(s) selected from group A".
[0114] The C6-14 aryl group, C6-14 aryl moiety and heterocyclicgroup of the above-mentioned group C are optionally substitutedby 1 to 3 substituent(s) selected from the above-mentioned groupB and specifically include the above-defined "C6-14 aryl groupoptionally substituted by 1 to 3 substituent(s) selected fromgroup B", the above-defined "heterocyclic group optionallysubstituted by 1 to 3 substituent(s) selected from group B", theabove-defined "C1-6 alkyl group" substituted by the above-defined"C6-14 aryl group optionally substituted by 1 to 3substituent(s) selected from group B", the above-defined "C1-6alkyloxy group" substituted by the above-defined "C6-14 aryl group optionally substituted by 1 to 3 substituent(s) selectedfrom group B", and a carbonyl group substituted by the "C6-14aryl group optionally substituted by 1 to 3 substituent(s)selected from group B".
[0115] In addition, the "C6-14 aryl C1-6 alkyl group" of theabove-mentioned group C includes a "C1-6 alkyl group"substituted by the above-defined "C6-14 aryl group optionallysubstituted by 1 to 3 substituent(s) selected from group B",wherein the alkyl group moiety is substituted by 1 to 3substituent(s) selected from the above-defined "group A", andspecifically, carbamoylphenylmethyl group, 1-carboxy-2-phenylethylgroup, 1-hydroxymethyl-2-phenylethyl group, 1-carboxymethyl-2-phenylethylgroup, 1-benzyloxycarbonyl-2-phenylethylgroup and the like can be mentioned.
[0116] In addition, the "C6-14 aryl C1-6 alkyloxy group" of theabove-mentioned group C includes a "C1-6 alkyloxy group"substituted by the above-defined "C6-14 aryl group optionallysubstituted by 1 to 3 substituent(s) selected from group B",wherein the alkyl group moiety is substituted by 1 to 3substituent(s) selected from the above-defined "group A", andspecifically, carbamoylphenylmethyloxy group, 1-carboxy-2-phenylethyloxygroup, 1-hydroxymethyl-2-phenylethyloxy group, 1-carboxymethyl-2-phenylethyloxygroup, 1-benzyloxycarbonyl-2-phenylethyloxygroup and the like can be mentioned.
[0117] R^c2 and R^c3 may form, "together with the adjacent nitrogenatom, a nitrogen-containing heterocycle", and the "nitrogen-containingheterocycle" contains at least one nitrogen atomamong the above-mentioned "heterocyclic groups", and a bondextends from the nitrogen atom. The "nitrogen-containingheterocycle" may further contain, besides nitrogen atom, ahetero atom selected from oxygen atom and sulfur atom.
[0118] Preferably, 1-pyrrolidinyl group, 3-hydroxypyrrolidin-1-ylgroup, 3-oxopyrrolidin-1-yl group and morpholino group can bementioned.
[0119] When X is -C(R^x1) (R^x2)-#, -C (R^x1) (R^x2) -C (R^x3) (R^x4) -#, -C(R^x1) (R^x2)-C(R^x3) (R^x4)-C(R^x5) (R^x6)-#, -C(R^x1) (R^x2)-C(R^x7) =C(R^x8)-#, or-C(R^x7) =C(R^x8)-C(R^x1) (R^x2)-#, and when R^x1 and R^x2, R^x3 and R^x4, orR^x5 and R^x6 form a C3-8 cycloalkyl together with the adjacentcarbon atom, X is, for example,
[0120] The cycloalkyl moiety is preferably a cyclopentyl group ora cyclohexyl group.
[0121] R¹ is preferably
[0122] Ring D is preferably the above-defined "C3-10 carbon ringgroup optionally substituted by 1 to 3 substituent(s) selectedfrom group B", more preferably, a phenyl group optionallysubstituted by 1 to 3 substituent(s) selected from the above-defined"group B", and more preferably, a phenyl groupoptionally substituted by 1 to 3 substituent(s) selected from ahalogen atom and -OR^b1 wherein R^b1 is a hydrogen atom or a C1-6alkyl group.
[0123] R¹ is preferably the above-defined "C1-6 alkyl groupoptionally substituted by 1 to 3 substituent(s) selected fromgroup A", more preferably the above-defined "C1-6 alkyl group".
[0124] R² is preferably a hydrogen atom, a C6-14 aryl C1-6 alkylgroup or -SO₂R^d1, more preferably a hydrogen atom.
[0125] X is preferably -C(R^x1) (R^x2)-C(R^x3) (R^x4)-#,-C(R^x1) (R^x2)-C(R^x3) (R^x4)-C(R^x5) (R^x6)-#, -C(R^x7)=C(R^x8)-#, -N=C(R^x9)-#, or -C (R^x10)=N-#, more preferably -C (R^x1) (R^x2)-C(R^x3) (R^x4)-#, or-C(R^x7)=C(R^x8)-#.
[0126] One of the more preferable embodiments is -C(R^x1) (R^x2)-C(R^x3)(R^x4)-#,and the other is -C(R^x7)=C(R^x8)-#.
[0127] Y¹ -----Y² -----Y³ of ring B is preferably C=C(R^y1)-N(R^y2),N-C(R^y1)=N, N-C(R^y1)=C(R^y2), or C=N-N(R^y2), more preferablyN-C(R^y1)=C(R^y2).
[0128] Preferable embodiments of the formula [I] include thefollowing formulas [I]-1, [I]-2, [I]-3 and [I]-4:
[0129] R^x1 to R^x10 are preferably selected froma hydrogen atom,a C3-8 cycloalkyl C1-6 alkyl group,a cyano group,a C1-7 alkyl group, a C6-14 aryl group,a C6-14 aryl C1-6 alkyl group,-CO₂R^c1,-CONR^c2R^c3 or-COR^c4 wherein each symbol and substituent is as defined above.
[0130] It is also preferable that R^x3 and R^x4 form a C3-8cycloalkyl together with the adjacent carbon atom.
[0131] As R^x1 to R^x10, hydrogen atom, cyano group, methyl group,ethyl group, propyl group, isopropyl group, butyl group,isobutyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethylgroup, 1-hydroxypropyl group, 3-hydroxypropyl group,1-hydroxy-2-methylpropyl group, methoxymethyl group, 2-methylsulfanylethylgroup, 2-methylsulfonylethyl group, phenylgroup, benzyl group, phenethyl group, 3-phenylpropyl group,carboxyl group, methoxycarbonyl group, formyl group, acetylgroup, dimethylcarbamoyl group and the like can be mentioned, orR^x3 and R^x4 may form a cyclopentyl group or a cyclohexyl group,together with the adjacent carbon atom.
[0132] R^x1 to R^x10 are more preferably hydrogen atoms.
[0133] R^y1 is preferably selected froma hydrogen atom,a C1-7 alkyl group,a C6-14 aryl group,-CO₂R^c1,-CONR^c2R^c3,-COR^c4 anda C6-14 arylcarbonyl groupwherein each symbol and substituent is as defined above.
[0134] R^y1 is specifically hydrogen atom, methyl group, isopropylgroup, isobutyl group, tert-butyl group, cyanomethyl group,hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group,1-hydroxy-2-methylpropyl group, 1-hydroxy-2,2-dimethylpropylgroup, methoxymethyl group, isopropyloxymethyl group,isobutyloxymethyl group, 2-hydroxy-3,3-dimethylbutyl group, methylsulfanylmethyl group, isopropylsulfanylmethyl group,methylsulfonylmethyl group, isopropylsulfonylmethyl group,pivaloylmethyl group, phenoxymethyl group,benzyloxycarbonylmethyl group, phenyl group, carboxyl group,methoxycarbonyl group, carbamoyl group, methylcarbamoyl group,dimethylcarbamoyl group, diethylcarbamoyl group, N-ethyl-N-methylcarbamoylgroup, N-isopropyl-N-methylcarbamoyl group,formyl group, acetyl group, propionyl group, isobutyryl group,pivaloyl group, benzoyl group, 1-(benzyloxycarbonyl)-2-phenylethylgroup and the like.
[0135] These substituents are particularly preferable when X is-C(R^x1) (R^x2)-C(R^x3) (R^x4)-#.
[0136] R^y1 is particularly preferably a hydrogen atom.
[0137] R^y2 is preferably selected froma hydrogen atom,a halogen atom,a C1-7 alkyl group,a C6-14 aryl group,a heterocyclic group,-CO₂R^c1,-CONR^c2R^c3,-COR^c4,-NR^c4R^c5,-NR^c6COR^c7,-NR^c8SO₂R^c9,-SR^c10,-SO₂R^c12,-NR^c13CONR^c14R^c15,-NR^c16CO₂R^c17, and-NR^c18COCOR^c19 wherein each symbol and substituent is as defined above.
[0138] One of the preferable embodiments of R^y2 is heterocyclicgroup.
[0139] More preferably, R^y2 is a heterocyclic group bonded to Y³via a carbon atom, wherein at least one of the α-position of thecarbon atom is a hetero atom selected from the group consistingof nitrogen atom, oxygen atom and sulfur atom. The heterocyclicgroup is optionally substituted by 1 to 3 substituent(s)selected from group B, and specifically, 2-thiazolyl group, 4-methyl-thiazol-2-ylgroup, 5-methyl-thiazol-2-yl group, 5-thiazolylgroup, 2-oxazolyl group, 1-methyl-imidazol-2-yl group,3-pyrazolyl group, 1,2,4-triazol-3-yl group, 2-methyl-1,2,4-triazol-3-ylgroup, 5-tetrazolyl group, 3-methyl-1,2,4-thiadiazol-5-ylgroup, 2-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinylgroup, 2-pyrazinyl group, 3-pyridazinyl group, 2-benzofuranylgroup and the like can be mentioned.
[0140] Other preferable embodiments of R^y2 include   -CO₂R^c1 (carboxyl group, methoxycarbonyl group,isopropyloxycarbonyl group, 2,2-dimethylpropyloxycarbonyl groupand cyclohexyloxycarbonyl group can be specifically mentioned),   -CONR^c2R^c3 (carbamoyl group, methylcarbamoyl group,ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoylgroup, butylcarbamoyl group, isobutylcarbamoyl group,dimethylcarbamoyl group, diethylcarbamoyl group, N-butyl-N-methylcarbamoylgroup, 2-fluoroethylcarbamoyl group, 2-hydroxyethylcarbamoylgroup, 2-methoxyethylcarbamoyl group, N-methyl-N-(2-methoxyethyl)carbamoylgroup, 2-oxopropylcarbamoylgroup, 2-hydroxypropylcarbamoyl group, carboxymethylcarbamoylgroup, methoxycarbonylmethylcarbamoyl group, 2,2,2-trifluoroethylcarbamoylgroup, 2-(trifluoroacetyloxy)ethylcarbamoylgroup,methylcarbamoylmethylcarbamoyl group,dimethylcarbamoylmethylcarbamoyl group, 2-(methylsulfonyl)ethylcarbamoylgroup, phenylcarbamoyl group,benzylcarbamoyl group, N-benzyl-N-methylcarbamoyl group, 2-fluorobenzylcarbamoylgroup, 4-fluorobenzylcarbamoyl group, 4-tert-butylbenzylcarbamoylgroup, 4-(dimethylamino)benzylcarbamoylgroup, 4-(methylsulfonyl)benzylcarbamoyl group, 4-(acetylamino)benzylcarbamoylgroup, 1-naphthylmethylcarbamoylgroup, diphenylmethylcarbamoyl group, 1,2-diphenylethylcarbamoylgroup, 1,3-diphenylpropylcarbamoyl group, 2-pyridylmethylcarbamoylgroup, 3-pyridylmethylcarbamoyl group, 4-pyridylmethylcarbamoylgroup, 2-furylmethylcarbamoyl group, 4-methoxypyrimidin-2-ylmethylcarbamoylgroup, 2-(2-oxopyrrolidin-1-yl)ethylcarbamoylgroup, 1-pyrrolidinylcarbonyl group, 3-hydroxypyrrolidin-1-ylcarbonylgroup, 3-oxopyrrolidin-1-ylcarbonylgroup and morpholinocarbonyl group can bespecifically mentioned) and   -COR^c4 (acetyl group, propionyl group, 2,2-dimethyl-3-hydroxypropionylgroup, 2-methyl-2-phenylpropionyl group, 2,2-dimethyl-3-methoxypropionylgroup, 3-acetyloxy-2,2-dimethylpropionylgroup, isobutyryl group, 2,2-dimethylbutyrylgroup, pivaloyl group, 3-methylbutyryl group, 2,2-dimethylbutyrylgroup and benzoyl group can be specificallymentioned).
[0141] More preferred is -COR^c4 wherein R^c4 is more preferably anunsubstituted C1-6 alkyl group.
[0142] Still more preferable embodiment of R^y2 include   -NR^c4R^c5 (e.g., amino group, ethylamino group, isopropylaminogroup, isobutylamino group and diethylamino group),   -NR^c6COR^c7 (e.g., acetylamino group, propionylamino group,butyrylamino group, isobutyrylamino group, pivaloylamino group,benzoylamino group, 4-fluorobenzoylamino group, 3,3-dimethylbutyrylaminogroup, (methoxyacetyl)amino group, 2-isopropyl-3-methylbutyrylaminogroup, 2-methyl-2-phenylpropionylaminogroup, N-acetyl-N-methylamino group, N-acetyl-N-isobutylaminogroup, benzylcarbonylamino group, 4-fluorobenzylcarbonylaminogroup, 3-phenylpropionylamino group,cyclopentylcarbonylamino group, 2-pyridylcarbonylamino group, 3-pyridylcarbonylaminogroup, 4-pyridylcarbonylamino group can bementioned. ),   -NR^c8SO₂R^c9 (e.g., methylsulfonylamino group, phenylsulfonylamino group, benzylsulfonylamino group, 2-thienylsulfonylamino groupand N-methyl-N-(methylsulfonyl)amino group),   -NR^c13CONR^c14R^c15 (e.g., dimethylcarbamoylamino group),   -NR^c16CO₂R^c17 (e.g., methoxycarbonylamino group) and   -NR^c18COCOR^c19 (e.g., 2-oxopropionylamino group).
[0143] R^y2 is still more preferably -NR^c6COR^c7, -NR^c8SO₂R^c9,-NR^c13CONR^c14R^c15, -NR^c16CO₂R^c17 or -NR^c18COCOR^c19, particularlypreferably -NR^c6COR^c7 (R^c6 is more preferably a hydrogen atom andR^c7 is more preferably an unsubstituted C1-6 alkyl group).
[0144] The "pharmaceutically acceptable salt thereof" may be anysalt as long as it forms a non-toxic salt with the compounds ofthe above-mentioned formulas [I], [I]-1, [I]-2, [I]-3 and [I]-4,and can be obtained by a reaction with an inorganic acid such ashydrochloric acid, sulfuric acid, phosphoric acid, hydrobromicacid and the like; an organic acid such as oxalic acid, malonicacid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid,gluconic acid, ascorbic acid, methylsulfonic acid,benzylsulfonic acid and the like; an inorganic base such assodium hydroxide, potassium hydroxide, calcium hydroxide,magnesium hydroxide, ammonium hydroxide and the like; an organicbase such as methylamine, diethylamine, triethylamine,triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, guanidine, choline, cinchonineand the like; or an amino acid such as lysine, arginine, alanineand the like. The present invention also encompasses hydrateand solvate of each compound.
[0145] The present invention also encompasses prodrugs andmetabolites of each compound.
[0146] By the "prodrug" is meant a derivative of the compound ofthe present invention, which has a chemically or metabolicallydecomposable group and which, after administration to a body,restores to the original compound to show its inherent efficacy,including a complex and a salt free of covalent bond.
[0147] The prodrug is utilized for, for example, improvingabsorption by oral administration or targeting of a target site.
[0148] As the site to be modified, highly reactive functionalgroups in the compound of the present invention, such ashydroxyl group, carboxyl group, amino group, thiol group and thelike, are mentioned.
[0149] Examples of the hydroxyl-modifying group include methylgroup, benzyl group, trimethylsilyloxymethyl group, acetyl group,propionyl group, isobutyryl group, pivaloyl group, benzoyl group,4-methylbenzoyl group, dimethylcarbamoyl group, sulfo group andthe like. Examples of the carboxyl-modifying group includeethyl group, pivaloyloxymethyl group, 1-(acetyloxy)ethyl group,1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethylgroup, carboxylmethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methylgroup, phenyl group, o-tolylgroup and the like. Examples of the amino-modifying groupinclude hexylcarbamoyl group, 3-methylthio-1-(acetylamino)propylcarbonylgroup, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methylgroup, (5-methyl-2-oxo-1,3-dioxol-4-yl)methylgroup and the like.
[0150] Preferably, prodrugs of the compounds of the formulas [I],[I]-1, [I]-2, [I]-3 and [I]-4, wherein the hydroxyl group onring B is modified by methyl group, benzyl group ortrimethylsilyloxymethyl group, can be mentioned.
[0151] The compound of the present invention can be administeredto a mammal (human, mouse, rat, hamster, rabbit, cat, dog,bovine, sheep, monkey and the like) as an anti-HIV agent, anintegrase inhibitor, an antiviral agent and the like.
[0152] When the compound of the present invention is used as apharmaceutical preparation, it is admixed with pharmaceuticallyacceptable carriers, excipients, diluents, extending agents,disintegrants, stabilizers, preservatives, buffers, emulsifiers,flavoring agents, coloring agents, sweetening agents,thickeners, correctives, dissolution aids, and other additives,that are generally known per se, such as water, vegetable oil, alcohol (e.g., ethanol or benzyl alcohol etc.), polyethyleneglycol, glycerol triacetate, gelatin, carbohydrate (e.g.,lactose, starch etc.), magnesium stearate, talc, lanolin,petrolatum and the like, formed into tablet, pill, powder,granule, suppository, injection, eye drop, liquid, capsule,troche, aerosol, elixir, suspension, emulsion, syrup and thelike by a conventional method, and administered systemically ortopically, and orally or parenterally.
[0153] While the dose varies depending on age, body weight,symptom, treatment effect, administration method and the like,it is generally 0.01 mg to 1 g per administration for an adult,which is given once to several times a day orally or in a dosageform of an injection such as intravenous injection and the like.
[0154] As a preferable embodiment of the compound of the presentinvention, a compound having high pharmacological activity (e.g.,a compound having a strong HIV integrase-inhibitory activity, acompound having a strong anti-HIV (e.g., HIV-1 IIIB strain)activity, a compound that resists easy occurrence of drugresistant viruses, a compound effective against multiple drugresistant viruses), a compound having fine bioavailability (e.g.,a compound showing high oral absorbability, a compound showinghigh cell membrane (e.g., Caco2) permeability, a compound stableto metabolic enzyme (e.g., S9), a compound maintained at highblood concentration for a long time (e.g., high bloodconcentration after 8 hours from administration), a compoundshowing low binding rate to a protein (e.g., human plasmaprotein, human serum albumin, α1-acidic glycoprotein), a highlysafe compound (e.g., a compound showing low inhibitory activityagainst P450(CYP)) and the like can be mentioned.
[0155] An anti-HIV agent is generally required to sustain itseffect for a long time, so that can be effective not only fortemporal suppression of viral growth but also prohibition ofviral re-growth. This means that a prolonged administration isnecessary and that a high single dose may be frequentlyinevitable to sustain effect for a longer period through the night. Such prolonged and high dose administration increasesthe risk of causing side effects.
[0156] In view of this, one of the preferable modes of thenitrogen-containing fused ring compound of the present inventionis such compound permitting high absorption by oraladministration, and such compound capable of maintaining bloodconcentration of the administered compound for an extendedperiod of time.
[0157] Furthermore, a compound that exhibits a strong anti-HIVactivity, high absorbability by oral administration, and long-termsustention of blood concentration is desirable.
[0158] A compound showing less effect of addition of serum (e.g.,human serum, fetal bovine serum, equine serum) in in vitro testsand capable of maintaining strong integrase inhibitory activityand strong anti-HIV activity is also one of the preferableembodiments.
[0159] By the "prophylaxis of AIDS" is meant, for example,administration of a pharmaceutical agent to an individual whotested HIV positive but has not yet developed the disease stateof AIDS, administration of a pharmaceutical agent to anindividual who shows an improved disease state of AIDS aftertreatment but who carries HIV still to be eradicated and whoserelapse of AIDS is worried, and administration of apharmaceutical agent out of a fear of possible infection.
[0160] Examples of the "other anti-HIV agents" to be used for amultiple drug combination therapy include an anti-HIV antibody,an HIV vaccine, immunostimulants such as interferon and thelike, an HIV ribozyme, an HIV antisense drug, a reversetranscriptase inhibitor, a protease inhibitor, an inhibitor ofbond between a bond receptor (CD4, CXCR4, CCR5 and the like) ofa host cell recognized by virus and the virus, and the like.
[0161] Specific examples of the HIV reverse transcriptaseinhibitor include Retrovir(R) (zidovudine), Epivir(R)(lamivudine), Zerit(R) (sanilvudine), Videx(R) (didanosine),Hivid(R) (zalcitabine), Ziagen(R) (abacavir sulfate), Viramune (R) (nevirapine), Stocrin (R) (efavirenz), Rescriptor (R)(delavirdine mesylate), Combivir(R) (zidovudine+lamivudine),Trizivir(R) (abacavir sulfate+lamivudine+zidowdine),Coactinon (R) (emivirine), Phosphonovir(R), Coviracil(R),alovudine (3'-fluoro-3'-deoxythymidine), Thiovir(thiophosphonoformic acid), Capravirin (5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)imidazole-2-methanolcarbamic acid), Tenofovir disoproxil fumarate ((R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonicacidbis(isopropoxycarbonyloxymethyl)ester fumarate), DPC-083 ((4S)-6-chloro-4-[(1E)-cyclopropylethenyl]-3,4-dihydro-4-trifluoromethyl-2(1H)-quinazolinone),DPC-961 ((4S)-6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone),DAPD. ((-)-β-D-2,6-diaminopurine dioxolane),Immunocal, MSK-055, MSA-254, MSH-143, NV-01, TMC-120, DPC-817and the like, wherein (R) means a registered trademark(hereinafter the same) and the names of other pharmaceuticalagents are general names.
[0162] Specific examples of the HIV protease inhibitor includeCrixivan(R) (indinavir sulfate ethanolate), saquinavir,Invirase(R) (saquinavir mesylate), Norvir(R) (ritonavir),Viracept(R) (nelfinavir mesylate), lopinavir, Prozei(R)(amprenavir), Kaletra(R) (ritonavir+lopinavir), mozenavirdimesylate ([4R-(4α,5α,6β)]-1,3-bis[(3-aminophenyl)methyl]-hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-onedimethanesulfonate), tipranavir (3'-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenylethyl-6-propyl-2H-pyran-3-yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonamide),lasinavir(N-[5(S)-(-tert-butoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxybenzyl)hexanoyl]-L-valine2-methoxyethylenamide),KNI-272 ((R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide),GW-433908, TMC-126, DPC-681,buckminsterfullerene, MK-944A (MK944 (N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-[4-(2-benzo[b]furanylmethyl)-2(S)-(tert-butylcarbamoyl)piperazin-1-yl]pentanamide)+indinavir sulfate), JE-2147 ([2(S)-oxo-4-phenylmethyl-3(S)-[(2-methyl-3-oxy)phenylcarbonylamino]-1-oxabutyl]-4-[(2-methylphenyl)methylamino]carbonyl-4(R)-5,5-dimethyl-1,3-thiazole),BMS-232632 ((3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedicarboxylicacid dimethyl ester), DMP-850((4R,5S,6S,7R)-1-(3-amino-1H-indazol-5-ylmethyl)-4,7-dibenzyl-3-butyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one),DMP-851 and thelike.
[0163] The HIV integrase inhibitor is exemplified by S-1360 andthe like, the DNA polymerase inhibitor or DNA synthesisinhibitor is exemplified by Foscavir(R), ACH-126443 (L-2',3'-didehydro-dideoxy-5-fluorocytidine),entecavir ((1S,3S,4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]guanine),calanolide A ([10R-(10α,11β,12α)]-11,12-dihydro-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-2H,6H,10H-benzo[1,2-b:3,4-b':5,6-b"]tripyran-2-one),calanolide B, NSC-674447 (1,1'-azobisformamide),Iscador (viscum album extract) and the like,the HIV antisense drug is exemplified by HGTV-43, GEM-92 and thelike, the anti-HIV antibody or other antibody is exemplified byNM-01, PRO-367, KD-247, Cytolin(R), TNX-355 (CD4 antibody), AGT-1,PRO-140 (CCR5 antibody) and the like, the HIV vaccine orother vaccine is exemplified by ALVAC(R), AIDSVAX(R), Remune(R),HIV gp41 vaccine, HIV gp120 vaccine, HIV gp140 vaccine, HIVgp160 vaccine, HIV p17 vaccine, HIV p24 vaccine, HIV p55vaccine, AlphaVax Vector System, canarypox gp160 vaccine,AntiTat, MVA-F6 Nef vaccine, HIV rev vaccine, C4-V3 peptide,p2249f, VIR-201, HGP-30W, TBC-3B, PARTICLE-3B and the like,Antiferon (interferon-α vaccine) and the like, the interferon orinterferon agonist is exemplified by Sumiferon(R),MultiFeron(R), interferon-τ, Reticulose and the like, the CCR5antagonist is exemplified by SCH-351125 and the like, the pharmaceutical agent acting on HIV p24 is exemplified by GPG-NH2(glycyl-prolyl-glycinamide) and the like, the HIV fusioninhibitor is exemplified by FP-21399 (1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfonyl]naphthyl-2,5-dimethoxyphenyl-1,4-dihydrazone), T-1249,Synthetic Polymeric Construction No3, pentafuside and the like,the IL-2 agonist or antagonist is exemplified by interleukin-2,Imunace(R), Proleukin(R), Multikine(R), Ontak(R) and the like,the TNF-α antagonist is exemplified by Thalomid(R)(thalidomide), Remicade(R) (infliximab), curdlan sulfate, the α-glucosidaseinhibitor is exemplified by Bucast(R) and the like,the purine nucleoside phosphorylase inhibitor is exemplified bypeldesine (2-amino-4-oxo-3H,5H-7-[(3-pyridyl)methyl]pyrrolo[3,2-d]pyrimidine)and the like, the apoptosis agonist or inhibitoris exemplified by Arkin Z(R), Panavir(R), Coenzyme Q10 (2-deca(3-methyl-2-butenylene)-5,6-dimethoxy-3-methyl-p-benzoquinone)and the like, the cholinesterase inhibitor isexemplified by Cognex(R) and the like, and the immunomodulatoris exemplified by Imunox(R), Prokine(R), Met-enkephalin (6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenorphin),WF-10(10-fold dilute tetrachlorodecaoxide solution), Perthon, PRO-542and the like.
[0164] In addition, Neurotropin(R), Lidakol(R), Ancer 20(R),Ampligen(R), Anticort(R), Inactivin(R) and the like, PRO-2000,Rev M10 gene, HIV specific cytotoxic T cell (CTL immunotherapy,ACTG protocol 080 therapy, CD4-ζ gene therapy), SCA bindingprotein, RBC-CD4 complex and the like are exemplified.
[0165] As the "other anti-HIV agents" to be used for a multipledrug combination therapy with the compound of the presentinvention, preferred are a reverse transcriptase inhibitor and aprotease inhibitor. Two or three, or even a greater number ofpharmaceutical agents can be used in combination, wherein acombination of pharmaceutical agents having different actionmechanisms is one of the preferable embodiments. In addition,selection of pharmaceutical agents free of side effect duplication is preferable. Specific examples of the combinationof pharmaceutical agents include a combination of a groupconsisting of efavirenz, indinavir, nelfinavir, ritonavir +indinavir, ritonavir + lopinavir and ritonavir + saquinavir, anda group consisting of didanosine + lamivudine, zidovudine +didanosine, stavudine + didanosine, zidovudine + lamivudine andstavudine + lamivudine (Guidelines for the Use of AntiretroviralAgents in HIV-Infected Adults and Adolescents. August 13, 2001).Particularly preferred is Invirase(R) (saquinavir mesylate).
[0166] Some examples of the production method of the compoundused for embodiment of the present invention are shown in thefollowing. However, the production method of the compound ofthe present invention is not limited to these examples.
[0167] Even in the absence of description in the productionmethod, efficient production can be afforded by introducing,where necessary, a protecting group into a functional groupfollowed by deprotection in a subsequent step, subjecting afunctional group to each step as a precursor and converting thegroup to a desired functional group in a suitable step,exchanging the order of respective production methods and steps,and the like.
[0168] The work-up treatment in each step can be applied by atypical method, wherein isolation and purification is performedby selecting or combining conventional methods as necessary,such as crystallization, recrystallization, distillation,partitioning, column chromatography, thin layer chromatography,preparative HPLC and the like.
[0169] The abbreviations used in the present specification are asfollows. Me means methyl group, Et means ethyl group, Bn meansbenzyl group, n-Bu (or Bu) means butyl group, t-Bu means tert-butylgroup, Ac means acetyl group, Boc means tert-butoxycarbonylgroup, MOM means methoxymethyl group and Ms meansmethanesulfonyl group. Production method 1 Production method 1-1
[0170]
[0171] Compound [I] can be synthesized by reacting compound [1]in an organic solvent such as tetrahydrofuran, dioxane,dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone,tert-butanol, isopropanol and thelike, in the presence of a base such as sodium hydride, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassiumtert-butoxide, triethylamine, diisopropylethylamine and the likeat room temperature to cooling to give Compound [I].
[0172] When a compound wherein R² is a hydrogen atom is desired,the reaction only needs to be conducted by a conventional methodunder the conditions to make W¹ leave. When a compound whereinR² is a C1-6 alkyl group, a C6-14 aryl C1-6 alkyl group or -SO₂R^d1is desired, the reaction only needs to be conducted under mildconditions under which these substituents do not leave (the sameapplied to the following production methods). Production method 1-2
[0173]
[0174] A compound represented by the formula [I-1] can besynthesized by subjecting compound [2] to a ring closurereaction under acidic conditions in a solvent or without solventat room temperature to under heating.
[0175] As the acid to be used, inorganic acids such ashydrochloric acid, sulfuric acid, phosphoric acid,polyphosphoric acid and the like, organic acids such as aceticacid, trifluoroacetic acid, camphorsulfonic acid, p-toluenesulfonicacid, methanesulfonic acid,trifluoromethanesulfonic acid and the like, acidic salts such aspyridinium p-toluenesulfonate and the like, and the like can bementioned, and as the solvent, ether solvents such astetrahydrofuran, dioxane, diethyl ether and the like, benzenesolvents such as benzene, toluene, chlorobenzene,dichlorobenzene and the like, alcohol solvents such as ethanol,isopropanol, tert-butanol and the like, and halogenatedhydrocarbon solvents such as methylene chloride, chloroform,dichloroethane and the like can be mentioned. A combination ofan organic acid and a benzene solvent often produce good results.In addition, preferable options include, for example, a reactionunder the conditions of using an acid such as phosphoric acid,polyphosphoric acid, sulfuric acid and the like without using a solvent, and the conditions of using acetic acid ortrifluoroacetic acid as a solvent and adding aqueoushydrochloric acid thereto. Production method 2
[0176]
[0177] Compound [I] can be synthesized by subjecting compound [3]to ring closure reaction under acidic or basic conditions atroom temperature to under heating.
[0178] When W² is a hydrogen atom, for example, a ring closurereaction can be achieved using a condensation agent such asdicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,carbonyldiimidazole and thelike and conducting a reaction in the presence or absence of acondensation additive such as 1-hydroxybenzotriazole, N-hydroxysuccinimideand the like in an ether solvent such astetrahydrofuran, dioxane, diethyl ether and the like, a benzenesolvent such as benzene, toluene and the like, a hydrocarbonsolvent such as cyclohexane and the like, an amide solvent suchas dimethylformamide, dimethylacetamide, 1,3-dimethylimidazolidinoneand the like, a ketone solvent such asacetone, 2-butanone and the like or a halogenated hydrocarbonsolvent such as methylene chloride, chloroform and the like.
[0179] When W² is an alkyl group, a ring closure reaction can beachieved by conducting a reaction in the presence of an acidcatalyst such as camphorsulfonic acid, p-toluenesulfonic acidand the like or a base catalyst such as dimethylaminopyridine and the like in a solvent such as benzene, toluene and the likeat room temperature to under heating, particularly preferablyunder heating. Production method 3 Production method 3-1
[0180]
[0181] Compound [I-2] can be synthesized by reacting compound [4]in an organic solvent such as tetrahydrofuran, dioxane,dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone,tert-butanol, isopropanol, ethanoland the like, or a mixed solvent of these with water, in thepresence or absence of an organic base such as triethylamine,diisopropylethylamine and the like or a carbonate base such assodium carbonate, potassium carbonate, sodium hydrogen carbonateand the like at room temperature to under heating. Production method 3-2
[0182]
[0183] Compound [I-2] can be synthesized by subjecting compound[5] to the same reaction operation as in Production method 1-1. Production method 3-3
[0184]
[0185] Compound [I-2] can be synthesized by subjecting compound[6] to the same reaction operation as in production method 1-2. Production method 3-4
[0186]
[0187] Compound [I-3] can be obtained by subjecting compound [7]to a ring closure reaction in the same manner as in Productionmethod 3-3. Production method 4
[0188]
[0189] Compound [4], compound [5], compound [6] and compound [7] can be obtained by performing a condensation amidation reactionas illustrated above in the same manner as in Production method2.
[0190] In addition, a method comprising converting a carboxylgroup to an acid halide, followed by condensation, is highlyversatile, and often leads to good results. Specifically, astarting compound is reacted with thionyl chloride, oxalylchloride and the like in a halogenated hydrocarbon solvent suchas methylene chloride, chloroform and the like or a benzenesolvent such as benzene, toluene and the like in the presence orabsence of a catalytic amount of dimethylformamide, thereafterreacted in the presence of a base to complete the condensationreaction. Examples of the base to be used include potassiumcarbonate, sodium carbonate, sodium hydrogen carbonate,triethylamine, pyridine and the like, and good results are oftenobtained when an organic base such as triethylamine, pyridineand the like is used.
[0191] When these reactions are conducted and when other reactivemoieties are present, the methods usually employed for generalorganic reactions often produce good results, wherein they maybe protected beforehand and deprotected after the reaction, orcondensation reaction is conducted in the form of a stableprecursor and thereafter converted to a desired form and thelike. Specifically, when two nitrogen atoms are present, amethod comprising protecting the one desired to be free fromreaction, a method comprising carrying out a condensationreaction using a compound wherein a leaving group moiety is ahydroxyl group, thereby avoiding a reaction between leavinggroups L¹ to L³ with a nitrogen atom, after which the hydroxylgroup is converted to a leaving group and the like can bementioned.
[0192] Compound [8], compound [10] and compound [13] can beprepared by a method described in JP-A-2-502281 (WO88/06588),WO03/016275, J. Med. Chem., 42, 4814-4823, 1999 and the like, ora method analogous thereto.
[0193] Compound [9], compound [11], compound [12] and compound[14] can be prepared as a secondary amine by a conventionalmethod. Production method 5
[0194]
[0195] Compound [17] can be obtained by reacting compound [15] orcompound [18] as illustrated above in the same manner as inProduction method 3. When these reactions are conducted andwhen other reactive moieties are present, as described inProduction method 4, the methods usually employed for generalorganic reactions often produce good results, wherein they maybe protected beforehand and deprotected after the reaction, orcondensation reaction is conducted in the form of a stableprecursor and thereafter converted to a desired form and thelike.
[0196] When the amide moiety (R¹-HNCO-) of compound [15] andcompound [18] is carboxylic acid or carboxylic acid ester (W²-OCO-),L⁵ may be R¹-NH-.
[0197] Moreover, L⁵-X- may be C(R^x7) (OMe)₂-CH(R^x8)- or C(R^x7) (OMe)₂-CH(R^x8)-C(R^x1)(R^x2)- wherein each symbol is as defined above. Production method 6
[0198]
[0199] Compound [15] and compound [18] can be obtained byperforming a condensation amidation reaction as illustratedabove in the same manner as in Production method 2. Production method 7
[0200] Compound [I]-1 wherein, in the formula [I],Y¹ -----Y² -----Y³ is N-C(R^y1)=C(R^y2), can be synthesized by theaforementioned production methods (except Production method 3-4).
[0201] Compound [10'] can be obtained by reacting compound [8']with NH₃.
[0202] When producing compound [I]-1, fine results may beachieved by using a compound wherein R^y2 is a hydrogen atom andintroducing R^y2 or a precursor thereof in any of the above-mentionedsteps.
[0203] Specific examples are given in the following. Production method 7-1
[0204]
[0205] Compound [8'-2] can be obtained by reacting compound [8'-1]with a brominating reagent such as bromine,phenyltrimethylammonium tribromide and the like.
[0206] As the solvent, chloroform has high versatility, butacetic acid, toluene, chlorobenzene and the like may be alsoused. In addition, an alcohol solvent such as methanol, ethanoland the like may be used in combination with these solvents. Production of compound [8'-3] wherein R^y2 is C1-7 alkyl group,C3-8 cycloalkyl C1-6 alkyl group, C6-14 aryl C1-6 alkyl group,C1-6 alkyloxy group, C6-14 aryl C1-6 alkyloxy group, C6-14 arylgroup, heterocyclic group, cyano group, -CO₂R^c1, -CONR^c2R^c3,-SO₂NR^c2R^c3, C6-14 arylcarbonyl group, -NR^c4R^c5, -NR^c6COR^c7,-NR^c8SO₂R^c9, -NR^c13CONR^c14R^c15, -NR^c16CO₂R^c17 or -NR^c18COCOR^c19, whereineach symbol is as defined above.
[0207] Synthesis is performed according to a method described in a) Handbook of Palladium-Catalysed Organic Reactions: SyntheticAspects and Catalytic Cycles. Jean-Luc Malleron et al. (1997)Academic Pr. b) Palladium in Heterocyclic Chemistry: A Guide for theSynthetic Chemist (Tetrahedron Organic Chemistry Series, V. 20).Jie Jack Li et al. (2000) Elsevier Science Ltd. c) Handbook of Organopalladium Chemistry for Organic Synthesis. Ei-Ichi Negishi et al. (2002) John Wiley & Sons Inc. and thelike, by subjecting compound [8'-2] to a coupling reaction usingpalladium as a catalyst.
[0208] More specifically, the following methods can be mentioned. Production of compound wherein R^y2 is C6-14 aryl group orheterocyclic group.
[0209] For example, the corresponding compound [8'-3] can beobtained by heating compound [8'-2] and R^y2-SnBu₃ in dioxane inthe presence of a catalytic amount oftetrakis(triphenylphosphine)palladium(0).
[0210] When carrying out this reaction, fine results are oftenobtained using R^y2-B(OH)₂ instead of R^y2-SnBu₃. While many usefuloptions of palladium catalyst are described in the above-mentionedreference literatures, one of the options is acombined use of palladium(II) acetate and 1,3-bis(diphenylphosphino)propane.The usable solvent is notlimited to those mentioned above, and unless the reaction isparticularly inhibited, a comparatively wide variety of solventssuch as tetrahydrofuran, toluene and the like can be used. Whencarrying out this reaction, fine results are often obtained bycarrying out the reaction in an inert gas to avoid interferenceby oxygen and water. Production of compound wherein R^y2 is C1-7 alkyl group, C3-8cycloalkyl C1-6 alkyl group or C6-14 aryl C1-6 alkyl group.
[0211] A desired compound [8'-3] can be obtained by, for example,reacting compound [8'-2] with R^y2-SnBu₃ in the same manner asabove.
[0212] Here, in the case of a compound wherein R^y2 is R^y2'-CX⁵H-CY⁵H-(wherein X⁵ and Y⁵ are each a lower alkyl group such asmethyl group, ethyl group and the like and R^y2' is a group suchas a C1-7 alkyl group, a C3-8 cycloalkyl C1-6 alkyl group and aC6-14 aryl C1-6 alkyl group, wherein the alkyl moiety is free ofCX⁵H-CY⁵H moiety), fine results are often obtained by using R^y2'-CX⁵=CY⁵-SnBu₃ to give compound [8'-3] wherein R^y2 isR^y2'-CX⁵=CY⁵-, and subjecting this compound to a catalyticreduction to give compound [8'-3] wherein R^y2 is R^y2'-CX⁵H-CY⁵H-. Production of compound wherein R^y2 is C1-6 alkyloxy group or C6-14aryl C1-6 alkyloxy group.
[0213] A desired compound [8'-3] can be obtained by, for example,reacting compound [8'-2] with R^y2'ONa (wherein R^y2' is a C1-6alkyl group or C6-14 aryl C1-6 alkyl group) in toluene in thepresence of bis(dibenzylideneacetone)palladium(0) or 1,1'-bis(diphenylphosphino)ferrocene. Production of compound wherein R^y2 is cyano group.
[0214] The corresponding compound [8'-3] can be obtained by, forexample, heating compound [8'-2] and zinc cyanide in thepresence of a catalytic amount oftetrakis(triphenylphosphine)palladium(0) in dimethylformamide. Production of compound wherein R^y2 is -CO₂R^c1 or -CONR^c2R^c3.
[0215] A compound [8'-3] wherein R^y2 is -CO₂R^c1 can be obtained by,for example, heating compound [8'-2] under a carbon monoxideatmosphere in dimethyl sulfoxide in the presence of R^c1OH,triethylamine, palladium(II) acetate and 1,3-bis(diphenylphosphino)propane.
[0216] A compound [8'-3] wherein R^y2 is -CO₂H can be obtained byusing methanol for R^c1OH to give compound [8'-3], wherein R^y2 is-CO₂CH₃, and subjecting this compound to hydrolysis by aconventional method using aqueous sodium hydroxidesolution/tetrahydrofuran and the like.
[0217] Compound [8'-3] wherein R^y2 is -CONR^c2R^c3 can be obtained bycondensation of this compound with NHR^c2R^c3. As used herein, thecondensation reaction can be carried out according to theaforementioned Production method 2 and Production method 4. Production of compound wherein R^y2 is -NR^c4R^c5.
[0218] A desired compound [8'-3] can be obtained by, for example,heating compound [8'-2] and HNR^c4R^c5 in the presence of cesiumcarbonate and a catalytic amount of palladium(II) acetate and2,2'-bis(di-tert-butylphosphino)-1,1'-binaphthyl in benzene. Production of compound wherein R^y2 is -NR^c6COR^c7, -NR^c8SO₂R^c9,-NR^c13CONR^c14R^c15, -NR^c16CO₂R^c17 or -NR^c18COCOR^c19.
[0219] Compound [8'-3] wherein R^y2 is -NR^c6COR^c7 can be obtained by,for example, heating compound [8'-2] and HNR^c6COR^c7 in toluene inthe presence of sodium tert-butoxide, a catalytic amount ofpalladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene.
[0220] While compound [8'-3] wherein R^y2 is -NR^c8SO₂R^c9,-NR^c13CONR^c14R^c15, -NR^c16CO₂R^c17 and -NR^c18COCOR^c19 can be alsosynthesized in the same manner, finer results are sometimesobtained when the reaction is carried out step by step. That is,NH₂CO₂t-Bu and compound [8'-2] are subjected to a reactionsimilar to the one mentioned above, whereby compound [8'-3]wherein R^y2 is -NHCO₂t-Bu can be obtained. This is treated withtrifluoroacetic acid, hydrochloric acid-dioxane and the likeaccording to a conventional method to give compound [8'-5]wherein R^y2 is -NH₂ can be obtained.
[0221] The corresponding compound [8'-3] can be synthesized byreacting the obtained compound [8'-5] with the correspondingcarboxylic acid (e.g., R^c7CO₂H), carboxylic acid anhydride (e.g.,R^c7CO₂COR^c7) or acid chloride (e.g., R^c7COCl), chlorocarbonic acidester (R^c17OCOCl), isocyanate (R^c14-NCO), chlorocarbonic acidamide (R^c14R^c15NCOCl), sulfonyl chloride (R^c9SO₂Cl) and the like,as described in the above-mentioned Production method 2 andProduction method 4.
[0222] R^c6, R^c8, R^c13, R^c16 or R^c18 may be introduced into -NH₂ priorto the above-mentioned reactions or after the reactions by aconventional method. Production of compound wherein R^y2 is amino group.
[0223] Compound [8'-4] can be obtained by reacting compound [8'-1] with nitric acid, fuming nitric acid, nitroniumtetrafluoroborate and the like.
[0224] As the solvent, acetic acid, chloroform and the like aregenerally used and various conditions known as nitrationconditions of aromatic ring may be used.
[0225] Compound [8'-5] can be obtained by subjecting [8'-4] tocatalytic reduction, reduction with a metal powder such as iron,zinc and the like, or reduction with a metal ion such as tinchloride and the like.
[0226] As a solvent for reduction with a metal powder, aceticacid, hydrochloric acid-alcohol, hydrochloric acid-tetrahydrofuranand the like are generally used and forreduction using tin chloride, methanol or ethanol is generallyused.
[0227] The above-mentioned introduction of Br and conversion toR^y2 are not limited by compound [8] and can be performed at adesired or suitable timing in the whole steps in the alreadydescribed Production methods, wherein introduction of Br andconversion to R^y2 may be conducted in different steps.Particularly, introduction of Br sometimes provide fine resultswhen done in compound [5], [6], [10], [17], [18], [10] or [I-1]. Production method 7-2
[0228]
[0229] As a different method of introducing a functional group, a method comprising reacting compound [15'-1] with a base and thenreacting with an electrophile can be mentioned.
[0230] Specific examples of electrophile include esters,aldehydes, ketones, disulfides, carbon dioxide and the like.
[0231] As the base to be used, lithium diisopropylamide,potassium hexamethyldisilamide, n-butyllithium and the like canbe mentioned, and as a solvent, tetrahydrofuran, diethyl ether,dimethoxyethane and the like can be mentioned. When lithiumdiisopropylamide is used in tetrahydrofuran, fine results areoften obtained. As the reaction temperature, when a reaction iscarried out at room temperature to under cooling, fine resultsare often obtained. In this way, the introduced functionalgroup can be also converted to a desired and suitable R^y2 byvarious known reactions.
[0232] As concrete examples, the following production methods canbe mentioned. Production of compound wherein R^y2 is -COR^c4.
[0233] Compound [15'-2] wherein R^y2 is -CH(OH)R^c4 can be obtainedby adding R^c4-CHO as an electrophile to compound [15'-1] treatedwith lithium diisopropylamide at -78°C in tetrahydrofuran.
[0234] The obtained compound [15'-2] wherein R^y2 is -CH(OH)R^c4 canbe converted to compound [15'-2] wherein R^y2 is -COR^c4 by atreatment with a sulfur trioxide pyridine complex in thepresence of triethylamine and dimethyl sulfoxide in a solventthat does not itself inhibit the reaction such as chloroform.This oxidation reaction is not limited to the above-mentionedconditions, and the conditions comprising using 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martinreagent) as an oxidant in chloroform also affords fineresults. While the reaction is carried out at room temperatureto under cooling under any conditions, the range of from 0°C toroom temperature is more preferable. Production of compound wherein R^y2 is -COOH, -SR^c10, -SOR^c11 or -SO₂R^c12.
[0235] Using carbon dioxide or disulfide (R^c10SSR^c10 etc.) as anelectrophile, compound [15'-2] wherein R^y2 is -COOH or -SR^c10 canbe obtained. Compound [15'-2] wherein R^y2 is -SR^c10 is treatedwith a peracid such as m-chloroperbenzoic acid and the like inchloroform, whereby compound [15'-2] wherein R^y2 is -SOR^c11 or-S0₂R^c12 can be obtained.
[0236] The introduction of E by electrophile and conversion to R^y2are not limited by compound [15] and can be performed at adesired or suitable timing in the whole steps in the alreadydescribed Production methods, wherein introduction of E andconversion to R^y2 may be conducted in different steps.
[0237] However, in order to control side reaction, it is oftenbetter to not introduce E by electrophile in the presence of abase in compounds [3], [8] and [10]. Production method 8 Production method 8-1
[0238]
[0239] Compound [I-5] can be obtained by converting compound[10'] to compound [19] and sequentially condensing the compoundwith a compound represented by R^x9-CH(OMe)₂.
[0240] For conversion of compound [10'] to compound [19] here,R¹-NHNH-W (W is amino-protecting group) is used instead of R¹-NH₂,and a method according to the method described in Productionmethod 6 is performed.
[0241] A condensation reaction of compound [19] to compound [I-5]is carried out in the presence of an acid catalyst such ashydrochloric acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate and the like in a benzene solvent such asbenzene, toluene, chlorobenzene and the like or an alcoholsolvent such as methanol, ethanol and the like at roomtemperature to under heating. Production method 8-2
[0242]
[0243] Compound [I-6] can be obtained by converting compound [8']to compound [20] and sequentially condensing with a compoundrepresented by R^x10-CH(OMe)₂.
[0244] For conversion of compound [8'] to compound [20] here, W-NH-NH₂(W is amino-protecting group) is used instead of L⁵-X-NH₂,and a method according to the method described in Productionmethod 5 is performed. A condensation reaction of compound [20]to compound [I-6] is carried out under acidic conditions in thesame manner as in Production method 8-1. Production method 3-5
[0245]
[0246] Compound [I]-2 is a part of the compound represented bythe formula [I] and produced according to the aforementionedmethod, wherein preferable results are often obtained when the production follows this production method.
[0247] That is, compound [22] is synthesized by reacting compound[21] prepared according to the a method described in a reference(Breslow, D.S. et al., J. Am. Chem. Soc., 1946, 68, 1232) or amethod analogous thereto with R^y1-C(NH₂)=NH under acidicconditions or basic conditions. As the acid to be used,hydrochloric acid, p-toluenesulfonic acid and the like can bementioned, and the acid is generally applied to the reaction inthe form of an amidine salt. Where necessary, the acid may befurther added. As the base, sodium methoxide, potassiumcarbonate and the like can be mentioned, and as the solvent,methanol, ethanol, dioxane, tetrahydrofuran and the like can bementioned. This reaction can be carried out in such a solventthat does not particularly inhibit the reaction undercomparatively wide pH conditions. As a preferable method, forexample, conditions under which the reaction is carried out inmethanol using sodium methoxide as a base under heating can bementioned.
[0248] The subsequent production step to produce compound [I]-2from compound [22] via compound [23] is performed according tothe aforementioned Production method 4 and Production method 3.Prior to this conversion, it is necessary to hydrolyze compound[22] into carboxylic acid in a solvent such as alcohol,tetrahydrofuran and the like using sodium hydroxide and the like. Production method 3-6
[0249]
[0250] Preferable results are often obtained when the productionof compound [I]-3 follows this production method.
[0251] That is, compound [24] derived from amino acid is reactedwith methyl orthoformate in methanol or without solvent in thepresence of an acid catalyst such as hydrochloric acid, p-toluenesulfonicacid, pyridinium p-toluenesulfonate and the like,and thereafter deprotected, whereby compound [25] can beobtained.
[0252] Compound [26] can be obtained by reacting compound [25]with methyl chloroglyoxylate in the presence of a base such aspyridine, triethylamine and the like in a solvent such aschloroform, toluene, tetrahydrofuran and the like or withoutsolvent. Fine results are often obtained when this reaction iscarried out under cooling.
[0253] Compound [27] can be obtained by reacting compound [26]with W²-OAc. When performing this reaction, fine results areoften obtained when W²-OAc is treated with a base such as lithiumdiisopropylamide, lithium hexamethyldisilamide and the like in asolvent such as tetrahydrofuran and the like to give an enolate, which is then reacted with compound [26]. While the reaction iscarried out at room temperature to under cooling, preferableresults are often obtained when the reaction is particularlycarried out at a temperature not more than 0°C.
[0254] Compound [28] can be obtained by hydrolyzing compound [27]under acidic conditions. As the acid to be used, 4N (or below)hydrochloric acid is preferable, and the reaction is carried outin tetrahydrofuran or dioxane.
[0255] Compound [29] can be obtained by treating compound [28]with a base. As the base to be used, a metal salt such aspotassium carbonate, sodium carbonate and the like, a metalamide such as lithium diisopropylamide, potassiumhexamethyldisilamide and the like, and an organic base such astriethylamine, ethyldiisopropylamine, pyridine and the like canbe mentioned, and preferable results are often obtained whentriethylamine, ethyldiisopropylamine and the like are used.There are many options of solvent, and, for example, chloroform,tetrahydrofuran, dioxane, methanol, ethanol, toluene and thelike can be mentioned, which are obviously subject to limitationdepending on the kind of a base to be used.
[0256] A step to produce compound [I]-3 from compound [29] viacompound [30] can be performed according to the aforementionedProduction method 5 and Production method 1-1 or 1-2. Production method 3-7
[0257]
[0258] Compound [32] can be synthesized by reacting compound [31]prepared by the method described in a reference (Micovic, I.V.et al., J. Chem. Soc., Perkin Trans. 1(1996) 16, 2041) or amethod analogous thereto with a compound H₂N-NH-R^y2 in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, toluene andthe like at room temperature to under heating.
[0259] Compound [I]-4 can be obtained by reacting compound [32]with oxalyl chloride in the presence of an organic base such astriethylamine, ethyldiisopropylamine, pyridine and the like in asolvent such as chloroform, tetrahydrofuran, dioxane, tolueneand the like. While the reaction temperature is subject to nolimitation, preferable results are often obtained when thereaction is carried out under cooling to room temperature. Examples
[0260] The nitrogen-containing fused ring compound represented bythe formula [I] and a pharmaceutically acceptable salt thereofof the present invention and production methods thereof are nowspecifically explained by way of Examples. However, the presentinvention is not limited by these Examples. Example 1Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0261]
[0262] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid (0.4 g) prepared according to the method described inreferences (JP-A-2-502281 (WO88/06588), J. Med. Chem., 1999, 42,4814-4823) in chloroform (30 ml) were added oxalyl chloride(0.21 ml) and dimethylformamide (0.01 ml), and the mixture wasstirred at room temperature for 30 min. The reaction solvent was evaporated under reduced pressure, toluene was added, themixture was concentrated and dissolved in chloroform (5 ml).3,4-Dichlorobenzylamine (0.23 ml) and triethylamine (0.34 ml)were added successively under ice-cooling, and the mixture wasstirred under ice-cooling for 20 min. 5% Aqueous potassiumhydrogen sulfate solution was added to the obtained reactionmixture and the mixture was extracted with chloroform. Theorganic layer was washed with saturated brine and dried oversodium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=1:1-1:8) to give N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide(0.43 g).¹H-NMR(CDCl₃)δ 9.15(t,1H,J=6.0Hz), 8.19(d,1H,J=5.8Hz), 7.54(s,1H),7.53(d,1H,J=8.4Hz), 7.31-7.20(m,5H), 6.51(d,1H,J=5.8Hz),5.17(s,2H), 4.46(d,1H,J=6.0Hz). Step 2
[0263] To a solution of N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamideobtained in the previous step intetrahydrofuran (1 ml), ethanol (1 ml) and water (0.2 ml) wereadded successively ethanolamine (0.05 ml) and 2N aqueous sodiumcarbonate solution (0.06 ml), and the mixture was stirred atroom temperature for 1 hr and at 35°C for 4 hrs. The solvent wasevaporated, and the obtained crystals were washed successivelywith ethyl acetate and water and dried to give N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(0.142 g).¹H-NMR(DMSO-d₆)δ 9.46(t,1H,J=5.8Hz), 7.60(d,1H,J=7.7Hz),7.56(d,1H,J=2.1Hz), 7.32(d,1H,J=8.3Hz), 7.30-7.27(m,5H),7.25(dd,1H,J=2.1,8.3Hz), 6.24(d,1H,J=7.7Hz), 5.05(s,2H), 5.06-5.01(m,1H),4.41(d,1H,J=5.8Hz), 3.88-3.81(m,2H), 3.65-3.57(m,2H). Step 3
[0264] To N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(0.142. g) obtained inthe previous step was added dry tetrahydrofuran (2 ml), and the mixture was cooled under an argon atmosphere at 0°C.Diisopropylethylamine (0.026 ml) and methanesulfonyl chloride(0.009 ml) were successively added dropwise at the sametemperature, and the mixture was stirred at room temperature for1 hr. Diisopropylethylamine (0.053 ml) and methanesulfonylchloride (0.019 ml) were successively added dropwise again at 0°C,and the mixture was stirred at room temperature for 1 hr. 1NAqueous hydrochloric acid was added to the obtained reactionmixture under ice-cooling, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed withsaturated brine and dried over sodium sulfate. The solvent wasevaporated and the obtained crude product was dissolved in drytetrahydrofuran (4 ml). Sodium hydride (60%) (8 mg) was added,and the mixture was heated at 80°C. Sodium hydride (60%) (8 mg)was added every 30 minutes, and after adding 5 times in total,1N aqueous hydrochloric acid was added under ice-cooling, andthe mixture was extracted three times with ethyl acetate. Theorganic layer was washed with saturated brine and dried oversodium sulfate. The solvent was evaporated and the residue waspurified by thin layer chromatography (ethylacetate:methanol=5:2) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(22 mg) .¹H-NMR(DMSO-d₆)δ 7.64(d,1H,J=7.4Hz), 7.62-7.56(m,2H), 7.51-7.46(m,2H),7.34-7.22(m,4H), 6.26(d,1H,J=7.4Hz), 5.08(s,2H),4.67(s,2H), 4.17-4.08(m,2H), 3.63-3.55(m,2H). Step 4
[0265] To 9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(12 mg) obtained in the previousstep were added acetic acid (0.75 ml) and conc. hydrochloricacid (0.15 ml) and the mixture was stirred at 90°C for 20 min.The solvent was evaporated, and the obtained residue wascrystallized from hexane:ethyl acetate=1:2 to give 2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (8 mg). ¹H-NMR(DMSO-d₆)δ 7.96(d,1H,J=7.2Hz), 7.67(d,1H,J=1.9Hz),7.62(d,1H,J=8.4Hz), 7.36(dd,1H,J=1.9,8.4Hz), 6.73(d,1H,J=7.2Hz),4.74(s,2H), 4.42-4.36(m,2H), 3.79-3.74(m,2H). Example 2Synthesis of 2-(3,4-dichlorobenzyl)-10-hydroxy-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,9-dione
[0266]
[0267] N-(3,4-Dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide(60 mg) obtained in the same manner as in Example 1,step 1 was dissolved in tetrahydrofuran (0.5 ml), ethanol (0.5ml) and water (0.1 ml), and 3-amino-1-propanol (0.0226 ml) andsodium carbonate (8 mg) were successively added. The mixturewas stirred at room temperature for 7 hr. The solvent wasevaporated, and the obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:methanol=100:0-4:1) to giveN-(3,4-dichlorobenzyl)-3-benzyloxy-1-(3-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(43 mg).¹H-NMR(DMSO-d₆)δ 9.47(t,1H,J=6.0Hz), 7.65(d,1H,J=7.4Hz),7.57(d,1H,J=1.9Hz), 7.34-7.25(m,7H), 6.26(d,1H,J=7.4Hz),5.05(s,2H), 4.65(t,1H,J=4.9Hz), 4.42(d,2H,J=6.0Hz),3.86(dd,2H,J=7.2,7.2Hz), 3.35(dd,2H,J=6.3,10.9Hz), 1.84-1.77(m,2H). Step 2
[0268] N-(3,4-Dichlorobenzyl)-3-benzyloxy-1-(3-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(30 mg) obtained in theprevious step was dissolved in tetrahydrofuran (1.5 ml) and themixture was cooled to 0°C under an argon atmosphere.Diisopropylethylamine (0.034 ml) and methanesulfonyl chloride(0.0065 ml) were successively added dropwise at the sametemperature and the mixture was stirred at room temperature for2 hr. Diisopropylethylamine (0.017 ml) and methanesulfonylchloride (0.005 ml) were successively added dropwise again at 0°C,and the mixture was stirred at room temperature for 1.5 hr. Tothe obtained reaction mixture was added 1N aqueous hydrochloricacid under ice-cooling, and the mixture was extracted twice withethyl acetate. The combined organic layer was washedsuccessively with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over sodium sulfate. Thesolvent was evaporated and the obtained crude product wasdissolved in tetrahydrofuran (1.5 ml). Sodium hydride (60%)(5mg) was added at room temperature, and sodium hydride (60%)(8mg) was added every 30 minutes. After adding 3 times in total,1N aqueous hydrochloric acid was added under ice-cooling, andthe mixture was extracted twice with ethyl acetate. Thecombined organic layer was washed successively with saturatedaqueous sodium hydrogen carbonate solution and saturated brineand dried over sodium sulfate. The solvent was evaporated, andthe obtained residue was purified by thin layer chromatography(ethyl acetate:methanol=2:1) to give 10-benzyloxy-2-(3,4-dichlorobenzyl)-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,9-dione(23 mg).¹H-NMR(CDCl₃)δ 7.49-7.46(m,3H), 7.39(d,1H,J=8.3Hz), 7.30-7.26(m,3H),7.22(dd,1H,J=2.3,8.3Hz), 7.09(d,1H,J=7.5Hz),6.46(d,1H,J=7.5Hz), 5.69(d,1H,J=10.9Hz), 5.06(d,1H,J=10.9Hz),4.71(d,1H,J=14.7Hz), 4.48(d,1H,J=14.7Hz), 3.82-3.77(m,2H),3.07(dd,1H,J=6.8,15.5Hz), 2.96-2.85(m,1H), 1.92-1.79(m,1H),1.74-1.61(m,1H). Step 3
[0269] 10-Benzyloxy-2-(3,4-dichlorobenzyl)-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,9-dione(15 mg) obtainedin the previous step was dissolved in trifluoroacetic acid (1.0ml), and the mixture was stirred at room temperature for 30 minand then at 60°C for 1.5 hr. The solvent was evaporated, toluenewas added, and the mixture was concentrated, which operationswere performed 3 times. Ethyl acetate was added and the mixturewas concentrated, which operations were performed 2 times. Theobtained residue was crystallized from ethyl acetate/hexane togive 2-(3,4-dichlorobenzyl)-10-hydroxy-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,9-dione(11 mg).¹H-NMR(DMSO-d₆)δ 7.79(brs,1H), 7.66(d,1H,J=8.3Hz),7.65(d,1H,J=2.3Hz), 7.38(dd,1H,J=2.3,8.3Hz), 6.50(brs,1H),4.68(brs,2H), 4.10(brs,2H), 3.33(bt,2H,J=6.4Hz),1.94(bt,2H,J=6.4Hz). Example 3Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0270]
[0271] N-(3,4-Dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide(50 mg) obtained in the same manner as in Example 1,Step 1 was dissolved in tetrahydrofuran (0.5 ml), ethanol (0.5 ml) and water (0.1 ml). DL-1-Amino-2-propanol (0.0191 ml) andsodium carbonate (7 mg) were successively added, and the mixturewas stirred overnight at room temperature. The solvent wasevaporated, and the obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:methanol=100:0-4:1) to giveN-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(34 mg).¹H-NMR(DMSO-d₆)δ 9.43(t,1H,J=6.3Hz), 7.57(s,1H),7.57(d,1H,J=7.4Hz), 7.36(d,1H,J=8.1Hz), 7.31-7.26(m,6H),6.23(d,1H,J=7.4Hz), 5.08(d,1H,J=10.9Hz), 5.04(d,1H,J=10.9Hz),5.02(d,1H,J=6.3Hz), 4.44(dd,1H,J=6.3,14.8Hz),4.37(dd,1H,J=6.3,14.8Hz), 3.81(brs,1H), 3.69(dd,1H,J=3.7,14.4Hz),3.60(dd,1H,J=8.8,14.4Hz), 0.94(d,3H,J=6.3Hz). Step 2
[0272] N-(3,4-Dichlorobenzyl)-3-benzyloxy-1-(2-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(34 mg) obtained in theprevious step was dissolved in tetrahydrofuran (1.5 ml) and themixture was cooled to 0°C under an argon atmosphere.Diisopropylethylamine (0.0385 ml) and methanesulfonyl chloride(0.0074 ml) were successively added dropwise at the sametemperature, and the mixture was stirred at room temperature for1 hr. Diisopropylethylamine (0.0385 ml) and methanesulfonylchloride (0.0074 ml) were successively added dropwise at 0°C andthe mixture was stirred at room temperature for 1.5 hr. To theobtained reaction mixture was added 1N aqueous hydrochloric acidunder ice-cooling, and the mixture was extracted twice withethyl acetate. The combined organic layer was washedsuccessively with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over sodium sulfate.The solvent was evaporated and the obtained crude product wasdissolved in tetrahydrofuran (1.5 ml). Sodium hydride (60%) (5mg) was added at room temperature, and sodium hydride (60%) (8mg) was added every 30 minutes. After adding 3 times in total,1N aqueous hydrochloric acid was added under ice-cooling, andthe mixture was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturatedaqueous sodium hydrogen carbonate solution and saturated brine,and dried over sodium sulfate. The solvent was evaporated, andthe obtained residue was purified by thin layer chromatography(ethyl acetate:methanol=2:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (8 mg).¹H-NMR(CDCl₃)δ 7.62-7.59(m,2H), 7.45-7.42(m,2H), 7.35-7.27(m,3H),7.20(dd,1H,J=2.3,8.3Hz), 7.13(d,1H,J=7.5Hz), 6.52(d,1H,J=7.5Hz),5.58(d,1H,J=10.2Hz), 5.25(d,1H,J=14.7Hz), 5.24(d,1H,J=10.2Hz),4.09(dd,1H,J=3.8,12.8Hz), 3.97(d,1H,J=14.7Hz), 3.62-3.58(m,2H),1.04(d,3H,J=6.8Hz). Step 3
[0273] 9-Benzyloxy-2-(3,4-dichlorobenzyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(8 mg) obtained in theprevious step was dissolved in trifluoroacetic acid (1.0 ml) andthe mixture was stirred at 60°C for 1.5 hr. The solvent wasevaporated, toluene was added, and the mixture was concentrated,which operations were performed 3 times. Ethyl acetate wasadded and the mixture was concentrated, which operations wereperformed twice. The obtained residue was crystallized fromethyl acetate/hexane to give 2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(6 mg).¹H-NMR(DMSO-d₆)δ 7.84(brs,1H), 7.70(d,1H,J=1.9Hz),7.63(d,1H,J=8.4Hz), 7.40(dd,1H,J=1.9,8.4Hz), 6.57(brs,1H),5.03(d,1H,J=15.3Hz), 4.45(d,1H,J=15.3Hz), 4.42-4.39(m,1H), 4.22-4.19(m,1H),4.00(m,1H), 1.18(d,3H,J=6.5Hz). Example 4Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0274]
[0275] 2-tert-Butoxycarbonylamino-2-methylpropionic acid (2 g)was dissolved in tetrahydrofuran (20 ml), and 3,4-dichlorobenzylamine(1.2 ml), 1-hydroxybenzotriazole (1.81 g)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.26 g) wereadded. The mixture was stirred at room temperature for 1 hr.To the obtained reaction mixture was added saturated aqueoussodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washedsuccessively with saturated aqueous sodium hydrogen carbonatesolution, 5% aqueous potassium hydrogen sulfate solution andsaturated brine and dried over sodium sulfate. The solvent wasevaporated, and the obtained solid was washed with ethylacetate/hexane and collected by filtration to give crudecrystals (2.98 g) of tert-butyl [1-(3,4-dichlorobenzylcarbamoyl)-1-methylethyl]carbamate. Step 2
[0276] The crude crystals (1.0 g) of tert-butyl [1-(3,4-dichlorobenzylcarbamoyl)-1-methylethyl]carbamateobtained in theprevious step was dissolved in tetrahydrofuran (5 ml) and cooledto 0°C under an argon atmosphere. A borane - tetrahydrofurancomplex (1.0 M/tetrahydrofuran solution)(15 ml) was addeddropwise at the same temperature, removed from an ice-bath andstirred at room temperature for 2 hr. A borane -tetrahydrofuran complex (1.0 M/tetrahydrofuran solution)(5 ml)was added every 30 minutes twice in total. To the obtained reaction mixture was added methanol (10 ml) under ice-cooling,and the solvent was evaporated. The obtained residue wasdissolved in tetrahydrofuran (10 ml) and 1N aqueous sodiumhydroxide solution (4 ml) and the mixture was stirred at 90°C for1 hr. The obtained reaction mixture was extracted twice withtoluene, and the combined organic layer was washed withsaturated brine and dried over sodium sulfate. The solvent wasevaporated and the obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=1:1) to give tert-butyl[2-(3,4-dichlorobenzylamino)-1,1-dimethylethyl]carbamate(290 mg).¹H-NMR(DMSO-d₆)δ 7.59(d,1H,J=1.9Hz), 7.56(d,1H,J=8.3Hz),7.31(dd,1H,J=1.9,8.3Hz), 6.20(brs,1H), 3.69(brs,2H),2.48(brs,2H), 2.17(brs,1H), 1.35(s,9H), 1.16(s,6H).
[0277] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid (150 mg) obtained in the same manner as in Example 1, Step1 in chloroform (3 ml) were added oxalyl chloride (0.069 ml) anddimethylformamide (0.005 ml) and the mixture was stirred at roomtemperature for 1 hr. The reaction solvent was evaporated underreduced pressure. Toluene was added and the mixture wasconcentrated, which operations were performed twice and theresidue was dissolved in chloroform (2 ml). This solution wasadded dropwise under ice-cooling to a solution of tert-butyl [2-(3,4-dichlorobenzylamino)-1,1-dimethylethyl]carbamate (192 mg)obtained in Step 2 and triethylamine (0.11 ml) in chloroform (3ml), and the mixture was stirred under ice-cooling for 1 hr. 5%Aqueous potassium hydrogen sulfate solution was added to theobtained reaction mixture and the mixture was extracted withchloroform. The organic layer was washed successively withsaturated aqueous sodium hydrogen carbonate solution andsaturated brine and dried over sodium sulfate. The solvent wasevaporated and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1) to give crude tert-butyl{2-[N-(3-benzyloxy-4-oxo-4H-pyran-2-carbonyl)-N-(3,4-dichlorobenzyl)amino]-1,1-dimethylethyl}carbamate(270 mg). Step 4
[0278] Crude tert-butyl {2-[N-(3-benzyloxy-4-oxo-4H-pyran-2-carbonyl)-N-(3,4-dichlorobenzyl)amino]-1,1-dimethylethyl}carbamate(90 mg) obtained in the previous stepwas dissolved in 4N hydrochloric acid/dioxane solution (2 ml)and the mixture was stirred at room temperature for 30 min. Thesolvent was evaporated and azeotropic distillation withchloroform was performed 3 times. The obtained residue wasdissolved in ethanol (3 ml) and saturated aqueous sodiumcarbonate solution (1.5 ml) and stirred at 50°C for 30 min.Water was added to the obtained reaction mixture and the mixturewas extracted twice with ethyl acetate. The combined organiclayer was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated and the obtained residuewas purified by thin layer chromatography (ethylacetate:methanol=3:2) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(50 mg).¹H-NMR(CDCl₃)δ 7.65(dd,2H,J=1.5,7.9Hz), 7.46(d,1H,J=1.9Hz),7.45(d,1H,J=8.3Hz), 7.37-7.29(m,4H), 7.22(dd,1H,J=1.9,8.3Hz),6.50(d,1H,J=7.5Hz), 5.37(s,2H), 4.65(s,2H), 3.26(s,2H),1.39(s,6H). Step 5
[0279] 9-Benzyloxy-2-(3,4-dichlorobenzyl)-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(30 mg) obtained inthe previous step was dissolved in trifluoroacetic acid (2.0 ml)and the mixture was stirred at 65°C for 2 hr. The solvent wasevaporated, toluene was added and the mixture was concentrated,which operations were performed 3 times. Ethyl acetate wasadded and the mixture was concentrated, which operations wereperformed twice. The obtained residue was crystallized fromdiisopropyl ether to give 2-(3,4-dichlorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(22 mg).¹H-NMR(DMSO-d₆)δ 7.96(bd,1H,J=7.9Hz), 7.68(d,1H,J=1.9Hz),7.65(d,1H,J=8.1Hz), 7.40(dd,1H,J=1.9,8.1Hz), 6.49(brs,1H),4.74 (s,2H), 3.67(s,2H), 1.44(s,6H). Example 5Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0280]
[0281] tert-Butyl N-(2-aminoethyl)carbamate (1.51 g) wasdissolved in chloroform (20 ml) and 3,4-dichlorobenzaldehyde(1.65 g), acetic acid (0.54 ml) and sodium triacetoxyborohydride(2.6 g) were added at room temperature. The mixture was stirredovernight. Saturated aqueous sodium hydrogen carbonate solutionwas added to the obtained reaction mixture and the mixture wasstirred and extracted three times with chloroform. The combinedorganic layer was washed with saturated brine and dried oversodium sulfate. The solvent was evaporated and the obtainedresidue was purified by silica gel column chromatography(chloroform:methanol=9:1) to give tert-butyl [2-(3,4-dichlorobenzylamino)ethyl]carbamate(2.1 g).¹H-NMR(DMSO-d₆)δ 7.59(d,1H,J=1.9Hz), 7.56(d,1H,J=8.3Hz),7.31(dd,1H,J=1.9,8.3Hz), 6.73(brs,1H), 3.67(brs,2H), 3.00(bdd,2H,J=6.0,12.4Hz), 2.47(m,2H), 2.27(brs,1H), 1.37(s,9H).
[0282] Kojic acid (5 g) was dissolved in chloroform (50 ml) andtriethylamine (7.4 ml) and dimethylaminopyridine (5 mg) wereadded. Then tert-butyldimethylsilyl chloride (5.3 g) was addedunder ice-cooling, and the mixture was stirred at the sametemperature for 1 hr. To the obtained reaction mixture wasadded 5% aqueous potassium hydrogen sulfate solution, and themixture was extracted with chloroform. The organic layer waswashed with saturated aqueous sodium hydrogen carbonate solutionand saturated brine, and dried over sodium sulfate. The solventwas evaporated and the obtained residue was dissolved inchloroform (50 ml). Diisopropylethylamine (8.0 ml) was addedand chloromethyl methyl ether (3.2 ml) was added. The mixturewas stirred under ice-cooling for 30 min. The ice-bath wasremoved and the mixture was stirred overnight at roomtemperature. 5% Aqueous potassium hydrogen sulfate solution wasadded to the obtained reaction mixture and the mixture wasextracted with chloroform. The organic layer was washed withsaturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over sodium sulfate. The solvent wasevaporated and the obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=4:1-2:1) to give 5-(tert-butyldimethylsilyloxy)-2-methoxymethoxymethyl-4H-pyran-4-one (5.5 g).¹H-NMR(DMSO-d₆)δ 8.19(s,1H), 6.41(s,1H), 4.66(s,2H), 4.39(s,2H),3.28(s,3H), 0.92(s,9H), 0.16(s,6H). Step 3
[0283] 5-(tert-Butyldimethylsilyloxy)-2-methoxymethoxymethyl-4H-pyran-4-one(5.5 g) obtained in the previous step was dissolvedin tetrahydrofuran (30 ml), tetra(n-butyl)ammonium fluoride (1.0M/tetrahydrofuran solution)(19.2 ml) was added under ice-coolingand the mixture was stirred for 30 min. 5% Aqueous potassiumhydrogen sulfate solution was added to the obtained reactionmixture to adjust to pH=3, and the mixture was extracted 4 timeswith ethyl acetate. The combined organic layer was washed withsaturated brine and dried over sodium sulfate. The solvent wasevaporated and the obtained solid was washed with ethylacetate/hexane. The obtained solid (2.3 g) was dissolved inwater (20 ml) and 1N aqueous sodium hydroxide solution (12.7 ml).36% Aqueous formaldehyde solution was added at room temperatureand the mixture was stirred for 6 hr. 5% Aqueous potassiumhydrogen sulfate solution was added to the obtained reactionmixture to adjust to pH=3, and sodium chloride was added. Themixture was extracted 5 times with ethyl acetate, and thecombined organic layer was washed with saturated brine and driedover sodium sulfate. The solvent was evaporated and theobtained residue was dissolved in dimethylformamide (10 ml).Potassium carbonate (1.97 g) was added and benzyl chloride (0.82ml) was added at room temperature, and the mixture was stirredovernight. 5% Aqueous potassium hydrogen sulfate solution wasadded to the obtained reaction mixture to adjust to pH=3, andthe mixture was extracted three times with ethyl acetate. Thecombined organic layer was washed with saturated brine and driedover sodium sulfate. The solvent was evaporated and theobtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1-1:4) to give 3-benzyloxy-2-hydroxymethyl-6-methoxymethoxymethyl-4H-pyran-4-one(783 mg). ¹H-NMR(DMSO-d₆)δ 7.47-7.32(m,5H), 6.43(s,1H), 5.48(t,1H,J=6.0Hz),5.03(s,2H), 4.68(s,2H), 4.40(s,2H), 4.28(d,2H,J=6.0Hz),3.29(s,3H). Step 4
[0284] 3-Benzyloxy-2-hydroxymethyl-6-methoxymethoxymethyl-4H-pyran-4-one(783 mg) obtained in the previous step was dissolvedin acetone (8.0 ml) and saturated aqueous sodium hydrogencarbonate solution (8.0 ml), and potassium bromide (30 mg) and2,2,6,6-tetramethylpiperidine 1-oxyl, free radical (39 mg) wereadded, and 6% aqueous sodium hypochlorite solution (3.4 ml) wasadded dropwise under ice-cooling. The mixture was stirred for30 min and 6% aqueous sodium hypochlorite solution (3.3 ml) wasfurther added dropwise. The mixture was further stirred for 30min. Water was added to the obtained reaction mixture andwashed twice with ethyl acetate. 5% Aqueous potassium hydrogensulfate solution was added to the aqueous layer to adjust topH=3, and the mixture was extracted twice with ethyl acetate.The combined organic layer was washed with saturated brine anddried over sodium sulfate. The solvent was evaporated to give3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carboxylicacid (710 mg).¹H-NMR(DMSO-d₆)δ 7.44-7.30(m,5H), 6.54(s,1H), 5.11(s,2H),4.65(s,2H), 4.43(s,2H), 3.27(s,3H).
[0285] 3-Benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carboxylicacid (658 mg) obtained in Step 4 was dissolved indimethylformamide (5 ml), and tert-butyl [2-(3,4-dichlorobenzylamino)ethyl]carbamate(596 mg) obtained in Step 1,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (429 mg) and 1-hydroxybenzotriazole(343 mg) were added at room temperature,and the mixture was stirred for 1 hr. Saturated aqueous sodiumhydrogen carbonate solution was added to the obtained reactionmixture and the mixture was extracted twice with ethyl acetate.The combined organic layer was washed with saturated brine anddried over sodium sulfate. The solvent was evaporated and theobtained residue was purified by silica gel columnchromatography (chloroform:methanol=15:1) to give crude tert-butyl{2-[N-(3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carbonyl)-N-(3,4-dichlorobenzyl)amino]ethyl}carbamate(1.12 g). Step 6
[0286] The crude tert-butyl {2-[N-(3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carbonyl)-N-(3,4-dichlorobenzyl)amino]ethyl}carbamate(1.12 g) obtained in theprevious step was dissolved in 4N hydrochloric acid/dioxanesolution (10 ml) and the mixture was stirred at room temperaturefor 30 min. The solvent was evaporated, toluene was added, andthe mixture was concentrated, which operations were performed 3times. The obtained residue was dissolved in ethanol (40 ml)and saturated aqueous sodium carbonate solution (10 ml), and themixture was stirred at 50°C for 30 min. The solvent wasevaporated, and the resulting crystals were washed with 5%aqueous potassium hydrogen sulfate solution and a small amountof ethyl acetate, and collected by filtration to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(433 mg).¹H-NMR(DMSO-d₆)δ 7.64(d,1H,J=1.5Hz), 7.63(d,1H,J=8.3Hz),7.51(dd,2H,J=1.5,8.3Hz), 7.37-7.29 (m,4H), 6.40(s,1H),5.67(t,1H,J=5.7Hz), 5.08(s,2H), 4.68(s,2H), 4.43(d,2H,J=5.7Hz),4.10-4.04(m,2H), 3.63-3.57(m,2H). Step 7
[0287] 9-Benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(15 mg) obtained inthe previous step was dissolved in trifluoroacetic acid (1 ml)and the mixture was stirred at room temperature for 1 hr. Thesolvent was evaporated, toluene was added, and the mixture wasconcentrated, which operations were performed 3 times. Ethylacetate was added and the mixture was concentrated, whichoperations were performed twice. The obtained residue wascrystallized from ethyl acetate/diisopropyl ether to give 2-(3,4-dichlorobenzyl)-9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(12 mg).¹H-NMR(DMSO-d₆)δ 12.20(brs,1H), 7.66(d,1H,J=1.9Hz),7.62(d,1H,J=8.1Hz), 7.36(dd,2H,J=1.9,8.1Hz), 6.25(s,1H),5.65(t,1H,J=5.6Hz), 4.71(s,2H), 4.41(d,2H,J=5.6Hz), 4.15-4.13(m,2H),3.68-3.65(m,2H). Example 6Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylicacid
[0288]
[0289] 9-Benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(100 mg) obtained inExample 5, Step 6 was dissolved in acetone (1.6 ml) andsaturated aqueous sodium hydrogen carbonate solution (1.0 ml)and potassium bromide (3 mg) and 2,2,6,6-tetramethylpiperidine1-oxyl, free radical (3 mg) were added, and 6% aqueous sodiumhypochlorite solution (3.4 ml) was added dropwise under ice-cooling.After stirring for 15 min, the ice bath was removedand the mixture was stirred at room temperature for 4 hr.Furthermore, 6% aqueous sodium hypochlorite solution (0.1 ml) was added dropwise and the mixture was stirred for 1.5 hr. Theobtained reaction mixture was poured into 5% aqueous potassiumhydrogen sulfate solution and stirred for 30 min. The resultingcrystals were collected by filtration to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylicacid (94 mg).¹H-NMR(DMSO-d₆)δ 7.64(d,1H,J=1.9Hz), 7.62(d,1H,J=8.4Hz),7.49(dd,2H,J=1.9,8.4Hz), 7.36-7.29(m,4H), 6.70(s,1H), 5.11(s,2H),4.67(s,2H), 4.26-4.24(m,2H), 3.59-3.56(m,2H). Step 2
[0290] 9-Benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylicacid (25 mg)obtained in the previous step was dissolved in trifluoroaceticacid (2 ml) and the mixture was stirred at room temperature for1 hr. The solvent was evaporated, toluene was added, and themixture was concentrated, which operations were performed 3times. Methanol was added and the mixture was concentrated.Ethyl acetate was added and the mixture was concentrated. Theobtained residue was crystallized from methanol/ethyl acetate togive 2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylicacid (20 mg).¹H-NMR(DMSO-d₆)δ 7.69(d,1H,J=2.2Hz), 7.64(d,1H,J=8.4Hz),7.39(dd,2H,J=2.2,8.4Hz), 6.58(s,1H), 4.73(s,2H), 4.44-4.41(m,2H),3.71-3.68(m,2H). Example 7Synthesis of 2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0291]
[0292] To a solution of 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(860 mg) obtained in Example 5, Step 6 in chloroform (80 ml) wasadded Dess-Martin reagent (843 mg). After stirring at roomtemperature for 1 hr, the solvent was evaporated and chloroform(50 ml) was added to the obtained residue and a solid productwas filtered off. The filtrate was concentrated and purified bysilica gel column chromatography (chloroform:acetone=1:2) togive 9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carbaldehyde(621 mg).¹H-NMR(CDCl₃)δ 9.58(s,1H), 7.62-7.55(m,2H), 7.46-7.40(m,2H),7.37-7.26(m,3H), 7.16(dd,1H,J=2.0,8.1Hz), 6.97(s,1H), 5.39(s,2H),4.65(s,2H), 4.43-4.37(m,2H), 3.43-3.36(m,2H). Step 2
[0293] A solution of 9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carbaldehyde(205 mg) obtained in the previous step in dry tetrahydrofuran(40 ml) was cooled in a dry ice - acetone bath. tert-Butylmagnesiumchloride (2.0 M/diethyl ether solution) (0.448ml) was added dropwise at the same temperature and the mixturewas stirred for 30 min. Then 5% aqueous potassium hydrogensulfate solution was added to adjust to pH=2, and the mixturewas extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography (chloroform:methanol=12:1) to give crude 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(1-hydroxy-2,2-dimethylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(220 mg).
[0294] To a solution of the above-mentioned crude 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(1-hydroxy-2,2-dimethylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(132 mg) inchloroform (4 ml) was added Dess-Martin reagent (65 mg) and themixture was stirred at room temperature for 20 min. Saturatedaqueous sodium hydrogen carbonate solution and sodium sulfitewere added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over sodium sulfate. The solvent wasevaporated and the residue was purified by silica gel columnchromatography (ethyl acetate:chloroform=4:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(38 mg).¹H-NMR(CDCl₃)δ 7.63-7.57(m,2H), 7.46-7.38(m,2H), 7.37-7.26(m,3H),7.15(dd,1H,J=2.1,8.1Hz), 6.42(s,1H), 5.38(s,2H), 4.63(s,2H),3.69-3.61(m,2H), 3.43-3.36(m,2H), 1.27(s,9H). Step 3
[0295] To 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(36 mg) obtained in the previous step was addedtrifluoroacetic acid (4 ml) and the mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, toluene wasadded, and the mixture was concentrated, which operations wereperformed twice. The obtained residue was crystallized fromethyl acetate:diisopropyl ether=1:4 to give 2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(26 mg).¹H-NMR(DMSO-d₆)δ 12.40(brs,1H), 7.68(d,1H,J=2.1Hz),7.62(d,1H,J=8.4Hz), 7.38(dd,1H,J=2.1,8.4Hz), 6.15(s,1H), 4.71(s,2H), 3.92-3.85(m,2H), 3.67-3.59(m,2H), 1.22(s,9H). Example 8Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0296]
[0297] To a solution of N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide(49 mg) obtained in the same manner as inExample 1, Step 1 in tetrahydrofuran (0.5 ml), ethanol (0.5 ml)and water (0.1 ml) were successively added aminoacetaldehydedimethyl acetal (0.026 ml) and sodium carbonate (6.4 mg), andthe mixture was stirred at room temperature for 1 hr and then at45°C for 4 hr, and at 60°C for 20 hr. The solvent was evaporatedand the residue was purified by silica gel column chromatography(ethyl acetate:methanol=100:0-5:1) to give N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(30 mg).¹H-NMR(CDCl₃)δ 7.35(d,1H,J=2.0Hz), 7.30-7.20(m,7H),7.09(t,1H,J=6.3Hz), 7.05(dd,1H,J=2.0,8.0Hz), 6.33(d,1H,J=7.4Hz),5.20(s,2H), 4.51(t,1H,J=5.1Hz), 4.32(d,2H,J=6.3Hz),3.86(d,1H,J=5.1Hz), 3.31(s,6H). Step 2
[0298] To a solution of N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(30mg) obtained in the previous step in toluene (3 ml) was addedcamphorsulfonic acid (15 mg) and the mixture was stirred at 110°Cfor 30 min. A saturated aqueous sodium hydrogen carbonatesolution was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The organic layers werecombined, washed with saturated brine, and dried over sodiumsulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography (ethylacetate:methanol=5:1-4:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione(17 mg).¹H-NMR(CDCl₃)δ 7.63(d,1H,J=7.4Hz), 7.43(d,1H,J=8.4Hz),7.39(d,1H,J=2.0Hz), 7.38-7.25(m,5H), 7.15(dd,1H,J=2.0,8.4Hz),6.70(d,1H,J=7.4Hz), 6.41(d,1H,J=6.3Hz), 6.20(d,1H,J=6.3Hz),5.39(s,2H), 4.89(s,2H). Step 3
[0299] To 9-benzyloxy-2-(3,4-dichlorobenzyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione(16 mg) obtained in the previous step wasadded trifluoroacetic acid (2 ml) and the mixture was stirred atroom temperature for 1 hr. The solvent was evaporated, toluenewas added, and the mixture was concentrated, which operationswere performed twice. The obtained residue was crystallizedfrom diisopropyl ether to give 2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione(9 mg).¹H-NMR(DMSO-d₆)δ 8.11(d,1H,J=7.3Hz), 7.71(d,1H,J=1.8Hz),7.66(d,1H,J=8.4Hz), 7.40(dd,1H,J=1.8,8.4Hz), 7.35(d,1H,J=6.2Hz),7.03(d,1H,J=6.2Hz), 6.76(d,1H,J=7.3Hz), 4.99(s,2H). Example 9Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0300]
[0301] To a solution of N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide(0.04 g) obtained in the same manner asin Example 1, Step 1 in tetrahydrofuran (3 ml) were added 1-amino-2-propanol(0.224g) and saturated aqueous sodium hydrogencarbonate solution (1 ml), and the mixture was stirred at 60°Cfor 4 hr. The reaction solvent was evaporated under reducedpressure, and ethyl acetate was added to the residue. Themixture was washed successively with 1N aqueous hydrochloricacid solution and saturated brine. After drying over magnesiumsulfate, the solvent was evaporated and the residue was purifiedby silica gel column chromatography (chloroform:methanol=20:1)to give N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(0.334g).¹H-NMR(DMSO-d₆)δ 9.45(t,1H), 7.58-7.56(m,2H), 7.37-7.23(m,7H),6.62(d,1H,J=5.7Hz), 5.09-5.05(m,3H), 4.50-4.31(m,4H), 3.81-3.42(m,4H),0.92(d,3H,J=5.7Hz). Step 2
[0302] N-(3,4-Dichlorobenzyl)-3-benzyloxy-1-(2-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(0.250 g) obtained in theprevious step was dissolved in chloroform (10 ml), Dess-Martinreagent (0.5 g) was added, and the mixture was stirred overnightat room temperature. The obtained reaction mixture was washedwith saturated aqueous sodium hydrogen carbonate solution anddried over magnesium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography(chloroform:methanol=10:1) to give crude crystals (0.304 g) ofN-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-1-(2-oxopropyl)-1,4-dihydropyridine-2-carboxamide.The crude crystals weredissolved in tetrahydrofuran-toluene (5:2, 7 ml), p-toluenesulfonicacid (0.03 g) was added, and the mixture wasstirred at 80°C for 10 hr. The obtained reaction mixture waspurified by silica gel column chromatography(chloroform:methanol=10:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-3-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione (0.063 g).¹H-NMR(DMSO-d₆)δ 7.93(d,1H,J=5.7Hz), 7.84-7.69(m,4H), 7.32-7.20(m,4H),7.03(s,1H), 6.62(d,1H,J=5.7Hz), 5.12(s,2H),5.07(s,2H), 2.01(s,3H). Step 3
[0303] 9-Benzyloxy-2-(3,4-dichlorobenzyl)-3-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione(0.063 g) obtained in the previous step wasdissolved in trifluoroacetic acid (2 ml) and the mixture wasstirred at room temperature for 3 hr. Thereafter, the reactionmixture was subjected to azeotropic distillation 3 times withtoluene. Crystallization from ethyl acetate - diisopropyl ethergave 2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione(0.05 g).¹H-NMR(DMSO-d₆)δ 8.19(d,1H,J=10Hz), 7.64-7.61(m,2H), 7.44(s,1H),7.33(dd,1H,J=7.3,11.2Hz), 7.05(d,1H,J=9.6Hz), 5.21(s,2H),2.12(s,3H). Example 10Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0304]
[0305] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid (3.00 g) in chloroform (30 ml) were added oxalyl chloride (2.00 g) and dimethylformamide (50 µl) and the mixture wasstirred at room temperature for 30 min. The solvent wasevaporated from the reaction mixture, toluene was added and themixture was concentrated to give acid chloride. To a solutionof 3-chlorobenzylamine (1.90 g) in chloroform (30 ml) was addedtriethylamine (1.85 g) and a solution of the above-mentionedacid chloride in chloroform (30 ml) was added dropwise withstirring the mixture at 0°C. After stirring at 0°C for 30 min,saturated aqueous sodium hydrogen carbonate solution (40 ml) wasadded to the reaction mixture, and the mixture was warmed toroom temperature and the organic layer was separated. Theaqueous layer was extracted with chloroform. The organic layerswere combined, washed with saturated brine, and dried oversodium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=1:1-1:2) to give 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (3.90 g).¹H-NMR(CDCl₃)δ 8.08(brs,1H), 7.84(d,1H,J=5.5Hz), 7.37-7.20 (m,7H),7.15(m,1H), 7.05(m,1H), 5.38(s,2H), 4.37(d,2H,J=5.8Hz). Step 2
[0306] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (1.20 g) obtained in the previous stepin toluene (120 ml) were added pyridinium p-toluenesulfonate(815 mg) and 2-amino-3-methylbutanol (702 mg) and the mixturewas stirred at 110°C for 15 hr. 2-Amino-3-methylbutanol (833 mg)was added and the mixture was further stirred at 110°C for 30 hr.The solvent was evaporated from the reaction mixture, saturatedaqueous sodium carbonate solution (30 ml) was added and themixture was extracted twice with chloroform. The organic layerwas washed with saturated brine and dried over sodium sulfate.The solvent was evaporated and the residue was purified bysilica gel column chromatography (ethyl acetate-chloroform:methanol=10:1)to give a crude product containing N-(3-chlorobenzyl)-3-benzyloxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxamideas a main component. The total amount of this crude product was used in the next stepwithout further purification. Step 3
[0307] To a solution of crude product of N-(3-chlorobenzyl)-3-benzyloxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxamideobtained in the previous step indimethyl sulfoxide (8.5 ml) were successively addedtriethylamine (1.60 g) and sulfur trioxide pyridine complex (900mg) and the mixture was stirred at room temperature for 20 min.1M Hydrochloric acid (50 ml) was added to the reaction mixtureand the mixture was extracted twice with ethyl acetate. Theorganic layer was washed successively with water and saturatedbrine, and dried over sodium sulfate. The solvent wasevaporated and the residue was purified by silica gel columnchromatography (chloroform:methanol=100:1-20:1) to give 9-benzyloxy-2-(3-chlorobenzyl)-3-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(202 mg).¹H-NMR(DMSO-d₆)δ 7.70(d,1H,J=7.4Hz), 7.53-7.46(m,3H), 7.40-7.27(m,5H),6.83(d,1H,J=5.6Hz), 29(d,1H,J=7.4Hz), 5.12-5.02(m,4H),4.31(d,1H,J=14.6Hz), 3.83(dd,1H,J=10.0,1.5Hz),1.41(m,1H), 0.66(d,3H,J=6.7Hz), 0.55(d,3H,J=6.5Hz). Step 4
[0308] To 9-benzyloxy-2-(3-chlorobenzyl)-3-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(200 mg) obtainedin the previous step were successively added acetic acid (5 ml)and conc. hydrochloric acid (5 ml) and the mixture was stirredat 90°C for 15 hr. The solvent was evaporated from the reactionmixture, toluene was added and the mixture was concentrated.Crystallization from diisopropyl ether-ethyl acetate gave 2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (164 mg).¹H-NMR(DMSO-d₆)δ 13.0(brs,1H), 8.52(d,1H,J=7.4Hz), 7.50(s,1H),7.43-7.35(m,3H), 7.25(m,1H), 7.22(s,1H), 5.13(s,2H),3.25(Hept,1H,J=6.7Hz), 1.25(d,6H,J=6.7Hz). Example 11Synthesis of 2-[3-(2,6-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0309]
[0310] Lithium aluminum hydride (1.31 g) was suspended intetrahydrofuran (30 ml) and 3-(2,6-dichlorophenyl)acrylic acid(4.62 g) was added dropwise under ice-cooling over about 20 min.During the dropwise addition, tetrahydrofuran (20 ml) was added.After stirring at 0°C for 3.5 hr, the mixture was stirred at roomtemperature for 18 hr. 4N Aqueous potassium hydroxide solutionwas added to the reaction mixture and a solid component wasfiltered off. The filtrate was concentrated under reducedpressure, and to the residue was added 1N aqueous hydrochloricacid solution. The mixture was extracted twice with ethylacetate, and the organic layer was washed with saturated brineand dried over sodium sulfate. The solvent was evaporated togive a crude product (5.40 g) of 3-(2,6-dichlorophenyl)propan-1-ol. Step 2
[0311] To a solution of triphenylphosphine (6.14 g), phthalimide(3.44 g) and 3-(2,6-dichlorophenyl)propan-1-ol (crude product:5.40 g) obtained in the previous step in tetrahydrofuran (90 ml)was added dropwise diethyl azodicarboxylate (40% toluenesolution)(10.19 g) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was concentratedunder reduced pressure. Diethyl ether was added to the residueand precipitated solid component was filtered off. The filtratewas concentrated. Diethyl ether was added again to the obtainedresidue and the precipitated solid component was filtered off.The filtrate was concentrated and purified by silica gel columnchromatography (chloroform-hexane:ethyl acetate=4:1) to give acrude product (4.28 g) of 2-[3-(2,6-dichlorophenyl)propyl]isoindole-1,3-dione. Step 3
[0312] To a solution of 2-[3-(2,6-dichlorophenyl)propyl]isoindole-1,3-dione(crude product :4.28g) obtained in the previous step in ethanol (50 ml) was addedhydrazine monohydrate (2.79 ml) and the mixture was heated underreflux for 1 hr. The reaction mixture was cooled to roomtemperature, and 10% aqueous sodium carbonate solution (90 ml)was added. The mixture was extracted with chloroform (100 ml×2).The organic layer was washed with water and dried over sodiumsulfate. The solvent was evaporated to give a crude product(3.20 g) of 3-(2,6-dichlorophenyl)propylamine. Step 4
[0313] To a suspension of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid (0.30 g) in chloroform (10 ml) were added oxalyl chloride(0.13 ml) and dimethylformamide (0.01 ml), and the mixture wasstirred at room temperature for 30 min. The reaction solventwas evaporated under reduced pressure and toluene was added.The mixture was concentrated and chloroform (5 ml) was added. Asolution of 3-(2,6-dichlorophenyl)propylamine (0.31 g) obtainedin the previous step in chloroform (1 ml) and triethylamine(0.21 ml) were successively added under ice-cooling, and themixture was stirred under ice-cooling for 10 min. 1N Aqueoushydrochloric acid solution was added to the obtained reactionmixture and the mixture was extracted with chloroform. Theorganic layer was dried over sodium sulfate. The solvent wasevaporated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:2) to give N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide(0.24 g).¹H-NMR(CDCl₃)δ 7.81(d,1H,J=5.6Hz), 7.79(br,1H), 7.39-7.26(m,7H),7.08(dd,1H,J=7.6,8.6Hz), 6.49(d,1H,J=5.6Hz), 5.40(s,2H),3.31(dt,2H,J=5.2,7.2Hz), 2.82(dd,2H,J=7.9,8.1Hz), 1.62-1.57(m,2H). Step 5
[0314] To N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide(0.24 g) obtained in the previous step wereadded tetrahydrofuran (1.8 ml), ethanol (1.8 ml) andaminoacetaldehyde dimethyl acetal (0.012 ml), and the mixturewas stirred at 60°C for 46 hr. The solvent was evaporated andthe residue was purified by silica gel column chromatography(chloroform:methanol=100:0-10:1) to give N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(0.24 g).¹H-NMR(CDCl₃)δ 7.35-7.24(m,8H), 7.07(dd,1H,J=7.6,8.1Hz),6.42(d,1H,J=7.5Hz), 6.25(br,1H), 5.28(s,2H),4.57(dd,1H,J=3.1,5.1Hz), 3.89(d,2H,J=4.8Hz), 3.41-3.36(m,6H),3.29(m,2H), 2.85(dd,2H,J=7.2,8.6Hz), 1.71-1.62 (m,2H) . Step 6
[0315] To a solution of N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide(237 mg) obtained in the previous step in toluene(20 ml) was added camphorsulfonic acid (106 mg) and the mixturewas stirred at 110°C for 5 hr. After stirring at roomtemperature for 15 hr, camphorsulfonic acid (21 mg) was addedand the mixture was stirred at 110°C for 3 hr. Triethylamine (1ml) was added to the reaction mixture at room temperature andthe precipitated solid was filtered off. The filtrate wasconcentrated and purified by silica gel column chromatography(ethyl acetate:methanol=10:1-5:1) and thin layer chromatography(ethyl acetate:methanol=5:1) to give 9-benzyloxy-2-[3-(2,6-dichlorophenyl)propyl]-2H-pyrido[1,2-a]pyrazine-1,8-dione(120 mg).¹H-NMR(CDCl₃)δ 7.64(d,2H,J=7.9Hz), 7.38(d,1H,J=7.4Hz), 7.38-7.23(m,5H),7.08(dd,1H,J=7.7,8.4Hz), 6.71(d,1H,J=7.4Hz),6.43(d,1H,5.8Hz), 6.28(d,1H,J=6.0Hz), 5.35(s,2H),3.89(t,2H,J=7.4Hz), 2.98(dd,2H,J=7.2,8.4Hz), 1.99(m,2H). Step 7
[0316] Trifluoroacetic acid (1 ml) was added to 9-benzyloxy-2-[3-(2,6-dichlorophenyl)propyl]-2H-pyrido[1,2-a]pyrazine-1,8-dione(120 mg) obtained in the previous step and the mixture was leftstanding at room temperature for 1 hr. The solvent wasevaporated, toluene was added, and the mixture was concentrated,which operations were performed twice. The obtained crystalswere washed with diisopropyl ether to give 2-[3-(2,6-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione(92 mg) .¹H-NMR(DMSO-d₆)δ 8.16(d,1H,J=7.3Hz), 7.46(d,2H,J=7.7Hz),7.41(d,1H,J=6.2Hz), 7.28(m,1H), 7.11(d,1H,J=5.9Hz),6.85(d,1H,J=7.7Hz), 4.43(br,1H), 3.92(t,2H,J=7.0Hz),2.93(dd,2H,J=7.7,8.4Hz), 1.92(m,2H). Example 12Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dionehydrochloride
[0317]
[0318] To a solution of dimethyl 2-benzyloxy-3-hydroxy-2-butenedicarboxylate (3.0 g) in methanol (60 ml) were addedsodium methoxide (1.28 g) and formamidine hydrochloride (953 mg)under ice-cooling, and the mixture was stirred at 70°C for 1.5 hr.The reaction solvent was evaporated under reduced pressure, andwater was added to dissolve the residue. 5% Aqueous potassiumhydrogen sulfate solution was added, and the precipitated solidwas collected by filtration, washed with water and dried to givemethyl 5-benzyloxy-6-hydroxypyrimidine-4-carboxylate (1.1 g).¹H-NMR(DMSO-d₆)δ 13.1(brs,1H), 8.01(s,1H), 7.2-7.5(m,5H),5.12(s,2H), 3.75(s,3H). Step 2
[0319] Methanol (6 ml) and 1N aqueous sodium hydroxide solution(2.5 ml) were added to methyl 5-benzyloxy-6-hydroxypyrimidine-4-carboxylate(530 mg) obtained in the previous step, and themixture was stirred at room temperature for 1 hr. 2NHydrochloric acid (2.5 ml) was added to the reaction mixture,and methanol was evaporated under reduced pressure. Theprecipitate was collected by filtration, washed with water anddried to give 5-benzyloxy-6-hydroxypyrimidine-4-carboxylic acid(253 mg).¹H-NMR(DMSO-d₆)δ 13.5(brs,1H), 13.0(brs,1H), 8.00(s,2H), 7.2-7.5(s,2H). Step 3
[0320] 5-Benzyloxy-6-hydroxypyrimidine-4-carboxylic acid (103 mg)obtained in the previous step was dissolved inacetonitrile/tetrahydrofuran (2 ml), carbonyldiimidazole (88 mg)was added, and the mixture was stirred at room temperature for30 min. The mixture was added to a solution of N-(3,4-dichlorobenzyl)-N-(2,2-dimethoxyethyl)amineobtained in the samemanner as in Example 5, Step 1 in acetonitrile (2 ml), and themixture was stirred overnight at room temperature. The reactionmixture was evaporated under reduced pressure, and the residuewas dissolved in chloroform, washed with saturated brine anddried over magnesium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2-ethyl acetate) to give an oil (210 mg).This oil was dissolved in dioxane (5 ml), pyridinium p-toluenesulfonate(22 mg) was added, and the mixture was heatedunder reflux overnight. The reaction solvent was evaporatedunder reduced pressure, and the residue was dissolved inchloroform, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over magnesiumsulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography (ethyl acetate-ethylacetate:methanol=9:1) to give an oil (40 mg). This oilwas dissolved in acetic acid (600 µl) and conc. hydrochloricacid (200 µl) and the mixture was stirred at 100°C for 1.5 days.The reaction solvent was evaporated under reduced pressure.Toluene was added to the residue and the mixture wasconcentrated, which operations were performed twice, after whichthe residue was crystallized from methanol. The crystals werecollected by filtration and dried to give 2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dionehydrochloride (12 mg).¹H-NMR(DMSO-d₆)δ 1.08(brs,1H), 8.48(s,1H), 7.68(d,1H,J=4Hz),7.63(d,1H, J=8Hz), 7.3-7.4(m, 2H), 7.16(d,1H,J=8Hz),6.80(d,1H,J=8Hz), 4.90(s,2H). Examples 13-92
[0321] In the same manner as in Examples 1-12 or by a similarmethod or by a conventional method, the compounds of Examples13-92 to be shown in the Tables below were obtained. Example 118Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-7-(1-hydroxy-2,2-dimethylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0322]
[0323] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (300 mg) obtained in Example 10, Step 1and 2,2-dimethylpropionaldehyde (9 ml) in tetrahydrofuran (9 ml)was added dropwise 1.5 M lithium diisopropylamide -tetrahydrofuran/cyclohexane solution (4.5 ml) under nitrogen at-78°C. After stirring at the same temperature for 2 hr, thecooling bath was removed and 1N aqueous hydrochloric acid (15ml) and ethyl acetate (25 ml) were added, and the mixture waswarmed to room temperature. The organic layer was separatedfrom the aqueous layer and extracted with ethyl acetate (25 ml).The combined organic layer was dried, concentrated and purifiedby silica gel column chromatography (ethyl acetate:hexane=1:3)to give 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (0.22 g).¹H-NMR(CDCl₃)δ 8.07(brt,1H,J=5.8Hz), 7.82(s,1H), 7.35-7.18(m,7H),7.15(s,1H), 7.05(d,1H,J=7.0Hz), 5.33(s,2H), 4.43(d,1H,J=7.2Hz),4.39(d,2H,J=5.8Hz), 3.61(d,1H,J=7.2Hz), 0.96(s,9H). Step 2
[0324] To a solution of 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide(0.22 g) in tetrahydrofuran (1.5 ml)-ethanol(1.5 ml) was added aminoacetaldehyde dimethyl acetal (0.16 ml)and the mixture was stirred at 60°C for 24 hr. The solvent wasevaporated and purified by silica gel column chromatography(ethyl acetate:hexane=1:1-ethyl acetate) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (198 mg).¹H-NMR(CDCl₃)δ 7.73(brdd,1H,J=6.2,5.8Hz), 7.33-7.10(m,10H),5.76(brd,1H,J=7.4Hz), 5.17(d,1H,J=11.0Hz), 5.01(d,1H,J=11.0Hz),4.50(t,1H,J=5.0Hz), 4.39(dd,1H,J=6.2,15.1Hz),4.23(dd,1H,J=5.8,15.1Hz), 4.14(d,1H,J=7.4Hz), 3.29(s,3H),3.27(s,3H), 0.89(s,9H). Step 3
[0325] To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (60 mg) in dioxane (0.55 ml)was added conc. hydrochloric acid (0.55 ml) and the mixture wasstirred at 90°C for 2 hr. The solvent was evaporated, toluenewas added, and the mixture was concentrated, which operationswere performed twice. Crystallization from ethyl acetate-diisopropylether gave 2-(3-chlorobenzyl)-9-hydroxy-7-(1-hydroxy-2,2-dimethylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (44 mg).¹H-NMR(DMSO-d₆)δ 8.30(s,1H), 7.70(d,1H,J=6.2Hz), 7.50(s), 7.44-7.34(m,3H),7.26(d,1H,J=6.2Hz), 5.09(d,1H,J=14.9Hz),4.99(d,1H,J=14.9Hz), 4.76(s,1H), 0.87(s,9H). Example 125Synthesis of 2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0326]
[0327] To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (120 mg) obtained in Example118, Step 2 in dimethyl sulfoxide (5 ml) were addedtriethylamine (1.1 ml) and sulfur trioxide pyridine complex (450mg) and the mixture was stirred at room temperature for 1 hr. Asaturated aqueous ammonium chloride solution was added to thereaction mixture and the mixture was extracted twice with ethylacetate (30 ml). The combined ethyl acetate layer washed withwater, dried, concentrated and purified by silica gel columnchromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (104 mg).¹H-NMR(CDCl₃)δ 8.27 (brt,1H,J=6.0Hz), 7.26-7.14(m,8H),7.06(t,1H,J=7.7Hz), 5.08(s,2H), 4.54(t,1H,J=5.1Hz),4.34(d,2H,J=6.0Hz), 3.81(d,2H,J=5.1Hz), 3.28(s,6H), 1.20(s,9H). Step 2
[0328] To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (100 mg) in dioxane (1 ml) was addedconc. hydrochloric acid (1 ml) and the mixture was stirred at90°C for 2 hr. The solvent was evaporated, toluene was added,and the mixture was concentrated, which operations wereperformed twice. Crystallization from ethyl acetate-diisopropylether gave 2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (71 mg).¹H-NMR(DMSO-d₆)δ 8.09(s,1H), 7.48(s,1H), 7.43-7.32(m,3H),7.22(d,1H,J=6.2Hz), 6.94(d,1H,J=6.2Hz), 4.98(s,2H), 1.19(s,9H). Example 161Synthesis of 7-amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0329]
[0330] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (5.13 g) obtained in Example 10, Step 1in chloroform (100 ml) was added a solution of bromine (1.5 ml)in chloroform (50 ml) and the mixture was stirred with heatingunder reflux for 2 hr. A solution of bromine in chloroform (1.0ml) was added, and after stirring with heating for 16 hr, thesolvent was evaporated. Toluene was added to the residue andthe mixture was concentrated, which operations were performedtwice to give a crude product of 5-bromo-3-hydroxy-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide. The obtained crudeproduct was dissolved in dimethylformamide (50 ml), andpotassium carbonate (3.87 g) and benzyl bromide (2.75 ml) wereadded thereto. The reaction mixture was stirred at roomtemperature for 1 hr. Water (100 ml) and 1N aqueoushydrochloric acid (50 ml) were added to the reaction mixture andthe mixture was extracted twice with ethyl acetate (200 ml each).The ethyl acetate layer was washed, dried, concentrated andpurified by silica gel column chromatography (ethylacetate:hexane=1:3) to give 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (3.31 g). ¹H-NMR(CDCl₃)δ 8.21(s,1H), 8.01(brt,1H,J=5.9Hz), 7.41-7.20(m,7H),7.15(s,1H), 7.05(d,1H,J=7.3Hz), 5.38(s,2H), 4.39(d,2H,J=5.9Hz). Step 2
[0331] To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (1.50 g) in tetrahydrofuran(10 ml)-ethanol (10 ml) was added aminoacetaldehyde dimethylacetal (0.73 ml) and the mixture was stirred at 60°C for 1 hr.The solvent was evaporated and the residue was purified bysilica gel column chromatography (ethyl acetate:hexane=1:3-1:2)to give 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (1.35 g).¹H-NMR(CDCl₃)δ 8.03(brt,1H,J=6.2Hz), 7.65(s,1H), 7.33-7.11(m,9H),5.04(s,2H), 4.53(t,1H,J=5.1Hz), 4.34(d,2H,J=6.2Hz),3.83(d,2H,J=5.1Hz), 3.30(s,6H). Step 3
[0332] To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(3.89 g) in dimethyl sulfoxide (26 ml)-methanol(13 ml) were added palladium(II) acetate (0.16 g), 1,3-bis(diphenylphosphino)propane(0.3 g) and triethylamine (2 ml)and the mixture was stirred under carbon monoxide at 70°C for 24hr. The reaction mixture was concentrated and water was added,and the mixture was extracted twice with ethyl acetate (200 mleach). The ethyl acetate layer was washed with water, dried andconcentrated to give a crude product of methyl 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate(4.12 g).¹H-NMR(CDCl₃)δ 8.50 (brs,1H), 7.95(s,1H), 7.29-7.12(m,9H),4.97(s,2H), 4.56(t,1H,J=5.1Hz), 4.46(d,2H,J=6.3Hz),3.83(d,2H,J=5.1Hz), 3.73(s,3H), 3.27(s,6H). Step 4
[0333] To a solution of methyl 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate(2.0 g) in tetrahydrofuran (20ml)-methanol (10 ml) was added 4N aqueous lithium hydroxide solution (1.5 ml) and the mixture was stirred at 70°C for 1 hr.The precipitated solid was removed by thin layer of celite andwashed with methanol. The solvent was evaporated and 1N aqueoushydrochloric acid (6.5 ml) and water (50 ml) were added. Themixture was extracted twice with ethyl acetate (75 ml each).The ethyl acetate layer was dried, concentrated and crystallizedfrom ethyl acetate-diisopropyl ether to give 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylicacid (1.2 g).¹H-NMR(CDCl₃)δ 8.35 (s,1H), 7.42-7.09(m,9H), 6.55(brs,1H),5.34(s,2H), 4.50(t,1H,J=4.4Hz), 4.40(d,2H,J=5.9Hz),4.10(d,2H,J=4.4Hz), 3.31(s,6H). Step 5
[0334] To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylicacid (50 mg) in dimethylformamide (0.3 ml) were addedtriethylamine (0.07 ml) and diphenylphosphoryl azide (0.054 ml).After stirring at room temperature for 1 hr, tert-butanol (0.3ml) was added, and the mixture was heated to 100°C and stirredfor 1 hr. After cooling to room temperature, saturated aqueousammonium chloride solution (5 ml) and water (5 ml) were added,and the mixture was extracted twice with ethyl acetate (15 mleach). The ethyl acetate layer was washed with water, dried andconcentrated. The obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:2) to give tert-butyl[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]carbamate(40 mg).¹H-NMR(CDCl₃)δ 8.39(s,1H), 7.70(s,1H), 7.36-7.08(m,9H),6.43(brt,1H,J=6.2Hz), 5.27(s,2H), 4.52(t,1H,J=5.1Hz),4.37(d,2H,J=6.2Hz), 4.06(d,2H,J=5.1Hz), 3.28(s,6H), 1.55(s,9H). Step 6
[0335] tert-Butyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]carbamate(40mg) was dissolved in acetic acid (0.4 ml) and conc. hydrochloric acid (0.4 ml) was added. The mixture was stirred at 90°C for 5hr. The reaction mixture was concentrated, toluene was added tothe residue and the mixture was concentrated, which operationswere performed twice. Methanol was further added, and themixture was concentrated, which operations were performed twice.Crystallization from ethyl acetate-methanol-diisopropyl ethergave 7-amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (23 mg).¹H-NMR(DMSO-d₆)δ 12.29(brs,1H), 7.99(s,1H), 7.78(d,1H,J=6.0Hz),7.58(d,1H,J=6.0Hz), 7.49(s,1H), 7.43-7.33(m,3H), 5.10(s,2H). Example 165Synthesis of N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide
[0336]
[0337] 7-Amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (23mg) obtained in Example161 was dissolved in pyridine (0.1 ml) and acetic anhydride(0.0123 ml) was added. After stirring at room temperature for 1hr, water (3 ml) was added to the reaction mixture, and themixture was extracted twice with chloroform (6 ml each). Thechloroform layer was dried, concentrated and crystallized fromchloroform-methanol-diisopropyl ether to give 22 mg of a solid.This solid was suspended in tetrahydrofuran (0.4 ml)-methanol (1ml)-chloroform (1 ml) and 2N aqueous sodium hydroxide solution(0.043 ml) was added. The mixture was stirred at roomtemperature for 30 min. The reaction mixture was concentrated,1N aqueous hydrochloric acid (6 ml) was added, and the mixturewas extracted three times with chloroform (8 ml each). Thechloroform layer was dried, concentrated and crystallized fromchloroform-methanol-diisopropyl ether to give N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide(18 mg). ¹H-NMR(DMSO-d₆)δ 11.59(bs,1H), 9.44(s,1H), 9.08(s,1H), 7.49(s,1H),7.47(d,1H,J=6.0Hz), 7.42-7.32(m,3H), 6.95(d,1H,J=6.0Hz),4.97(s,2H), 2.17(s,3H). Example 94Synthesis of 7-bromo-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0338]
[0339] By subjecting 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(50 mg) obtained in Example 161, Step 2 to a reaction operationsimilar to that in Example 161, Step 6 and crystallization fromethyl acetate-methanol-diisopropyl ether, 7-bromo-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (30 mg) was obtained.¹H-NMR(DMSO-d₆)δ 8.63(s,1H), 7.48(s,1H), 7.44-7.33(m,3H),7.21(d,1H,J=6.2Hz), 6.95(d,1H,J=6.2Hz), 4.98(s,2H). Example 96Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0340]
[0341] To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(70 mg) obtained in Example 161, Step 2 in dimethoxyethane (1.4 ml)-water (0.7 ml) were successively addedphenylboronic acid (32 mg),tetrakis(triphenylphosphine)palladium(0) (31 mg) and sodiumcarbonate (42 mg), and the mixture was stirred at 80°C for 2 hr.After cooling to room temperature, the mixture was purified bysilica gel column chromatography (ethyl acetate:hexane=1:3-1:1)to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-phenyl-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (56 mg).¹H-NMR(CDCl₃)δ 7.27(brs,1H), 7.50(s,1H), 7.40-7.09(m,14H),5.15(s,2H), 4.55(t,1H,J=5.1Hz), 4.16(d,2H,J=6.0Hz),3.85(d,2H,J=5.1Hz), 3.28(s,6H). Step 2
[0342] 3-Benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-phenyl-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (52 mg)was dissolved in acetic acid (0.5 ml) and conc. hydrochloricacid (0.5 ml) was added, and the mixture was stirred at 90°C for2 hr. The reaction mixture was concentrated, toluene was addedto the residue and the mixture was concentrated, whichoperations were performed twice. Methanol was further added andthe mixture was concentrated and crystallized from ethylacetate-diisopropyl ether to give 2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (39mg).¹H-NMR(DMSO-d₆)δ 8.50(s,1H), 7.73(d,2H,J=7.0Hz), 7.53-7.36(m,8H),7.10(d,1H,J=6.2Hz), 5.04(s,2H). Example 104Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-7-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0343]
[0344] To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(138 mg) obtained in Example 161, Step 2 indioxane (2.5 ml) were added tributyl-2-propenyltin (245 mg) andtetrakis(triphenylphosphine)palladium(0) (60 mg), and themixture was stirred at 100°C for 4 hr. The solvent wasevaporated, toluene was added, and the mixture was concentratedagain. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (89 mg).¹H-NMR(CDCl₃)δ 7.75(brt,1H,J=6.0Hz), 7. 31-7. 09 (m,10H),5.80(d,2H,J=2.3Hz), 5.19(dq,1H,J=2.3,1.4Hz), 5.09(s,2H),4.52(t,1H,J=5.1Hz), 4.31(d,2H,J=6.0Hz), 3.82(d,2H,J=5.1Hz),3.29(s,6H), 2.05(brs,3H). Step 2
[0345] To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(60 mg) in methanol (1 ml) was added 5%palladium-carbon (20 mg) and the mixture was stirred under anatmospheric pressure of hydrogen for 16 hr. A solid wasfiltered off and the filtrate was concentrated to give 1-(2,2-dimethoxyethyl)-3-hydroxy-5-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (43 mg). ¹H-NMR(CDCl₃)δ 8.89(brt,1H,J=5.8Hz), 7.38-7.24(m,5H),4.63(d,2H,J=5.8Hz), 4.60(d,1H,J=4.9Hz), 4.51(d,2H,J=4.9Hz),3.23(sep,1H,J=6.8Hz), 1.23(d,6H,J=6.8Hz). Step 3
[0346] By subjecting 1-(2,2-dimethoxyethyl)-3-hydroxy-5-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(42 mg) to a reaction operation similar tothat in Example 161, Step 6 and crystallization from ethylacetate-methanol-diisopropyl ether, and further crystallizationfrom ethyl acetate-methanol, 2-(3-chlorobenzyl)-9-hydroxy-7-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (18mg) was obtained.¹H-NMR(DMSO-d₆)δ 8.27(s,1H), 7.51-7.45(m,2H), 7.42-7.31(m,3H),7.17(brd,1H,J=6.2Hz), 5.04(s,2H), 3.23(sep,1H,J=7.0Hz),1.19(d,6H,J=7.0Hz). Example 187Synthesis of methyl [2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetate
[0347]
[0348] To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(300 mg) obtained in Example 161, Step 2 intoluene were added under an argon stream tributyltin fluoride(518 mg), tris(dibenzylideneacetone)dipalladium(0)-chloroformadduct (58 mg), 1,1'-bis(diphenylphosphino)ferrocene (64 mg) and 1-(tert-butyldimethylsilyloxy)-1-methoxyethane (525 mg), and themixture was stirred at 100°C for 15 hr. After cooling to roomtemperature, aqueous sodium hydrogen carbonate was added to thereaction mixture and the mixture was extracted three times withethyl acetate. The extract was dried, concentrated and purifiedby silica gel column chromatography (ethyl acetate) to givemethyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate(184 mg).¹H-NMR(CDCl₃)δ 7.38(s,1H), 7.32-7.07(m,9H), 6.76(brt,1H,J=6.0Hz),5.24(s,2H), 4.52(t,1H,J=5.1Hz), 4.37(d,2H,J=6.0Hz),3.90(d,2H,J=5.1Hz), 3.72(s,3H), 3.48(s,2H), 3.31(s,6H). Step 2
[0349] Methyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate(30 mg)was dissolved in trifluoroacetic acid (1 ml) and the mixture wasstirred at 70°C for 4 hr. The mixture was cooled andconcentrated. Toluene was added to the residue and the mixturewas concentrated again, which operations were performed twice.Crystallization from ethyl acetate-diisopropyl ether gave methyl[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetate(17 mg).¹H-NMR(DMSO-d₆)δ 11. 50 (brs,1H), 8.05(s,1H), 7.48(s,1H), 7.42-7.31(m,3H),7.18(d,1H,J=6.1Hz), 6.86(d,1H,J=6.1Hz), 4.96(s,2H),3.59(s,3H), 3.47(s,2H). Example 191Synthesis of [2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]aceticacid
[0350]
[0351] To a solution of methyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate(150 mg) obtained in Example 187,Step 1 in tetrahydrofuran (1.5 ml)-methanol (1.5 ml) was added4N aqueous sodium hydroxide solution (0.11 ml), and the mixturewas stirred at 70°C for 30 min. The reaction mixture was warmedto room temperature, 1N aqueous hydrochloric acid (0.5 ml) andwater (15 ml) were added, and the mixture was extracted twicewith ethyl acetate (30 ml each). The ethyl acetate layer waswashed with water, dried, concentrated, and crystallized fromethyl acetate-diisopropyl ether to give [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]aceticacid (116 mg).¹H-NMR(CDCl₃)δ 7.42(s,1H), 7.43-7.08(m,9H), 6.81(brt,1H,J=5.8Hz),5.27(s,2H), 4.51(t,1H,J=4.6Hz), 4.39(d,2H,J=5.8Hz),4.01(d,2H,J=4.6Hz), 3.55(s,2H), 3.30(s,6H). Step 2
[0352] By subjecting [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]aceticacid(20 mg) to a reaction operation similar to that in Example 187,Step 2, and crystallization from ethyl acetate-diisopropyl ether,[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]aceticacid (13 mg) was obtained. ¹H-NMR(DMSO-d₆)δ 12.40(brs,1H), 11.52(brs,1H), 8.05(s,1H),7.48(s,1H), 7.42-7.31(m,3H), 7.19(d,1H,J=6.3Hz),6.87(d,1H,J=6.3Hz), 4.96(s,2H), 3.40(s,2H). Example 189Synthesis of 2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-methylacetamide
[0353]
[0354] To a solution of [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]aceticacid(25 mg) obtained in Example 191, Step 1 in dimethylformamide(0.2 ml), were successively added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (19 mg), 1-hydroxybenzotriazolehydrate (15 mg) and methylamine (2Mtetrahydrofuran solution)(0.073 ml), and the mixture was stirredat room temperature for 2 hr. The obtained reaction mixture wasapplied as it was to silica gel thin layer chromatography(chloroform:methanol=10:1) and crystallized from ethyl acetate-diisopropylether to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-methylcarbamoylmethyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (22 mg).¹H-NMR(CDCl₃)δ 7.48(s,1H), 7.45(brd,1H,J=4.8Hz), 7.34-7.05(m,9H),6.38(brt,1H,J=6.0Hz), 5.27(s,2H), 4.49(t,1H,J=4.8Hz),4.36(d,2H,J=6.0Hz), 3.95(d,2H,J=4.8Hz), 3.40(s,2H), 3.30(s,6H),2.73(d,3H,J=4.8Hz). Step 2
[0355] By subjecting 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-methylcarbamoylmethyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (21 mg) to a reaction operation similarto that in Example 187, Step 2, and crystallization from ethylacetate-diisopropyl ether, 2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-methylacetamide(11 mg) was obtained.¹H-NMR(DMSO-d₆)δ 11. 44 (brs, 1H), 8.01 (s,1H), 7.77(s, 1H),7.47(s,1H), 7.43-7.31(m,3H), 7.23(d,1H,J=6.0Hz),6.87(d,1H,J=6.0Hz), 4.96(s,2H), 3.27(s,2H), 2.55(d,3H,J=4.6Hz). Example 390Synthesis of 9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0356]
[0357] To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (2.0 g) obtained in Example161, Step 1 in tetrahydrofuran (10 ml)-ethanol (10 ml) was added2-aminoethanol (0.33 ml) and the mixture was stirred at roomtemperature and at 50°C respectively for 30 min. The solvent wasevaporated and the residue was crystallized from ethyl acetate-diisopropylether to give 3-benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(1.95 g).¹H-NMR(DMSO-d₆)δ 9.44 (brt,1H,J=5.8Hz), 8.19(s,1H), 7.39-7.16(m,9H),5.08(t,1H,J=5.1Hz), 5.05(s,2H), 4.43(d,2H,J=5.8Hz),3.92(t,2H,J=5.1Hz), 3.62(q,2H,J=5.1Hz). Step 2
[0358] 3-Benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (1.75 g)was suspended in tetrahydrofuran (50 ml), and N,N-diisopropylethylamine(3.72 ml) and methanesulfonyl chloride(1.38 ml) were added. After stirring at room temperature for 1hr, 0.5N aqueous hydrochloric acid (40 ml) was added, and themixture was extracted twice with ethyl acetate (100 ml each).The ethyl acetate layer was washed with aqueous sodium hydrogencarbonate, dried and concentrated. The obtained residue wasdissolved in dimethylformamide (50 ml) and 60% sodium hydridewas added by small portions with stirring at room temperature.After confirming the completion of the reaction by thin layerchromatography (TLC), the reaction mixture was ice-cooled, 0.33Naqueous hydrochloric acid (300 ml) was added, and the mixturewas extracted twice with ethyl acetate (250 ml each). The ethylacetate layer was washed with water, dried, concentrated, andcrystallized from ethyl acetate-hexane to give 9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(1.58 g).¹H-NMR(CDCl₃)δ 7.66(d,2H,J=6.7Hz), 7.56(s,1H), 7.37-7.25(m,6H),7.16(m,1H), 5.32(s,2H), 4.62(s,2H), 3.94-3.88(m,2H), 3.52-3.45(m,2H). Example 244Synthesis of 7-acetyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0359]
[0360] To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chloro-4-fluorobenzylamide(150 mg) produced in the same manneras for the compound described in Example 161, Step 2 in toluene(2 ml) were added tris(dibenzylideneacetone)dipalladium(0)-chloroformadduct (14 mg), 1,1'-bis(diphenylphosphino)ferrocene(15 mg) and tributyl(1-ethoxyvinyl)tin (189 mg) under an argonstream and the mixture was stirred at 90°C for 4 hr. Aftercooling to room temperature, the reaction mixture wasconcentrated and purified by subjecting to silica gel thin layerchromatography (ethyl acetate:hexane=2:1)(toluene:acetone=3:1)twice to give 5-acetyl-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chloro-4-fluorobenzylamide(60 mg).¹H-NMR(CDCl₃)δ 8.07(s,1H), 7.34-7.25(m,6H), 7.09-6.96(m,2H),6.67(brt,1H,J=6.0Hz), 5.25(s,2H), 4.48(t,1H,J=4.7Hz),4.31(d,2H,J=6.0Hz), 4.03(d,2H,J=4.7Hz), 3.31(s,6H), 2.73(s,3H). Step 2
[0361] By subjecting 5-acetyl-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chloro-4-fluorobenzylamide(59 mg) to a reaction operation similar tothat in Example 96, Step 2, and crystallization from ethylacetate-diisopropyl ether, 7-acetyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (35mg) was obtained. ¹H-NMR(DMSO-d₆)δ 8.48(s,1H), 7.65(m,1H), 7.43-7.40(m,2H),7.38(d,1H,J=6.3Hz), 6.93(d,1H,J=6.3Hz), 4.92(s,2H), 2.61(s,3H). Example 251Synthesis of 7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0362]
[0363] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid 4-fluorobenzylamide (0.6g) produced in the same manner asfor the compound described in Example 10, Step 1 and 2,2-dimethylpropionaldehyde(1.88 ml) in tetrahydrofuran (6 ml) wasadded dropwise 1.5 M lithium diisopropylamide-tetrahydrofuran/cyclohexanesolution (14.9 ml) under nitrogen at-78°C. After stirring at the same temperature for 2 hr, thecooling bath was removed and 2N aqueous hydrochloric acid (15ml) and ethyl acetate were immediately added, and the mixturewas heated to room temperature. The organic layer was separatedand the aqueous layer was extracted with ethyl acetate. Thecombined organic layer was dried, concentrated, and purified bysilica gel column chromatography (ethyl acetate:hexane=1:2-ethylacetate) to give 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylicacid 4-fluorobenzylamide (0.27 g).The total amount thereof was dissolved in chloroform (3 ml) and1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martin reagent)(291 mg) was added at room temperature, andthe mixture was stirred for 2.5 hr. 2-Propanol was added andthe mixture was stirred for 30 min, after which aqueous sodium hydrogen carbonate solution and aqueous sodium sulfite solutionwere added. The mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried andconcentrated. The obtained residue was purified by silica gelthin layer chromatography (ethyl acetate:hexane=1:1) to give 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylicacid 4-fluorobenzylamide (0.13 g).¹H-NMR (CDCl₃)δ 8.00(m,1H), 7.80(s,1H), 7.40-6.93(m,9H),5.34(s,2H), 4.39 (d,2H,J=5.76Hz), 1.24(s,9H). Step 2
[0364] To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylicacid 4-fluorobenzylamide (0.13 g) intetrahydrofuran (0.5 ml)-ethanol (0.5 ml) was addedaminoacetaldehyde dimethyl acetal (0.033 ml) and the mixture wasstirred at 70°C for 3 days. After cooling to room temperature,the solvent was evaporated to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 4-fluorobenzylamide (157 mg).¹H-NMR(CDCl₃)δ 8.08(m,1H), 7.31-7.15(m,8H), 6.84-6.78(m,2H),5.06(s,2H), 4.55(t,1H,J=5.1Hz), 4.35(d,2H,J=6.0Hz),3.82(d,2H,J=5.1Hz), 3.30(s,6H), 1.21(s,9H). Step 3
[0365] 3-Benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid4-fluorobenzylamide (157 mg) was dissolved in acetic acid (1.5ml) and conc. hydrochloric acid (0.5 ml) was added. The mixturewas stirred at 90°C for 3 hr. The reaction mixture wasconcentrated and crystallized from ethyl acetate to give 7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (92 mg).¹H-NMR(DMSO-d₆)δ 8.07(s,1H), 7.46-7.41(m,2H), 7.22-7.16(m,3H),6.91(d,1H,J=6.0Hz), 4.93(s,2H), 1.18(s,9H). Example 223Synthesis of 2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride
[0366]
[0367] To a solution of 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide(0.22 g) obtained in the same manner as inExample 118, Step 1 in chloroform (2 ml) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(0.23 g).The mixture was stirred at room temperature for 30 min, aqueoussodium hydrogen carbonate solution and aqueous sodium sulfitesolution were added and the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturatedbrine, dried and concentrated to give 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide(225 mg).¹H-NMR(CDCl₃)δ 8.02(1H,t,J=6.0Hz), 7.81(1H,s), 7.36-7.16(7H,m),7.14(1H,s), 7.04(1H,d,J=7.0Hz), 5.36(2H,s), 4.39(2H,d,J=6.0Hz),1.26(9H,s). Step 2
[0368] To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylicacid 3-chlorobenzylamide (113 mg) intetrahydrofuran (0.7 ml)-ethanol (0.7 ml) was added 2-aminoethanol(0.015 ml) and the mixture was stirred at 60°C for11 hr. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (ethylacetate:hexane=3:1) to give 3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg).¹H-NMR(CDCl₃)δ 8.37(1H,t,J=6.0Hz), 7.36(1H,s), 7.30(1H,s), 7.28-7.07(8H,m),4.94(2H,s), 4.76(1H,br s), 4.28(2H,d,J=6.0Hz), 4.03-3.95(2H,m),3.84-3.76(2H,m), 1.15(9H,s). Step 3
[0369] To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(91 mg) in tetrahydrofuran (3 ml) was addedN,N-diisopropylethylamine (0.187 ml) and the mixture was ice-cooled.Methanesulfonyl chloride (0.07 ml) was added at thesame temperature over 30 min with stirring. After confirmationof the completion of the reaction by thin layer chromatography,5% aqueous potassium hydrogen sulfate solution was added to thereaction mixture and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed successively withbrine, aqueous sodium hydrogen carbonate solution and brine,dried and concentrated. The obtained residue was dissolved indimethylformamide (2 ml) and 60% sodium hydride (50 mg) wasadded by small portions with stirring at room temperature.After stirring for 30 min, the reaction mixture was ice-cooledand 5% aqueous potassium hydrogen sulfate solution was added,and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with brine, dried and concentrated.The obtained residue was purified by silica gel thin layerchromatography (ethyl acetate) to give 9-benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(44 mg).¹H-NMR(CDCl₃)δ 7.61-7.59(2H,m), 7.29-7.22(8H,m), 5.39(2H,s),4.68(2H,s), 3.96-3.92(2H,m), 3.52-3.46(2H,m), 1.32(9H,s). Step 4
[0370] 9-Benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(43 mg) wasdissolved in trifluoroacetic acid (2 ml) and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated and toluene was added, and the mixture wasconcentrated again. Subsequently, a suitable amount ofhydrochloric acid/ethyl acetate solution was added, and themixture was concentrated again. Ethyl acetate (0.6 ml)-diisopropylether (1 ml) was added to the obtained residue andthe obtained solid was collected by filtration to give 2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (25.6 mg).¹H-NMR(DMSO-d₆)δ 7.73(1H,s), 7.45-7.30 (4H,m), 4.71(2H,s),4.25(2H,t,J=5.6Hz), 3.72(2H,t,J=5.6Hz), 1.20(9H,s). Example 154Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid isopropylamide
[0371]
[0372] To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylicacid (25.4 mg) obtained in Example 161, Step 4 intetrahydrofuran (0.3 ml) were successively added triethylamine(0.021 ml) and thionyl chloride (0.0056 ml) at 0°C with stirring.After stirring at room temperature for 10 min, the mixture wasice-cooled again and isopropylamine (0.0086 ml) was added.After stirring at room temperature for 30 min, 5% aqueouspotassium hydrogen sulfite solution was added, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer waswashed with brine, dried and concentrated. Trifluoroacetic acidwas added to the obtained residue and the mixture was stirred at 70°C for 5.5 hr. Trifluoroacetic acid was evaporated, toluenewas added and the mixture was concentrated, which operationswere performed twice. Crystallization from ethyl acetate (2 ml)gave 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid isopropylamide (13.6 mg).¹H-NMR(DMSO-d₆)δ 11.79(1H,s), 10.10(1H,d,J=7.9Hz), 8.74(1H,s),7.51-7.49(2H,m), 7.40-7.34(3H,m), 7.01(1H,d,J=6.5Hz), 4.96(2H,s),4.05(1H,sept,J=6.5Hz), 1.18(6H,d,J=6.5Hz). Example 249Synthesis of 2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0373]
[0374] To a solution of 9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(3.8 g) obtained inExample 1, Step 3 in chloroform (90 ml)-methanol (60 ml) wasadded phenyltrimethylammonium tribromide (5.0 g) and the mixturewas stirred at room temperature for 13 hr. An aqueous sodiumsulfite solution was added to the reaction mixture and themixture was extracted twice with chloroform. The combinedextract was washed with brine and purified as it was by silicagel column chromatography (chloroform-methanol=19:1-10:1) togive 9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(2.44 g).¹H-NMR(DMSO-d₆)δ 8.36(s,1H), 7.6-7.7(m,2H), 7.5-7.6(m,2H), 7.2-7.4(m,4H),5.08(s,2H), 4.68(s,2H), 4.1-4.3(m,2H), 3.6-3.8(m,2H). Step 2
[0375] To a solution of 9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (150 mg) in dioxane (5 ml) were addedtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (63mg), tri-2-furylphosphine (57 mg) and (2-thiazolyl)tributyltin(0.285 ml) under an argon stream and a microwave at 80W wasirradiated under sealing for 1 hr. The obtained reactionmixture was concentrated, and then purified by silica gel columnchromatography (chloroform:methanol=40:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(95 mg).¹H-NMR(CDCl₃)δ 8.49(s,1H), 7.85(d,1H,J=3.3Hz), 7.6-7.8(m,2H),7.1-7.5(m,7H), 5.47(s,2H), 4.64(s,2H), 4.11(t,2H,J=5.4Hz),3.56(t,2H,J=5.4Hz). Step 3
[0376] 9-Benzyloxy-2-(3,4-dichlorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(93 mg) was dissolvedin trifluoroacetic acid (2 ml). After leaving at roomtemperature for 1.5 hr, the mixture was concentrated. Toluenewas added to the residue and the mixture was concentrated again,which operations were performed twice. Ethyl acetate was addedand the solid was collected by filtration to give 2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(53 mg).¹H-NMR(DMSO-d₆)δ 12.25(brs,1H), 8.71(s,1H), 7.89(d,1H,J=3.2Hz),7.69(d,1H,J=2Hz), 7.6-7.65(m,2H), 7.39(dd,1H,J=8.4Hz,2Hz),4.74(s,2H), 4.4-4.5(m,2H), 3.75-3.85(m,2H). Example 219Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacidmethylamide
[0377]
[0378] By subjecting 9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(600 mg) produced bythe same method as in Example 249, Step 1 to a reactionoperation similar to that in Example 161, Step 3, a mixture ofmethyl 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylateand methyl 2-(3-chlorobenzyl)-1,8-dioxo-9-hydroxy-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylatewas obtained. This mixturewas dissolved in dimethylformamide (17 ml) and treated withbenzyl bromide (1.36 g) and potassium carbonate (1.75 g) andpurified by silica gel column chromatography (ethyl acetate-chloroform:methanol=10:1)to give methyl 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate(480 mg).¹H-NMR(CDCl₃)δ 8.02(s,1H), 7.66(d,2H,J=6Hz), 7.2-7.4(m,6H), 7.1-7.2(m,1H),5.33(s,2H), 4.62(s,2H), 3.94(t,2H,J=5.3Hz),3.91(s,3H), 3.50(t,2H,J=5.3Hz). Step 2
[0379] Methyl 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate(420 mg) wasdissolved in tetrahydrofuran (8 ml)-water (2 ml), and 4N aqueouslithium hydroxide solution (0.58 ml) was added with stirring.After stirring at 70°C for 1 hr, the mixture was concentrated.Water (5 ml) and then 5% aqueous potassium hydrogen sulfatesolution (15 ml) were added with stirring. The precipitatedcrystals were collected by filtration to give 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (352 mg).¹H-NMR(DMSO-d₆)δ 8.70(brs,1H), 7.2-7.6(m,9H), 5.16(s,2H),4.72(s,2H), 4.3-4.6(m,2H), 3.6-3.8(m,2H). Step 3
[0380] By subjecting 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid(350 mg) to a reaction operation similar to that in Example 154,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid methylamide (182 mg) wasobtained.¹H-NMR(DMSO-d₆)δ 12.28(s,1H), 9.8-10.0(m,1H), 8.38(s,1H),7.46(s,1H), 7.25-7.4(m,3H), 4.72(s,2H), 4.40(t,2H,J=5.5Hz),3.75(t,2H,J=5.5Hz), 2.83(d,3H,J=4.9Hz). Example 362Synthesis of 2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0381]
[0382] 9-Benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid (200 mg)obtained in Example 219, Step 2 was suspended in tetrahydrofuran(6 ml), and triethylamine (0.07 ml) and thionyl chloride (0.037ml) were added at room temperature with stirring. Afterstirring at room temperature for 10 min, the mixture was cooledto -78°C and 1.0 M 1,1-dimethylpropylmagnesium chloride/ethersolution was added dropwise. After further stirring at the sametemperature for 20 min, 5% aqueous potassium hydrogen sulfatesolution (5 ml) and ethyl acetate (6 ml) were added, and water(5 ml) was further added. The mixture was extracted twice withethyl acetate-tetrahydrofuran (1:1, 30 ml each). The organiclayer was dried and concentrated, and ethyl acetate was added tothe residue. The obtained solid was collected by filtration togive 9-benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (59 mg).¹H-NMR(CDCl₃)δ 7.63-7.59(m,2H), 7.36-7.17(m,8H), 5.89(s,2H),4.68(s,2H), 3.97-3.91(m,2H), 3.51-3.46(m,2H), 1.78(q,2H,J=7.6Hz),1.28(s,6H), 0.83(t,3H,J=7.6Hz). Step 2
[0383] 9-Benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(55 mg) wasdissolved in trifluoroacetic acid (0.5 ml) and the mixture wasstirred at room temperature for 30 min. The solvent wasevaporated and toluene was added, and the mixture wasconcentrated, which operations were performed twice.Crystallization from chloroform-diisopropyl ether gave 2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(32 mg).¹H-NMR(DMSO-d₆)δ 12.08(bs,1H), 7.70(s,1H), 7.46(s,1H), 7.44-7.32(m,3H),4.72(s,2H), 4.30-4.22(m,2H), 3.76-3.69(m,2H),1.65(q,2H,J=7.4Hz), 1.16(s,6H), 0.77(t,3H,J=7.4Hz). Example 205Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-7-propionyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0384]
[0385] 5-Benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylicacid (517mg) obtained in Example 161, Step 4 and triethylamine (0.43 ml)were added to tetrahydrofuran (7 ml), and thionyl chloride(0.098 ml) was subsequently added at 0°C. The mixture wasstirred at room temperature for 3 min and the reaction mixture was cooled to -78°C. 1M Lithium aluminum hydride/tetrahydrofuransolution (1.55 ml) was added dropwise. After stirring at thesame temperature for 3 min, 5% aqueous potassium hydrogensulfate solution was added, and the mixture was extracted withethyl acetate. The ethyl acetate layer was dried, concentratedand purified by silica gel column chromatography (ethyl acetate-ethylacetate:methanol=20:1) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-hydroxymethyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide (240 mg).¹H-NMR(CDCl₃)δ 7.33-7.15(8H,m), 7.11(1H,d,J=7.4Hz),6.88(1H,t,J=6.0Hz), 5.23(2H,s), 4.54-4.35(3H,m),4.34(2H,d,J=6.0Hz), 3.93(2H,d,J=5.1Hz), 3.32(6H,s). Step 2
[0386] By subjecting 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-hydroxymethyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(235 mg) to a reaction operation similar tothat in Example 223, Step 1, 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-formyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(197 mg) was obtained.¹H-NMR(CDCl₃)δ 10.28(1H,s), 7.89(1H,s), 7.31-7.19(8H,m),7.11(1H,d,J=7.9Hz), 6.72(1H,t,J=6.0Hz), 5.29(2H,s),4.49(1H,t,J=4.9Hz), 4.37(2H,d,J=6.0Hz), 3.99(2H,d,J=4.9Hz),3.30(6H,s). Step 3
[0387] To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-formyl-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(168 mg) in tetrahydrofuran (6 ml) was addeddropwise 0.89 M ethylmagnesium bromide (1.09 ml) with stirringat -78°C. After stirring at the same temperature for 10 min, 5%aqueous potassium hydrogen sulfate solution was added, and themixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried and concentrated.The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=2:1-4:1) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (137 mg).¹H-NMR(CDCl₃)δ 7.30-7.16(8H,m), 7.10(1H,d,J=7.4Hz),6.78(1H,t,J=5.1Hz), 5.23(2H,s), 4.56(1H,d,J=7.4Hz),4.49(1H,t,J=4.9Hz), 4.46(1H,dd,J=7.4,10.2Hz), 4.35(2H,d,J=5.1Hz),3.92(2H,d,J=4.9Hz), 3.30(3H,s), 3.29(3H,s),1.83(2H,dq,J=7.2,10.2Hz), 0.94(3H,t,J=7.2Hz). Step 4
[0388] By subjecting 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(102 mg) to a reaction operation similar tothat in Example 223, Step 1, 3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-propionyl-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(92 mg) was obtained.¹H-NMR(CDCl₃)δ 8.09(1H,s), 7.28-7.21(8H,m), 7.08(1H,d,J=7.4Hz),6.54(1H,d,J=6.0Hz), 5.27(2H,s), 4.47(1H,t,J=5.1Hz),4.34(2H,d,J=6.0Hz), 4.04(2H,d,J=5.1Hz), 3.29(6H,s),3.21(2H,q,J=7.1Hz), 1.16(3H,t,J=7.1Hz). Step 5
[0389] By subjecting 3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-propionyl-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(89 mg) to a reaction operation similar tothat in Example 96, Step 2, 2-(3-chlorobenzyl)-9-hydroxy-7-propionyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (56mg) was obtained.¹H-NMR(DMSO-d₆)δ 8.48(1H,s), 7.47(1H,s), 7.44-7.29(4H,m),6.93(1H,d,J=6.0Hz), 4.94(2H,s), 3.10 (3H,q,J=7.2Hz),1.03(3H,t,J=7.2Hz). Example 242Synthesis of N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]propionamide
[0390]
[0391] To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylicacid (1 g) obtained in Example 161, Step 4 in tetrahydrofuran(15 ml)-toluene (15 ml) were added triethylamine (0.61 ml) anddiphenylphosphoryl azide (0.47 ml) and the mixture was stirredat room temperature for 30 min. The solvent was evaporated, andthe residue was dissolved in tetrahydrofuran (8 ml).Triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml)were added again and 2 hr later, and 3 hr later, triethylamine(1.22 ml, 0.61 ml) and diphenylphosphoryl azide (0.94 ml, 0.47ml) were respectively added, and stirring was continued. Afterconfirmation of disappearance of the starting material, 9-fluorenylmethanol(7.7 g) and toluene (10 ml) were added, andthe mixture was stirred under reflux with heating. After 20 min,triethylamine (2.5 ml) was added, and stirring was continuedwith heating for 1.5 hr. The mixture was concentrated, waterwas added to the residue and the mixture was extracted twicewith ethyl acetate. The combined ethyl acetate layer was washedwith brine, dried and concentrated. The residue was subjectedto silica gel column chromatography (ethyl acetate:hexane=1:1-chloroform:methanol=15:1)to give 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(886 mg).¹H-NMR(CDCl₃)δ 7.41-7.18(m,8H), 7.15-7.12(m,2H), 6.96(s,1H),5.15(s,2H), 4.53(t,1H,J=5.0Hz), 4.32(d,2H,J=5.8Hz), 3.93(brs,2H),3.86(d,2H,J=5.0Hz), 3.29(s,6H). Step 2
[0392] To a solution of 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(55 mg) in chloroform (1 ml) were added,triethylamine (0.033 ml) and propanoyl chloride (0.012 ml) at 0°C.After stirring at the same temperature for 20 min, aqueoussodium hydrogen carbonate solution was added and the reactionmixture was extracted with ethyl acetate. The ethyl acetatelayer was dried, concentrated and purified by silica gel thinlayer chromatography (chloroform:methanol=10:1) to give N-[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]propionamide(55 mg). By subjecting51 mg of the obtained compound to a reaction operation similarto that in Example 187, Step 2, N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]propionamide(27 mg) was obtained.¹H-NMR(DMSO-d₆)δ 11.59(s,1H), 9.34(s,1H), 9.12(s,1H), 7.50-7.45(m,2H),7.41-7.33(m,3H), 6.96(d,1H,J=6.0Hz), 4.98(s,1H),2.50(q,2H,J=7.5Hz), 1.06(t,3H,J=7.5Hz). Example 382Synthesis of 7-(2,2-dimethylbutyryl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0393]
[0394] By subjecting 5-benzyloxy-6-(4-fluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylicacid(100 mg) obtained by the same production method as in Example161, Step 4 to a reaction operation similar to that in Example362, Step 1, and purification by silica gel thin layerchromatography (chloroform:acetone=3:1), 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylbutyryl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 4-fluorobenzylamide (40 mg)was obtained. ¹H-NMR(CDCl₃)δ 7.86(br,1H), 7.29-7.18(m,8H),6.84(dd,2H,J=8.7Hz,8.7Hz), 5.10(s,2H), 4.54(t,1H,J=5.0Hz),4.35(d,2H,J=5.8Hz), 3.83(d,2H,J=5.0Hz), 3.30(s,6H),1.65(q,2H,J=7.5Hz), 1.19(s,6H), 0.83(t,3H,J=7.5Hz). Step 2
[0395] By subjecting 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylbutyryl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 4-fluorobenzylamide(40 mg) to a reaction operation similar tothat in Example 161, Step 6, 7-(2,2-dimethylbutyryl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (25 mg) was obtained.¹H-NMR(DMSO-d₆)δ 8.01(s,1H), 7.43(dd,2H,J=9.0Hz,5.5Hz),7.22(d,1H,J=6.3Hz), 7.19(dd,2H,J=9.0Hz,9.0Hz),6.90(d,1H,J=6.3Hz), 1.60(q,2H,J=7.5Hz), 1.13(s,6H),0.77(t,3H,J=7.5Hz). Example 283Synthesis of 2-(3-chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0396]
[0397] To a solution of 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(65 mg) obtained in Example 242, Step 1 inchloroform (1 ml) were successively added isobutylaldehyde(0.025 ml), acetic acid (0.016 ml) and sodiumtriacetoxyborohydride and the mixture was stirred at roomtemperature for 1 hr. Saturated brine (10 ml) was added to thereaction mixture and the mixture was extracted twice withchloroform (10 ml each). The organic layer was dried,concentrated and purified by silica gel thin layerchromatography (chloroform:methanol=10:1) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isobutylamino-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (68 mg).¹H-NMR(CDCl₃)δ 7.26-7.20(8H,m), 7.10(1H,d,J=7.4Hz),6.80(1H,t,J=6.0Hz), 6.63(1H,s), 5.22(2H,s), 4.55(1H,t,J=5.1Hz),4.34(2H,d,J=6.0Hz), 3.99(2H,d,J=5.1Hz), 3.31(6H,s),2.82(2H,d,J=7.0Hz), 1.93(1H,dt,J=6.5,7.0Hz), 1.01(6H,d,J=6.5Hz). Step 2
[0398] By subjecting 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isobutylamino-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chlorobenzylamide(66 mg) to a reaction operation similar tothat in Example 161, Step 6, 2-(3-chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride(43.5 mg) was obtained.¹H-NMR(DMSO-d₆)δ 8.07(1H,s), 7.64(1H,d,J=6.0Hz), 7.50-7.30(5H,m),5.09(2H,s), 2.99(2H,d,J=7.0Hz), 1.95(1H,dt,J=6.0,7.0Hz),0.91(6H,d,J=7.0Hz). Example 302Synthesis of N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-isobutylacetamide
[0399]
[0400] 2-(3-Chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (23 mg) was addedto chloroform (2 ml), and pyridine (0.062 ml) and acetylchloride (0.024 ml) were successively added at 0°C. The mixturewas stirred at room temperature for 2 hr. 5% Aqueous potassiumhydrogen sulfate solution was added to the obtained reactionmixture, and the mixture was extracted with ethyl acetate. Thesolvent was evaporated and the obtained residue was dissolved intetrahydrofuran (0.5 ml)-methanol (0.1 ml), and 1N aqueoussodium hydroxide solution (0.084 ml) was added. The mixture wasstirred at room temperature for 30 min. 2N Aqueous hydrochloricacid (0.056 ml) was added to the reaction mixture and themixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated.Crystallization from ethyl acetate-diisopropyl ether gave N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-isobutylacetamide(18.2 mg).¹H-NMR(DMSO-d₆)δ 8.27(1H,s), 7.49(1H,s), 7.39-7.32(3H,m),7.18(1H,d,J=6.0Hz), 6.92(1H,d,J=6.0Hz), 4.97(2H,s),3.53(1H,dd,J=13.7,8.6Hz), 3.12(1H,dd,J=13.7,7.2Hz), 1.76(3H,s),1.62(1H,ddt,J=7.2,8.6,6.5Hz), 0.82(6H,d,J=6.5Hz). Example 349Synthesis of N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide
[0401]
[0402] To a solution of 9-benzyloxy-7-bromo-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(170 mg) produced by the same method as in Example 249, Step 1in dioxane (1.7 ml) were added tert-butyl carbamate (49 mg),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (1.8mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg) andcesium carbonate (158 mg) under an argon stream and the mixturewas stirred at 100°C. After 10 hr, tert-butyl carbamate (49 mg),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (18mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg)were added, and the mixture was continuously stirred for 18 hrwith heating. After cooling to room temperature, insolublematerials were filtered off through celite. The solvent wasevaporated and the residue was purified by silica gel columnchromatography (chloroform:acetone=2:1) to give tert-butyl [9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]carbamate (156 mg).¹H-NMR(CDCl₃)δ 8.31(s,1H), 7.80(s,1H), 7.62(m,2H), 7.38-7.10(m,5H),7.12(dd,1H,J=8.3,8.3Hz), 5.33(s,2H), 4.65(s,2H),4.38(br,1H), 4.02-3.98(m,2H), 3.50-3.47(m,2H), 1.50(s,9H). Step 2
[0403] To a solution of tert-butyl [9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]carbamate(179 mg) in dioxane (2 ml) was added 4Nhydrochloric acid/dioxane solution (2 ml) and the mixture wasstirred at room temperature for 3.5 hr. The solvent wasevaporated and aqueous sodium hydrogen carbonate solution wasadded to the obtained residue. The mixture was extracted withchloroform. The chloroform layer was dried, concentrated andpurified by silica gel column chromatography (ethylacetate:methanol=5:1) to give 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(88mg).¹H-NMR(CDCl₃)δ 7.66-7.64(m,2H), 7.35-7.24(m,4H), 7.19-7.15(ddd,1H,J=1.9,4.4,8.6Hz),7.10(dd,1H,J=8.3,8.6Hz),6.96(s,1H), 5.27(s,2H), 4.59(s,2H), 3.91-3.88 (m,2H), 3.45-3.42(m,2H),2.42(br,2H). Step 3
[0404] To a solution of 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(29mg) in chloroform (0.6 ml) were added pyridine (0.0082 ml) andisobutyryl chloride (0.01 ml) at 0°C, and the mixture was stirredat room temperature for 1.5 hr. 5% Aqueous potassium hydrogensulfate solution was added and the mixture was extracted withethyl acetate. The obtained ethyl acetate layer was dried,concentrated and purified by silica gel thin layerchromatography (chloroform:methanol=10:1) to give N-[9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide(29 mg).¹H-NMR(CDCl₃)δ 8.80(s,1H), 8.62(s,1H), 7.66-7.64(m,2H),7.39(dd,1H,J=2.3,6.7Hz), 7.36-7.30(m,3H), 7.21(ddd,1H,J=2.3,4.6,8.4Hz), 7.14(dd,1H,J=8.3,8.8Hz),5.35(s,2H), 4.66(s,2H), 4.03-4.00(m,2H), 3.52-3.50(m,2H),2.63(sept,1H,J=7.0Hz), 1.25(d,6H,J=7.0Hz). Step 4
[0405] By subjecting N-[9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide(27 mg) to a reaction operation similar to thatin Example 223, Step 4, N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide(17 mg) was obtained.¹H-NMR(DMSO-d₆)δ 11.91(br,1H), 9.13(s,1H), 8.71(s,1H),7.64(dd,1H,J=1.6,7.9Hz), 7.43-7.39(m,2H), 4.70(s,2H), 4.30-4.26(m,2H),3.74-3.71(m,2H), 2.88(sept,1H,J=6.7Hz),1.07(d,6H,J=6.7Hz). Example 353Synthesis of N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide
[0406]
[0407] By subjecting 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(29mg) obtained in Example 349, Step 2 to a reaction operationsimilar to that in Example 349, Steps 3 and 4 except thatmethanesulfonyl chloride was used instead of isobutyryl chloride,N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide(4.7mg) was obtained.¹H-NMR(DMSO-d₆)δ 12.08(br,1H), 8.83(br,1H), 7.78(s,1H),7.63(dd,1H,J=1.7,7.7Hz), 7.42-7.40(m,2H), 4.71(s,2H), 4.30-4.27(m,2H),3.74-3.72(m,2H), 2.97(s,3H). Example 222Synthesis of 2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid methylamide hydrochloride
[0408]
[0409] 3-Benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chloro-4-fluorobenzylamide(380 mg) obtained by the same methodas in Example 161, Step 1 and 2-amino-3-methoxymethoxy-1-propanol(275 mg) were dissolved in tetrahydrofuran (2 ml)-ethanol(2 ml) and the mixture was stirred at 60°C for 1 hr. Thereaction mixture was concentrated and purified by silica gelcolumn chromatography (chloroform:methanol=10:1) to give 3-benzyloxy-5-bromo-1-(1-hydroxy-3-methoxymethoxy-2-propyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chloro-4-fluorobenzylamide(410 mg). Step 2
[0410] To a solution of oxalyl chloride (0.245 ml) in methylenechloride (1 ml) was added dropwise a solution of dimethylsulfoxide (0.269 ml) in methylene chloride (1 ml) under anitrogen stream at -78°C and the mixture was stirred for 10 min.A solution of 3-benzyloxy-5-bromo-1-(1-hydroxy-3-methoxymethoxy-2-propyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid 3-chloro-4-fluorobenzylamide(410 mg) in methylene chloride (16 ml) wasadded at the same temperature over 5 min. After stirring forfurther 10 min after the completion of the dropwise addition, triethylamine (1.37 ml) was added and the mixture was heated toroom temperature. The mixture was stirred at room temperaturefor 1 hr and concentrated. Water was added and the mixture wasextracted twice with ethyl acetate. The combined ethyl acetatelayer was washed with saturated brine, dried and concentrated.The obtained crude product was dissolved in chloroform (8 ml),and N,N-diisopropylethylamine (0.734 ml) and methanesulfonylchloride (0.101 ml) were successively added under ice-cooling.After stirring at room temperature for 2 hr, methanesulfonylchloride (0.05 ml) was added and the mixture was further stirredfor 1 hr. The reaction mixture was concentrated, and aqueoussodium hydrogen carbonate solution was added to the residue.The mixture was extracted twice with ethyl acetate. Thecombined ethyl acetate layer was washed with saturated brine,dried, concentrated and purified by silica gel columnchromatography (ethyl acetate:hexane=1:2-ethyl acetate) to give9-benzyloxy-7-bromo-2-(3-chloro-4-fluorobenzyl)-4-(methoxymethoxy)methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione(163mg).¹H-NMR(CDCl₃)δ 8.35(s,1H), 7.69-7.65(m,2H), 7.37-7.16(m,5H),7.13(dd,1H,J=8.7Hz,8.7Hz), 6.32(s,1H), 5.37(s,2H), 4.88(s,2H),4.68(s,2H), 4.46(s,2H), 3.42(s,3H). Step 3
[0411] By subjecting 9-benzyloxy-7-bromo-2-(3-chloro-4-fluorobenzyl)-4-(methoxymethoxy)methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione(125 mg) to a reaction operation similar to that inExample 161, Step 3, methyl 9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-4-(methoxymethoxy)methyl-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate(28 mg) was obtained.¹H-NMR(CDCl₃)δ 8.68(s,1H), 7.69-7.65(m,2H), 7.38-7.18(m,5H),7.13(dd,1H,J=8.5Hz,8.5Hz), 6.32(s,1H), 5.39(s,2H), 4.87(s,2H),4.69(s,2H), 4.46(s,2H), 3.96(s,3H), 3.41(s,3H). Step 4
[0412] By hydrolyzing methyl 9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-4-(methoxymethoxy)methyl-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate (27 mg) by the same methodas in Example 161, Step 4, and subsequently subjecting to amethod analogous to Example 154, 2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid methylamide hydrochloride (2.2 mg)was obtained.¹H-NMR(DMSO-d₆)δ 12.22(s,1H), 9.97(s,1H), 8.83(s,1H), 7.69-7.66(m,1H),7.44-7.41(m,2H), 7.16(s,1H), 5.68(t,1H,J=5.3Hz),4.96(s,2H), 4.50(d,2H,J=5.3Hz), 2.85(d,3H,J=4.6Hz). Example 316Synthesis of 9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride
[0413]
[0414] 3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (6.82 g) wassuspended in methanol (20 ml)-tetrahydrofuran (50 ml) and 2M(trimethylsilyl)diazomethane/hexane solution (25.8 ml) was addeddropwise under ice-cooling, and the mixture was stirred at roomtemperature for 1.5 hr. The solvent was evaporated underreduced pressure and the obtained residue was dissolved inchloroform (50 ml). Thereto was added bromine (14.2 ml) and themixture was stirred at 75°C for 2 days. After allowing themixture to return to room temperature, the mixture wasconcentrated under reduced pressure, and hexane was added to the residue. The precipitated solid was collected by filtration.The obtained solid was dissolved in dimethylformamide (40 ml)and potassium carbonate (4.59 g) and benzyl bromide (3.62 ml)were added. The mixture was stirred at 80°C for 40 min. Thesolvent was evaporated and 1N aqueous hydrochloric acid wasadded to the obtained residue. The mixture was extracted twicewith ethyl acetate. The combined ethyl acetate layer was washedwith saturated brine, dried, concentrated and purified by silicagel column chromatography (ethyl acetate:hexane=1:4-1:1). Theeluate was concentrated and the precipitated crystals werecollected by filtration to give methyl 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylate(4.69 g).¹H-NMR(CDCl₃)δ 8.10(s,1H), 7.47-7.44(m,2H), 7.38-7.32(m,3H),5.32(s,2H), 3.88(s,3H). Step 2
[0415] To a solution of methyl 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylate(2.3 g) in dioxane (25 ml) were addedtetrakis(triphenylphosphine)palladium(0) (1.57 g) and (2-thiazolyl)tributyltin(5.08 g) under an argon stream, and themixture was stirred at 100°C for 1.5 hr. The obtained reactionmixture was concentrated, and subsequently purified by silicagel column chromatography (ethyl acetate:hexane=1:4-1:2) to givemethyl 3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate(1.47 g).¹H-NMR(CDCl₃)δ 8.98(s,1H), 7.92(d,1H,J=3.2Hz), 7.53-7.48(m,3H),7.48-7.25(m,3H), 5.41(s,2H), 3.91(s,3H). Step 3
[0416] Methyl 3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate(1.47 g) was suspended in ethanol (15 ml)-dioxane(15 ml), and tert-butyl (2-aminoethyl)carbamate (0.816 ml) wasadded. After stirring at 70°C for 1.5 hr, the solvent wasevaporated and 4N hydrochloric acid/dioxane solution (70 ml) andchloroform (10 ml) were added to the residue. After stirring atroom temperature for 2 hr, the reaction mixture wasconcentration under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution (20 ml) and methanol (50 ml) wereadded to the residue and the mixture was stirred for 2 hr. Thesolvent was evaporated and the obtained solid was collected byfiltration and washed thoroughly with water to give 9-benzyloxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(1.07 g).¹H-NMR(DMSO-d₆)δ 8.84(s,1H), 8.66(brt,1H,J=3.7Hz),7.93(d,1H,J=3.2Hz), 7.68(d,1H,J=3.2Hz), 7.59(d,2H,J=6.8Hz),7.40-7.30(m,3H), 5.17(s,2H), 4.41-4.36(m,2H), 3.54-3.48(m,2H). Step 4
[0417] 9-Benzyloxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(30 mg) and 3-phenylpropyl bromide (0.02ml) were added to dimethyl sulfoxide (1 ml), and sodium hydride(7 mg) was added with stirring. After stirring for 20 min, 5%aqueous potassium hydrogen sulfate solution was added and themixture was extracted twice with ethyl acetate. The ethylacetate layer was washed with brine, dried, concentrated, andsubsequently purified by silica gel thin layer chromatography(chloroform-methanol=15:1) to give 9-benzyloxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(27 mg).¹H-NMR(CDCl₃)δ 8.50(s,1H), 7.86(d,1H,J=3.2Hz), 7.69-7.65(m,2H),7.42(d,1H,J=3.2Hz), 7.36-7.16(m,8H), 5.45(s,2H), 4.11-4.07(m,2H),3.62-3.53(m,4H), 2.70(t,2H,J=7.5Hz), 1.96(tt,2H,J=7.5Hz,7.5Hz). Step 5
[0418] To a solution of 9-benzyloxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(27 mg) in acetic acid (1 ml) was added conc. aqueoushydrochloric acid (0.5 ml) and the mixture was stirred at 90°Cfor 2 hr. The solvent was evaporated and ethyl acetate wasadded to the residue. The obtained solid was collected byfiltration to give 9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride(25 mg). ¹H-NMR(DMSO-d₆)δ 8.72(s,1H), 7.89(d,1H,J=3.1Hz),7.63(d,1H,J=3.1Hz), 7.30-7.14(m,5H), 4.45-4.40(m,2H), 3.82-3.77(m,2H),3.55(t,2H,J=7.1Hz), 2.64(t,2H,J=7.7Hz),1.91(tt,2H,J=7.1Hz,7.7Hz). Example 291Synthesis of 2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[0419]
[0420] According to a method analogous to the method described inExample 316, Step 3, 9-benzyloxy-7-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(1.05 g) was obtained frommethyl 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylate (1.2 g)obtained in Example 316, Step 1.¹H-NMR(DMSO-d₆)δ 8.61 (brt,1H,J=4.0Hz), 8.37(s,1H),7.53(dd,2H,J=8.4Hz,1.7Hz), 7.37-7.26(m,3H), 5.05(s,2H), 4.20-4.15(m,2H),3.46-3.41(m,2H). Step 2
[0421] According to a method analogous to the method described inExample 316, Step 4, 9-benzyloxy-7-bromo-2-(3,4-difluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(60 mg) wasobtained from 9-benzyloxy-7-bromo-3,4-dihydro-2H-pyrido[1,2-a)pyrazine-1,8-dione(50 mg).¹H-NMR(CDCl₃)δ 7.67-7.64(m,2H), 7.57(s,1H), 7.37-7.29(m,3H),7.18-7.10(m,2H), 7.04-6.99(m,1H), 5.33(s,2H), 4.61(s,2H), 3.96-3.92(m,2H),3.53-3.48(m,2H). Step 3
[0422] According to a method analogous to the method described inExample 249, Step 2, 9-benzyloxy-2-(3,4-difluorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(35 mg) was obtained from 9-benzyloxy-7-bromo-2-(3,4-difluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(60 mg).¹H-NMR(CDCl₃)δ 8.50(s,1H), 7.85(d,1H,J=3.3Hz), 7.69-7.65(m,2H),7.42(d,1H,J=3.3Hz), 7.38-7.30(m,3H), 7.20-7.12(m,2H), 7.07-7.02(m,1H),5.47(s,2H), 4.66(s,2H), 4.14-4.09(m,2H), 3.59-3.54(m,2H). Step 4
[0423] 9-Benzyloxy-2-(3,4-difluorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(35 mg) was dissolvedin trifluoroacetic acid (1 ml) and the mixture was stirred atroom temperature for 3 hr. Trifluoroacetic acid was evaporatedunder reduced pressure, toluene was added to the obtainedresidue and the mixture was concentrated, which operations wereperformed twice. Ethyl acetate was further added and theobtained solid was collected by filtration to give 2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione(14 mg).¹H-NMR(DMSO-d₆)δ 12.30(s,1H), 8.71(s,1H), 7.89(d,1H,J=3.2Hz),7.63(d,1H,J=3.2Hz), 7.52-7.40(m,2H), 7.28-7.22(m,1H), 4.72(s,2H),4.49-4.43(m,2H), 3.81-3.76(m,2H). Example 106Synthesis of 2-(3-chlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dioneStep 1
[0424]
[0425] To a solution of (N-benzyloxycarbonyl-N-methylamino)aceticacid (15 g) in tetrahydrofuran (150 ml) was addedcarbonyldiimidazole (16.3 g) under ice-cooling, and the mixturewas stirred at room temperature for 2 hr. A suspension ofmagnesium chloride (6.21 g) and ethyl potassium malonate (17.2g) in tetrahydrofuran (250 ml) was separately stirred at 50°C for7 hr and ice-cooled. The above-mentioned solution was addeddropwise thereto over 30 min with stirring. The mixture wasstirred for 12 hr and the solvent was evaporated under reducedpressure. Ethyl acetate and 5% aqueous potassium hydrogensulfate solution were added to the residue and the mixture wasstirred. The organic layer was washed with saturated aqueoussodium hydrogen carbonate solution and saturated brine, driedover sodium sulfate and concentrated under reduced pressure togive an oil (16.8 g). This oil was dissolved in tetrahydrofuran(120 ml)/ethanol (180 ml) and sodium borohydride (6.5 g) wasadded under ice-cooling. After 20 min, calcium chloride (9.54g) was added, and the mixture was stirred at room temperaturefor 1 hr. 1N Aqueous hydrochloric acid and ethyl acetate wereadded to the reaction mixture. The separated organic layer waswashed with saturated brine, dried over sodium sulfate, andconcentrated under reduced pressure to give an oil (12.48 g).This oil was dissolved in dimethylformamide (100 ml), and tert-butyldiphenylchlorosilane(12.81 ml) and imidazole (6.71 g) wereadded under ice-cooling, and the mixture was stirred for 1 hr.Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed with saturated brine, subsequently dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:3)to give benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxybutyl]-N-methylcarbamate(12.84 g).¹H-NMR(CDCl₃)δ 7.67(4H,d,J=7.0Hz), 7.48-7.28(11H,m), 5.14(2H,s),4.14(1H,br s), 3.89(2H,br s), 3.47-3.27(2H,m), 3.04(3H,s), 1.79-1.60(2H,m),1.07(9H,s). Step 2
[0426]
[0427] To a solution of benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxybutyl]-N-methylcarbamate(12.84 g) in chloroform (150 ml) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martin reagent)(15.50 g) under ice-cooling, and the mixture was stirred for 1hr. The reaction mixture was washed successively with saturatedaqueous sodium hydrogen carbonate solution, saturated aqueoussodium sulfite solution and saturated brine and dried oversodium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:4) to give benzylN-[4-(tert-butyldiphenylsilanyloxy)-2-oxobutyl]-N-methylcarbamate(10.92 g). To a solution of the obtainedcompound (7.95 g) in methanol (70 ml) were added methylorthoformate (70 ml) and pyridinium p-toluenesulfonate (4.08 g)and the mixture was stirred at 60°C for 18 hr. The reactionmixture was concentrated, and ethyl acetate was added to the residue and the precipitated solid was filtered off. Thefiltrate was concentrated under reduced pressure and the residuewas purified by silica gel column chromatography (ethylacetate:hexane=1:5) to give benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2,2-dimethoxybutyl]-N-methylcarbamate(2.25 g).¹H-NMR(CDCl₃)δ 7.74-7.62(4H,m), 7.45-7.22(11H,m), 5.07(1H,br s),4.96(1H,d,J=10.0Hz), 3.79(2H,br s), 3.41(2H,br s), 3.12(6H,br s),2.95(3H,s), 1.99(2H,s), 1.06 (9H,s) . Step 3
[0428]
[0429] To a solution of benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2,2-dimethoxybutyl]-N-methylcarbamate(3.22 g) in methanol (60 ml) was added 10% palladium-carbonunder a hydrogen atmosphere (3 atm), and the mixture was stirredfor 2.5 hr. Palladium-carbon was filtered off and the filtratewas concentrated to give an oil (2.44 g). This oil wasdissolved in pyridine (30 ml), methyl chloroglyoxylate (0.839 ml) was added under ice-cooling, and the mixture was stirred atthe same temperature for 30 min and at room temperature for 30min. The solvent was evaporated and saturated aqueous sodiumhydrogen carbonate solution was added to the obtained residue.The mixture was extracted with ethyl acetate and the organiclayer was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure togive an oil (2.968 g). To a solution of lithium enolateprepared from lithium bis(trimethylsilyl)amide (1Mtetrahydrofuran solution, 12.14 ml) and benzyl acetate (1.753ml) at -78°C in tetrahydrofuran (60 ml) was added the above-mentionedoil at -78°C and the mixture was stirred at the sametemperature for 20 min. Acetic acid (1.04 ml), water and ethylacetate were successively added to the reaction mixture and themixture was heated to room temperature and partitioned. Theaqueous layer was extracted with ethyl acetate, and the combinedorganic layer was washed with saturated brine, dried over sodiumsulfate, and concentrated under reduced pressure. Dioxane (50ml) and 2N aqueous hydrochloric acid solution (5 ml) were addedto the residue and the mixture was stirred at room temperaturefor 1 hr. The solvent was evaporated and subsequently, toluenewas added and concentrated again. The obtained residue wasdissolved in chloroform (40 ml) and triethylamine (20 ml) andthe mixture was stirred for 1 hr. The solvent was evaporatedand the residue was dissolved in pyridine (60 ml), and benzoylchloride (1.41 ml) was added under ice-cooling. After stirringfor 1 hr, the solvent was evaporated. Water was added to theresidue and the mixture was extracted twice with ethyl acetate.The organic layer was washed with saturated brine, dried oversodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:2) to give benzyl 3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate(2.519 g). This compound wasdissolved in methanol (75 ml) and 7.5% palladium-carbon was added. The mixture was stirred under a hydrogen atmosphere (1atm) for 1 hr. Palladium-carbon was filtered off and thefiltrate was concentrated. Crystallization from ethylacetate/hexane gave 3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylicacid (1.32 g).¹H-NMR(CDCl₃)δ 8.15(2H,d,J=8.3Hz), 7.62-7.56(5H,m), 7.49-7.36(8H,m),7.07(1H,s), 3.83(2H,t,J=6.0Hz), 3.52(3H,s),2.70(2H,t,J=6.0Hz), 1.06(9H,s). Step 4
[0430]
[0431] To a solution of 3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylicacid (0.956 g) in dimethylformamide(10 ml) were added 1-hydroxybenzotriazole hydrate (HOBT) (0.395g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(WSC) (0.495 g) and 3-chlorobenzylamine (0.274 ml) and themixture was stirred at room temperature for 2 hr. Water wasadded and the mixture was extracted twice with ethyl acetate.The organic layer was washed with saturated brine, dried oversodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-4-(3-chlorobenzylcarbamoyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-ylbenzoate (0.615 g). Thiscompound was dissolved in tetrahydrofuran (20 ml), and aceticacid (0.259 ml) and tetrabutylammonium fluoride (0.474 g) wereadded, and the mixture was stirred overnight at room temperature.The reaction mixture was concentrated, and the residue waspurified by silica gel thin layer chromatography(chloroform:methanol=10:1) to give 4-(3-chlorobenzylcarbamoyl)-5-(2-hydroxyethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-ylbenzoate (0.213 g).¹H-NMR(CDCl₃)δ 8.04(2H,d,J=7.4Hz), 7.64(1H,t,J=7.4Hz),7.46(2H,t,J=7.9Hz), 7.22(1H,s), 7.15(1H,s), 6.99(2H,d,J=7.9Hz),6.86(1H,t,J=7.9Hz), 6.67(1H,t,J=6.5Hz), 4.43(2H,d,J=6.0Hz),3.86-3.78(2H,m), 2.69(2H,t,J=6.0Hz), 2.67(1H,br s). Step 5
[0432]
[0433] To a solution of 4-(3-chlorobenzylcarbamoyl)-5-(2-hydroxyethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-ylbenzoate(0.1 g) in tetrahydrofuran (4 ml) were successively addeddiisopropylethylamine (0.119 ml) and methanesulfonyl chloride(0.035 ml) under ice-cooling. After 20 min,diisopropylethylamine (0.119 ml) and methanesulfonyl chloride(0.035 ml) were further added and the mixture was stirred underice-cooling for 20 min. Water was added and the mixture wasextracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, andconcentrated under reduced pressure. The residue wascrystallized from ethyl acetate/hexane and the crystals werecollected by filtration to give crystals (0.15 g). The crystalswere dissolved in dimethylformamide (3 ml) and sodium hydride(0.09 g, 60%) was added under ice-cooling. The mixture wasstirred at room temperature for 30 min. Ethyl acetate and 2Naqueous hydrochloric acid solution were added and the mixturewas extracted. The organic layer was washed with saturatedbrine, dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel thin layerchromatography (ethyl acetate-chloroform:methanol=6:1) andcrystallized from ethyl acetate/hexane and the crystals werecollected by filtration to give 2-(3-chlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(0.029 g).¹H-NMR(CDCl₃)δ 12.75(1H,s), 7.33-7.29(3H,m), 7.24-7.19(1H,m),6.61(1H,s), 4.71(2H,s), 3.57(3H,s), 3.46(2H,t,J=6.4Hz),2.73(2H,t,J=6.4Hz). Example 123Synthesis of 6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido[4,3-c]pyridazine-3,5-dioneStep 1
[0434]
[0435] To a solution of 3-chlorobenzylamine (15 g) in ethanol(150 ml) was added dropwise a solution of ethyl acrylate (11.5ml) in ethanol at room temperature and the mixture was stirredovernight. The reaction mixture was concentrated under reducedpressure and chloroform (500 ml), pyridine (50 ml) and 4-dimethylaminopyridine(3.9 g) were added to the residue. Ethylmalonyl chloride (13.6 ml) was added dropwise to this mixture under ice-cooling, and the mixture was stirred under ice-coolingfor 1 hr, and further at room temperature for 1 hr. Thereaction mixture was washed with 2N aqueous hydrochloric acid,saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over magnesium sulfate. The mixturewas concentrated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=2:1-3:2) to give an oil (25.6 g). A solution of thisoil (25.6 g) in toluene (50 ml) was added dropwise to asuspension of potassium carbonate (50 g) and 18-crown-6 (1.9 g)in toluene (250 ml) with heating under reflux and the mixturewas stirred at the same temperature for 12 hr. After cooling toroom temperature, the reaction mixture was poured into icedwater, 6N aqueous hydrochloric acid was added to adjust the pHof the reaction mixture to not more than 1 and the mixture wasextracted three times with chloroform. The chloroform layer wasdried, concentrated and 10% aqueous oxalic acid solution (200ml) was added to the obtained residue. The mixture was heatedunder reflux for 3 hr. The reaction mixture was cooled,extracted three times with chloroform, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:3-1:2) to give 1-(3-chlorobenzyl)piperidine-2,4-dione(6.2 g).¹H-NMR(CDCl₃)δ 7.1-7.4(4H,m), 4.67(2H,s), 3.51(2H,t,J=6.3Hz),3.44(2H,s), 2.58 (2H,t,J=6.3Hz) . Step 2
[0436]
[0437] 1-(3-Chlorobenzyl)piperidine-2,4-dione (1.2 g) wasdissolved in ethanol (25 ml), and methylhydrazine (0.5 ml) wasadded. The mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure and theobtained residue was purified by silica gel columnchromatography (chloroform:methanol=95:1) to give 1-(3-chlorobenzyl)-4-(methylhydrazono)piperidin-2-one(1.05 g).¹H-NMR(CDCl₃)δ 7.1-7.4(4H,m), 4.2-4.8(3H,m), 3.2-3.5(4H,m),2.95(3H,s), 2.3-2.7(2H,m). Step 3
[0438]
[0439] 1-(3-Chlorobenzyl)-4-(methylhydrazono)piperidin-2-one(1.05 g) was dissolved in chloroform (20 ml) and triethylamine(1.2 ml) and methyl oxalyl chloride (0.735 ml) were successivelyadded under ice-cooling. After stirring at room temperature for2 hr, the reaction mixture was washed with saturated aqueoussodium hydrogen carbonate solution and saturated aqueous sodiumchloride solution, and dried over magnesium sulfate. Themixture was concentrated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=2:3-ethyl acetate-chloroform:methanol=90:10)to give an oil (200 mg). This oilwas dissolved in tetrahydrofuran (4 ml), sodium hydride (27 mg)was added under ice-cooling and the mixture was stirred at thesame temperature for 30 min. 5% Aqueous potassium hydrogensulfate solution was added to the reaction mixture and themixture was extracted three times with ethyl acetate. The ethylacetate layer was washed with saturated brine and dried overmagnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gelcolumn chromatography (chloroform:methanol=90:10) to give 6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido[4,3-c]pyridazine-3,5-dione(92 mg). ¹H-NMR(DMSO-d₆)δ 13.41(1H,s), 7.39-7.33(4H,m), 4.70(2H,s), 3.64-3.56(5H,m),2.85(2H,t,J=6.5Hz). Example 438
[0440] 7-(2,2-Dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride (7.5 g) obtainedin the same manner as in Example 251 was suspended in ethylacetate (1.5 L) and saturated aqueous sodium hydrogen carbonate(500 ml) was added with stirring. After the suspended substancewas dissolved, the aqueous layer was separated and extractedwith a small amount of ethyl acetate. The combined ethylacetate layer was washed with saturated brine, dried over sodiumsulfate, and concentrated. Acetone-ethyl acetate was added tothe obtained residue and the obtained crystals were collected byfiltration to give 7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione(6.38 g).¹H-NMR(DMSO-d₆)δ 11.65(1H,br), 8.04(1H,s),7.44(2H,dd,J=8.8,5.1Hz), 7.19(2H,dd,J=8.8,8.8Hz),7.18(1H,d,J=6.0Hz), 6.88(1H,d,J=6.0Hz), 4.92(2H,s), 1.17(9H,s). Example 439
[0441] 7-(2,2-Dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione(100 mg) obtained in Example 438was suspended in tetrahydrofuran-methanol (3:1) (4 ml). 1MAqueous sodium hydroxide solution (270 µl) was added and themixture was stirred for 24.5 hr. The precipitate was collectedby filtration, washed with tetrahydrofuran and dried in vacuo at50°C to give 7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionesodium salt (94 mg).¹H-NMR(DMSO-d₆)δ 7.48(1H,s), 7.37(2H,dd,J=8.8,5.6Hz),7.12(2H,t,J=8.8Hz), 6.86(1H,d,J=6.3Hz), 6.57(1H,d,J=6.3Hz),4.78(2H,s), 1.21(9H,s).
[0442] Sodium salt, potassium salt, hydrochloride,trifluoroacetate, methanesulfonate, benzenesulfonate andtoluenesulfonate were obtained from the compound of Example 165by conventional methods.N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide sodium salt (Example 440)¹H-NMR(DMSO-d₆)δ 8.92(1H,brs), 8.54(1H,s), 7.41-7.26(4H,m),6.97(1H,brs), 6.60(1H,brs), 4.83(2H,s), 2.08 (3H,s).
[0443] A free compound and a sodium salt were obtained from thecompound of Example 223 by conventional methods.2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionesodium salt (Example441)¹H-NMR(DMSO-d₆)δ 7.39-7.24(5H,m), 4.65(2H,s), 4.17-4.05(2H,m),3.54-3.47(2H,m), 1.23(9H,s).
[0444] A free compound, a sodium salt, a potassium salt and abenzenesulfonic acid salt were obtained from the compound ofExample 251 by conventional methods. Examples 93-437
[0445] The compounds of Examples 93-437 other than the above-mentionedcompounds were obtained by methods similar oranalogous to those of Examples 1-12, 118, 125, 161, 165, 94, 96,104, 187, 191, 189, 390, 244, 251, 223, 154, 249, 219, 362, 205,242, 382, 283, 302, 349, 353, 222, 316, 291, 106, 123, 438 and439 or conventional methods.
[0446] The chemical structural formulas and physicochemical dataof Example compounds are shown in Tables 1-37.
[0447] The following explains evaluation methods of the HIVintegrase inhibitory activity of the compound of the presentinvention. (i) Construction of recombinant integrase gene expression system
[0448] The 185th phenylalanine of HIV integrase full length gene(J. Virol., 67, 425-437 (1993)) was substituted by histidine andinserted into the restriction enzyme NdeI and XhoI sites ofplasmid pET21a(+) (Novagen), whereby an integrase expressionvector pET21a-INH was constructed. (ii) Production and purification of integrase protein
[0449] Escherichia coli recombinant BL21(DE3) transformed withplasmid pET21a-INH obtained in (i) was shake cultured at 37°C ina liquid medium containing ampicillin. When the culture reachedthe logarithmic growth phase, isopropyl-β-D-thiogalactopyranosidewas added to promote expression ofintegrase gene. The culture was continued for 3 hr to promoteaccumulation of the integrase protein. The recombinant E. coliwas collected in pellets by centrifugal separation and preservedat -80°C.
[0450] The E. coli was suspended in Lysis buffer (20 mM HEPES (pH7.5), 5 mM DTT, 10 mM CHAPS, 10% glycerol) containing 1M sodiumchloride and subjected to repeat pressurization anddepressurization for rupture, and centrifugal separation at 4°C,40,000xg, 60 min to recover a water-soluble fraction(supernatant). This was diluted 10-fold with Lysis buffer freeof sodium chloride, mixed with SP-Sepharose (PharmaciaCorporation) and stirred at 4°C for 30 min to allow adsorption ofintegrase protein to the resin. The resin was washed with Lysisbuffer containing 100 mM sodium chloride and the integraseprotein was eluted with Lysis buffer containing 1M sodiumchloride.
[0451] The eluted integrase protein solution was applied to aSuperdex 75 (Pharmacia Corporation) column for gel filtration. The protein was eluted with Lysis buffer containing 1M sodiumchloride.
[0452] The obtained fractions of the integrase protein werecollected and preserved at -80°C. (iii) Preparation of DNA solution
[0453] The following DNA synthesized by Greiner was dissolved inTE buffer (10 mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA) andmixed with donor DNA, target DNA, and each complementary strand(+ and - strands) to 1 µM. The mixture was heated at 95°C for 5min, 80°C for 10 min, 70°C for 10 min, 60°C for 10 min, 50°C for10 min and 40°C for 10 min and preserved at 25°C to give a doublestranded DNA, which was used for the test.Donor DNA (- strand having biotin attached to the 5' terminal)
[0454] The donor DNA was diluted with TE buffer to 10 nM, ofwhich 50 µl was added to each well of streptavidin-coatedmicrotiter plate (Roche) and allowed to adsorb at 37°C for 60min. The DNA was washed with phosphate buffer (Dulbecco PBS,Sanko Junyaku Co., Ltd.) containing 0.1% Tween 20 and phosphatebuffer. Then, a reaction mixture (70 µl) having the followingcomposition, a test substance (10 µl) diluted with the reactionmixture and 100 µg/ml integrase protein (10 µl) were added toeach well and reacted at 37°C for 60 min.
[0455] Composition of the reaction mixture: 30 mM MOPS (3-morpholinopropanesulfonicacid), 5 mM magnesium chloride, 3mM DTT (dithiothreitol), 0.1 mg/ml BSA (bovine serum albumin), 5%glycerol, 10% DMSO (dimethyl sulfoxide), 0.01% Tween 20.
[0456] Then, 50 nM target DNA (10 µl) was added, reacted at 37°Cfor 10 min and washed with phosphate buffer containing 0.1%Tween 20 to stop the reaction.
[0457] Then, 100 mU/ml peroxidase labeled anti-digoxigeninantibody solution (Roche, 100 µl) was added, and the mixture wasreacted at 37°C for 60 min, followed by washing with phosphatebuffer containing 0.1% Tween 20.
[0458] A peroxidase color solution (Bio Rad, 100 µl) was addedand allowed to react at room temperature for 4 min. The colorreaction was stopped by adding 1N sulfuric acid (100 µl). Theabsorbance at 450 nm was measured.
[0459] The HIV integrase inhibitory activity (IC₅₀) of thecompound of the present invention was calculated from theinhibition rate according to the following formula.inhibition rate (%)=[1-(Object-Blank) / (Control-Blank) ]×100Object; absorbance of well in the presence of test compoundControl; absorbance of well in the absence of test compoundBlank; absorbance of well in the absence of test compound, inthe absence of integrase protein
[0460] The results are shown in Tables 38-46. IC₅₀ shows thefollowing ranges. + : not less than 1 µM and less than 10 µM ++ : not less than 0.1 µM and less than 1 µM +++ : not less than 0.01 µM and less than 0.1 µM ++++ : less than 0.01 µM Experimental Example 2 Evaluation of antivirus activity
[0461] The effect of combined use of the compound of the presentinvention and existent anti-HIV agents can be determined in thefollowing manner.
[0462] For example, the effect of combined use of two agentsfrom existent nucleoside reverse transcriptase inhibitors(zidovudine, lamivudine, tenofovir), non-nucleoside reversetranscriptase inhibitors (efavirenz) or protease inhibitors(indinavir, nelfinavir) and test substance A and the like areevaluated using CEM-SS cells infected with HIV-1 IIIB by XTTmethod.
[0463] In addition, the effect of combined use of three agentsof test substance A, zidovudine and lamivudine, or testsubstance A, tenofovir and lamivudine, and the like is evaluated.
[0464] Prior to the combined use test, IC₅₀ and CC₅₀ of eachpharmaceutical agent alone are measured. 5 concentrations ofpharmaceutical agent A and 9 concentrations of pharmaceuticalagent B, determined based on these results, are combined toevaluate the effect of combined use of two agents. For combineduse of three agents, a high concentration pharmaceutical agent Band a pharmaceutical agent C are mixed and pharmaceutical agentA and the concentration are combined for evaluation.
[0465] The test results of the test substance and combinationdrug alone or in combination thereof are analyzed based on theprograms of Prichard and Shipman MacSynergy II version 2.01 andDeltagraph version 1.5d. A three-dimensional plot is drawnfrom % inhibition at the concentrations of each combinedpharmaceutical agent, obtained from 3 times of tests, with 95%(or 68%, 99%) confidence limits, and the effect of the combineduse is evaluated based on the numerical values of µM²% calculatedtherefrom. The criteria of evaluation are shown in thefollowing. Definition of interaction µM²% Strong synergistic action >100 Slight synergistic action +51 - +100 Additive action +50 - -50 Slight antagonistic action -51 - -100 Strong antagonistic action <-100 Example No. IC₅₀ Example No. IC₅₀1 ++++ 3 +++ 4 +++ 5 +++ 6 +++ 7 ++++ 8 ++++ 9 +++ 10 +++ 11 ++++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 ++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 ++ 45 +++ 46 +++ 47 ++++ 48 +++ 49 +++ Example No. IC₅₀ Example No. IC₅₀50 +++ 51 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 ++++ 59 ++++ 60 +++ 61 +++ 62 +++ 63 ++++ 64 +++ 65 ++ 66 +++ 67 +++ 68 +++ 70 +++ 71 +++ 72 ++++ 73 +++ 75 +++ 76 +++ 78 ++++ 79 +++ 80 +++ 81 ++++ 82 +++ 83 +++ 84 ++++ 85 +++ 86 ++++ 87 ++++ 88 +++ 89 +++ 90 ++++ 91 +++ 92 ++++ 93 +++ 94 +++ 95 +++ 96 ++++ 97 +++ 98 +++ 99 +++ 100 +++ 101 +++ Example No. IC₅₀ Example No. IC₅₀102 +++ 103 +++ 104 +++ 105 +++ 106 +++ 107 +++ 108 +++ 109 ++ 110 ++ 111 +++ 112 +++ 113 +++ 114 ++++ 115 ++++ 116 ++++ 117 ++++ 118 +++ 119 ++ 120 ++++ 121 ++++ 122 ++++ 123 ++ 124 +++ 125 ++++ 126 +++ 127 ++++ 128 +++ 129 +++ 130 ++++ 131 +++ 132 +++ 133 ++++ 134 +++ 135 +++ 136 ++++ 137 +++ 138 +++ 139 +++ 140 +++ 141 ++++ 142 +++ 143 ++ 144 +++ 145 ++ 146 ++ 147 +++ 148 +++ 149 ++++ Example No. IC₅₀ Example No. IC₅₀150 +++ 151 +++ 152 ++ 153 +++ 154 +++ 155 ++++ 156 +++ 157 +++ 158 +++ 159 +++ 160 +++ 161 +++ 162 +++ 163 ++++ 164 +++ 165 +++ 166 +++ 167 +++ 168 +++ 169 ++ 170 +++ 171 ++++ 172 ++++ 173 +++ 174 +++ 175 ++++ 176 +++ 177 +++ 178 +++ 179 +++ 180 ++++ 181 +++ 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 +++ 193 +++ 194 +++ 195 +++ 196 +++ 197 +++ Example No. IC₅₀ Example No. IC₅₀198 +++ 199 +++ 200 ++ 201 +++ 202 +++ 203 ++++ 204 ++++ 205 ++++ 206 +++ 207 ++++ 208 ++++ 209 +++ 210 +++ 211 ++++ 212 +++ 213 +++ 214 ++++ 215 ++++ 216 +++ 217 ++++ 218 ++++ 219 +++ 220 +++ 221 ++++ 222 ++++ 223 +++ 224 +++ 225 ++++ 226 ++ 227 +++ 228 +++ 229 ++++ 230 ++++ 231 ++++ 232 ++++ 233 ++++ 234 ++++ 235 +++ 236 +++ 237 +++ 238 ++++ 239 ++++ 240 ++++ 241 ++++ 242 ++++ 243 ++++ 244 ++++ 245 +++ Example No. IC₅₀ Example No. IC₅₀246 +++ 247 +++ 248 ++++ 249 ++++ 250 +++ 251 ++++ 252 ++++ 253 ++++ 254 ++++ 255 ++++ 256 ++++ 257 ++++ 258 ++++ 259 ++++ 260 ++++ 261 +++ 262 ++++ 263 ++++ 264 ++++ 265 ++++ 266 ++++ 267 +++ 268 ++++ 269 ++++ 270 +++ 271 +++ 272 +++ 273 +++ 274 +++ 275 ++++ 276 ++++ 277 ++++ 278 ++++ 279 ++++ 280 +++ 281 +++ 282 ++++ 283 +++ 284 +++ 285 +++ 286 ++++ 287 ++++ 288 ++++ 289 ++++ 290 +++ 291 +++ 292 ++++ 293 +++ Example No. IC₅₀ Example No. IC₅₀294 ++++ 295 +++ 296 ++++ 297 +++ 298 ++++ 299 +++ 300 +++ 301 ++ 302 +++ 303 +++ 304 ++++ 305 ++++ 306 +++ 307 ++ 308 +++ 309 +++ 310 ++ 311 ++++ 312 +++ 313 +++ 314 +++ 315 +++ 316 +++ 317 +++ 318 +++ 319 +++ 320 ++++ 321 +++ 322 +++ 323 +++ 324 +++ 325 +++ 326 ++ 327 ++++ 328 +++ 329 +++ 330 ++++ 331 +++ 332 +++ 333 +++ 334 +++ 335 +++ 336 ++++ 337 ++++ 338 +++ 339 ++ 340 ++++ 341 ++++ Example No. IC₅₀ Example No. IC₅₀342 ++++ 343 ++++ 344 ++++ 345 ++++ 346 +++ 347 ++++ 348 +++ 349 +++ 350 ++++ 351 +++ 352 +++ 353 ++++ 354 +++ 355 +++ 356 +++ 357 +++ 358 +++ 359 +++ 360 ++++ 361 +++ 362 +++ 363 +++ 364 ++++ 365 +++ 366 ++ 367 +++ 368 +++ 369 ++++ 370 ++++ 371 +++ 372 +++ 373 ++++ 374 +++ 375 +++ 376 +++ 377 ++++ 378 ++++ 379 ++ 380 +++ 381 +++ 382 +++ 383 +++ 384 ++++ 385 +++ 386 +++ 387 +++ 388 ++ 389 +++ Example No. IC₅₀ Example No. IC₅₀391 +++ 392 +++ 393 +++ 394 +++ 395 ++++ 396 +++ 397 +++ 398 +++ 399 ++++ 400 ++++ 401 +++ 402 +++ 403 +++ 404 +++ 405 ++++ 406 +++ 407 +++ 408 +++ 409 +++ 410 +++ 411 +++ 412 +++ 413 ++ 414 ++ 415 +++ 416 +++ 417 +++ 418 +++ 419 ++++ 420 +++ 421 +++ 422 +++ 423 +++ 424 +++ 425 ++++ 426 +++ 427 +++ 428 +++ 429 +++ 430 +++ 431 +++ 432 ++++
[0466] As is clear from the above-mentioned results, the compoundof the present invention shows high inhibitory activity againstHIV integrase.
[0467] Therefore, these compounds can be a pharmaceutical agenteffective for the prophylaxis or treatment of AIDS, as an anti-HIV agent having an HIV integrase inhibitory activity. Inaddition, by the combined use with other anti-HIV agents such asa protease inhibitor, a reverse transcriptase inhibitor and thelike, it can be a more effective anti-HIV agent. Because itshows integrase-specific high inhibitory activity, the compoundcan be a pharmaceutical agent safe on human body, which causesonly a fewer side effects.
[0468] While a Formulation Example is given in the following, thepresent invention is not limited to this example. Formulation Example(a) Compound of Example 1 10 g (b) Lactose 50 g (c) Cornstarch 15 g (d) Carboxymethylcellulose sodium 44 g (e) Magnesium stearate 1 g
[0469] The total amount of (a), (b) and (c) and 30 g of (d) arekneaded with water, and, after vacuum drying, granulated. Thegranules are mixed with 14 g of (d) and 1 g of (e) and appliedto a tableting machine to give 1000 tablets, each containing 10mg of (a). Industrial Applicability
[0470] The present invention relates to a novel nitrogen-containingfused ring compound and a pharmaceutically acceptablesalt thereof, which are useful as anti-HIV agents, and novel useof a certain kind of nitrogen-containing fused ring compound anda pharmaceutically acceptable salt thereof as anti-HIV agents.More specifically, the present invention relates to an anti-HIVagent containing a nitrogen-containing fused ring compound or apharmaceutically acceptable salt thereof showing an anti-HIVactivity particularly based on an integrase inhibitory activity.They are effective for the prophylaxis or treatment of the onsetof AIDS. Particularly, since they have an integrase inhibitoryactivity, they can be effective anti-HIV agents and the present invention can provide pharmaceutical agents having an anti-HIVactivity, particularly pharmaceutical agents having an integraseinhibitory activity. Sequence Listing Free Text
[0471] SEQ ID NO:1: Donor + strand for activity determination of HIVintegraseSEQ ID NO:2: Donor - strand for activity determination of HIVintegraseSEQ ID NO:3: Target + strand for activity determination of HIVintegraseSEQ ID NO:4: Target - strand for activity determination of HIVintegrase
[0472] This application is based on patent application Nos.2003-293117 and 2004-134896 filed in Japan, the contents ofwhich are hereby incorporated by reference.

权利要求:
Claims (38)
[1] A nitrogen-containing fused ring compound represented by thefollowing formula [I] or a pharmaceutically acceptable saltthereof:
[2] The nitrogen-containing fused ring compound of claim 1,whereinY ¹ -----Y ² -----Y³ of ring B is C=C(R^y1)-N(R^y2), N-C(R^y1)=N,N-C(R^y1)=C(R^y2) or C=N-N(R^y2), wherein each symbol is as definedin claim 1, or a pharmaceutically acceptable salt thereof.
[3] The nitrogen-containing fused ring compound of claim 2, whichis represented by the following formula [I]-1, or apharmaceutically acceptable salt thereof:
[4] The nitrogen-containing fused ring compound of claim 2, whichis represented by the following formula [I]-2, or apharmaceutically acceptable salt thereof:
[5] The nitrogen-containing fused ring compound of claim 2, whichis represented by the following formula [I]-3, or apharmaceutically acceptable salt thereof:
[6] The nitrogen-containing fused ring compound of claim 2, whichis represented by the following formula [I]-4, or apharmaceutically acceptable salt thereof:
[7] The nitrogen-containing fused ring compound of any of claims1-6, wherein X is -C(R^x1) (R^x2)-C(R^x3) (R^x4)-#, -C(R^x1) (R^x2)-C(R^x3) (R^x4)-C(R^x5) (R^x6)-#, -C(R^x7) =C(R^x8)-#, -N=C(R^x9)-# or-C(R^x10)=N-# wherein each symbol is as defined in claim 1, or apharmaceutically acceptable salt thereof.
[8] The nitrogen-containing fused ring compound of claim 7,wherein X is -C(R^x1) (R^x2)-C(R^x3) (R^x4)-# or -C (R^x7) =C (R^x8) -# whereineach symbol is as defined in claim 1, or a pharmaceuticallyacceptable salt thereof.
[9] The nitrogen-containing fused ring compound of claim 8,wherein X is -C(R^x1) (R^x2)-C(R^x3) (R^x4)-# wherein each symbol is asdefined in claim 1, or a pharmaceutically acceptable saltthereof.
[10] The nitrogen-containing fused ring compound of claim 8,wherein X is -C(R^x7)=C(R^x8)-# wherein each symbol is as defined inclaim 1, or a pharmaceutically acceptable salt thereof.
[11] The nitrogen-containing fused ring compound of any of claims1-6, wherein R¹ is a group represented by the formula
[12] The nitrogen-containing fused ring compound of claim 11,wherein Z is a C1-6 alkylene, or a pharmaceutically acceptablesalt thereof.
[13] The nitrogen-containing fused ring compound of claim 11,wherein ring D is a C3-10 carbon ring group optionallysubstituted by 1 to 3 substituent(s) selected from group B, or apharmaceutically acceptable salt thereof.
[14] The nitrogen-containing fused ring compound of any of claims1-6, wherein R^x1 to R^x10 are each independently selected from thefollowing groups and R^x1 and R^x2, R^x3 and R^x4, and R^x5 and R^x6 eachindependently optionally form, together with the adjacent carbonatom, a C3-8 cycloalkyl, or a pharmaceutically acceptable saltthereof:
a hydrogen atom,
a C3-8 cycloalkyl C1-6 alkyl group,
a cyano group,
a C1-7 alkyl group,
a C6-14 aryl group,
a C6-14 aryl C1-6 alkyl group,
-CO₂R^c1,
-CONR^c2R^c3 and,
-COR^c4 wherein the above-mentioned C1-7 alkyl group and C1-6 alkylmoiety are optionally substituted by 1 to 3 substituent(s)selected from group A or a heterocyclic group, and other symbolsare as defined in claim 1.
[15] The nitrogen-containing fused ring compound of claim 14,wherein R^x1 to R^x10 are each a hydrogen atom, or apharmaceutically acceptable salt thereof.
[16] The nitrogen-containing fused ring compound of any of claims1-6, wherein R^y1 is selected from the following groups, or apharmaceutically acceptable salt thereof:
a hydrogen atom,
a C1-7 alkyl group,
a C6-14 aryl group,
-CO₂R^c1,
-CONR^c2R^c3,
-COR^c4 and,
a C6-14 arylcarbonyl group wherein the above-mentioned C1-7 alkyl group is optionallysubstituted by 1 to 3 substituent(s) selected from group A or aheterocyclic group, the above-mentioned C6-14 aryl group isoptionally substituted by 1 to 3 substituent(s) selected fromgroup B, and other symbols are as defined in claim 1.
[17] The nitrogen-containing fused ring compound of claim 16,wherein R^y1 is a hydrogen atom, or a pharmaceutically acceptablesalt thereof.
[18] The nitrogen-containing fused ring compound of any of claims1-6, wherein R^y2 is selected from the following groups, or apharmaceutically acceptable salt thereof:
a hydrogen atom,
a halogen atom,
a C1-7 alkyl group
a C6-14 aryl group,
a heterocyclic group,
-CO₂R^c1,
-CONR^c2R^c3,
-COR^c4,
-NR^c4R^c5,
-NR^c6COR^c7,
-NR^c8SO₂R^c9,
-SR^c10,
-SO₂R^c12,
-NR^c13CONR^c14R^c15,
-NR^c16CO₂R^c17 and,
-NR^c18COCOR^c19 wherein the above-mentioned C1-7 alkyl group is optionallysubstituted by 1 to 3 substituent(s) selected from group A or aheterocyclic group, the above-mentioned C6-14 aryl group andheterocyclic group are optionally substituted by 1 to 3substituent(s) selected from group B, and other symbols are asdefined in claim 1.
[19] The nitrogen-containing fused ring compound of claim 18,wherein R^y2 is a heterocyclic group optionally substituted by 1to 3 substituent(s) selected from group B, or a pharmaceuticallyacceptable salt thereof.
[20] The nitrogen-containing fused ring compound of claim 19,wherein R^y2 is a heterocyclic group optionally substituted by 1to 3 substituent(s) selected from group B, which is bonded to Y³via a carbon atom, wherein at least one α-position of the carbonatom is a hetero atom selected from the group consisting ofnitrogen atom, oxygen atom and sulfur atom, or apharmaceutically acceptable salt thereof.
[21] The nitrogen-containing fused ring compound of claim 18,wherein R^y2 is selected from -CO₂R^c1, -CONR^c2R^c3 and -COR^c4 whereineach symbol is as defined in claim 1, or a pharmaceuticallyacceptable salt thereof.
[22] The nitrogen-containing fused ring compound of claim 18,wherein R^y2 is selected from -NR^c4R^c5, -NR^c6COR^c7, -NR^c8SO₂R^c9,-NR^c13CONR^c14R^c15, -NR^c16CO₂R^c17 and -NR^c18COCOR^c19 wherein each symbolis as defined in claim 1, or a pharmaceutically acceptable saltthereof.
[23] The nitrogen-containing fused ring compound of claim 22,wherein R^y2 is selected from -NR^c6COR^c7, -NR^c8SO₂R^c9,-NR^c13CONR^c14R^c15, -NR^c16CO₂R^c17 and -NR^c18COCOR^c19 wherein each symbolis as defined in claim 1, or a pharmaceutically acceptable saltthereof.
[24] The nitrogen-containing fused ring compound of any of claims1-6, wherein R² is a hydrogen atom, or a pharmaceuticallyacceptable salt thereof.
[25] The nitrogen-containing fused ring compound of claim 1,which is selected from the group consisting of2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3,4-dichlorobenzyl)-10-hydroxy-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,9-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylicacid, 2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-[3-(2,6-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dionehydrochloride,2-(3,4-dichlorobenzyl)-9-hydroxy-4-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,4-benzyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-phenyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,4-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-3,3-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-4-spiro-1'-cyclopentane-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-4-spiro-1'-cyclohexane-1,8-dione,methyl 2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-4-carboxylate,2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-4-carboxylicacid,2-(3,4-dichlorobenzyl)-9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N,N-dimethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide, 3-benzyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,3-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N,N-dimethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-4-carboxamide,2-(3,4-dichlorobenzyl)-9-hydroxy-4-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-methoxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-methylsulfanylmethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-methanesulfonylmethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2-methanesulfonylethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2-methylsulfanylethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,methyl 2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylate,6-acetyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropylsulfanylmethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropylsulfonylmethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropoxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutoxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxyethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-phenoxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione, 2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-benzyl-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutyryl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carbaldehyde,2-(3,4-dichlorobenzyl)-9-hydroxy-6-phenyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-hydroxy-2-(3-phenylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chloro-2-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-hydroxy-2-phenethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxy-2-methylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,N-methyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,2-(4-chloro-3-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,6-benzoyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-propionyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione, 2-(3,4-dichlorobenzyl)-9-hydroxy-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N,N-diethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,N-isopropyl-N-methyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,N-ethyl-N-methyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(2-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,5-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,6-tert-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxy-2,2-dimethylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,3-benzyl-9-hydroxy-2-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(4-chlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(2-chlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-methoxybenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-hydroxy-2-methyl-3-phenethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,[2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-6-yl]acetonitrile,2-[3-(3-chlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-hydroxy-2-methyl-3-(3-phenylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione, 2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(3,4-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(3,5-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,benzyl [2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-6-yl]acetate,benzyl 2-[2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-6-yl]-3-phenylpropionate,2-(3,4-dichlorobenzyl)-9-hydroxy-6-(2-hydroxyethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-propyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-4-ethyl-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-hydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-isobutyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,methyl 2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carboxylate,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-[3-(2,3-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,methyl 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carboxylate,7-bromo-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride, 2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carboxylicacid,3-(3-chlorobenzyl)-5-hydroxy-3H-pyrazino[1,2-a]quinoline-4,6-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carbaldehyde,2-(3-chlorobenzyl)-9-hydroxy-4-hydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-4-(1-hydroxyethyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,4-acetyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carbonitrile,2-(3-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione,7-bromo-2-(3-chlorobenzyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-9-ylmethanesulfonate,7-bromo-2-(3-chlorobenzyl)-3,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,3-(3-chlorobenzyl)-5-hydroxy-2,3-dihydro-1H-pyrazino[1,2-a]quinoline-4,6-dione,2-(3-chlorobenzyl)-7-(3-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,2-(3-chlorobenzyl)-7-(4-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-(2-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-3-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(1-hydroxy-2,2-dimethylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-4-cyclohexylmethyl-9-hydroxy-7-phenyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-(furan-2-yl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3,4-dichlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,2-[3-(2-chloro-6-fluorophenyl)propyl]-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido[4,3-c]pyridazine-3,5-dione,7-(benzofuran-2-yl)-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-(2,2-dimethylpropyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(2-trifluoromethylphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(3-methoxyphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,7-bromo-2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride, 2-(3-chlorobenzyl)-7-(2-fluorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-7-phenyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(2-methoxyphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(4-methoxyphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-ethyl-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-(2,6-dimethylphenyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxyphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,7-benzoyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-(2-ethylphenyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-(3-chlorophenyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,7-benzyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(2-hydroxyphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-(4-hydroxyphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,8-hydroxy-6-methyl-2-(3-trifluoromethylbenzyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,8-hydroxy-2-(3-methoxybenzyl)-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6-dihydropyrido[4,3-c]pyridazine-3,5-dione,3-(3-chlorobenzyl)-5-hydroxy-3H-pyrido[2,1-f][1,2,4]triazine-4,6-dione,methyl 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate hydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(1-methyl-1H-imidazol-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-isobutyryl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,isopropyl 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate,2-(4-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid hydrochloride,N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid isopropylamide,N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N,N-diethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(4-bromobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-bromobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2,2-dimethylpropyl 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate,cyclohexyl 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate,7-amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-4-methyl-2H-pyrido[1,2-d][1,2,4]triazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(4H-1,2,4-triazol-3-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride, N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide,2-(4-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-[2-(2-chlorophenoxy)ethyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-propyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-butyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-isobutyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,methyl {[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carbonyl]amino}acetate,N-ethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-(2-methoxyethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carbonyl]amino}ethyltrifluoroacetate,N-(2-hydroxyethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chloro-2-hydroxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-benzyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-(2,2,2-trifluoroethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-butyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide, N-(2-methoxyethyl)-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-7-(pyrrolidine-1-carbonyl)-2Hpyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-(morpholine-4-carbonyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-chloro-3-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,methyl [2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetate,2-(3-chlorobenzyl)-9-hydroxy-7-(1H-tetrazol-5-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-methylacetamide,2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N,N-dimethylacetamide,[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]aceticacid,N-(2-hydroxypropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carbonyl]amino]aceticacid,N-dimethylcarbamoylmethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-methylcarbamoylmethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-phenyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(oxazol-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxypyrrolidine-1-carbonyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(2-oxopropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide, 2-(9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido[1,2-a]pyrazin-2-yl)-N-phenylacetamidehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(3-oxopyrrolidine-1-carbonyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(5-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide,7-acetyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-propionyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,9-hydroxy-2-(3-phenylallyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-methyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N,N-dimethyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-(2-methanesulfonylethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-[2-(2-oxopyrrolidin-1-yl)ethyl]-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-methylmethanesulfonamide,2-(3-chloro-5-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(pyridin-4-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxarnide,N-(4-fluorobenzyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-hydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride, 2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-5-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacid methylamide,N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-hydroxymethyl-1,8-dioxo-2,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylicacidmethylamide hydrochloride,2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-chloro-2-hydroxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido[1,2-a]pyrazin-2-yl)-N-methyl-N-phenylacetamidehydrochloride,N-methyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N,N-dimethyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,3-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2,2-dimethyl-3-oxopropylacetatehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxy-2,2-dimethylpropionyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(2-fluoroethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide, N-benzyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-7-phenylsulfanyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,7-benzenesulfinyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,7-benzenesulfonyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide,N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide,2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-4-hydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]propionamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-phenylacetamide,7-acetyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-methylsulfanyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-methanesulfonyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-methanesulfinyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-(5-methylthiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,2-(4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-methyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2Hpyrido[1,2-a]pyrazine-7-carboxamide,2-[3-(2-chloro-6-fluorophenyl)propyl]-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(4-methylthiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]butyramide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[2,2-a]pyrazin-7-yl]benzamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-3-phenylpropionamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-methylacetamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-methoxyacetamide,methyl 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate,3-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-1,1-dimethylurea,methyl [2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]carbamate,2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-oxopropionamide,N-benzyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-7-(1H-pyrazol-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione, N-(naphthalen-1-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-benzhydryl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(2-methyl-2-phenylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-(4-tert-butylbenzyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]cyclopentanecarboxamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-(4-fluorophenyl)acetamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2,2-dimethylpropionamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-phenylisobutyramide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-4-fluorobenzamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]pyridine-2-carboxamidetrifluoroacetate,2-(3-chlorobenzyl)-9-hydroxy-7-isopropylamino-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-7-diethylamino-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-isopropyl-3-methylbutyramide,2-(3-chlorobenzyl)-7-ethylamino-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride, N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]nicotinamidetrifluoroacetate,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]isonicotinamidetrifluoroacetate,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]furan-2-carboxamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]thiophene-2-carboxamide,2-(3-chlorobenzyl)-9-hydroxy-7-(pyridazin-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-chloro-3-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-chloro-2-methoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-1-methyl-1H-pyrrole-2-carboxamide,2-[3-(4-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-[3-(2-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-[3-(3-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-ylmethyl]-N-methylbenzamide,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-isobutylacetamide,N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide, N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]benzamide,N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide,2-(4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionetrifluoroacetate,2-(2-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(2-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-hydroxy-2-(naphthalen-2-ylmethyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(3-chloro-2-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(4-chloro-3-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(4-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-[3-(3-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-methoxyacetamide,N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-propanesulfonamide,N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]nicotinamidetrifluoroacetate, N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide,N-(2-methoxyethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-ethyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-{2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl}acetamide,N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamidehydrochloride,methyl 5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-ylmethyl]benzoate,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(benzofuran-2-ylmethyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-(1,2-diphenylethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide,2-[3-(2-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-(1,3-diphenylpropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,5-fluoro-2-{3-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-yl]propyl}-N-methylbenzamide,2-[3-(2-chloro-6-fluorophenyl)propyl]-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-hydroxy-2-(4-phenylbutyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,9-hydroxy-2-pentyl-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionetrifluoroacetate,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,7-acetyl-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-fluorobenzyl)-9-hydroxy-7-isobutyryl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isonicotinamidehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide,2-(4-chloro-2-hydroxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,9-hydroxy-2-(3-phenylbutyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]nicotinamidehydrochloride,N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide,2-(3-chloro-4-propoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,2-(4-benzyloxy-3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-chloro-2-propoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-chloro-2-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(2-benzyloxy-4-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-methyl-2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-{5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-ylmethyl]phenyl}acetamidehydrochloride,2-(3-chloro-2-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-ylmethyl]benzoicacidhydrochloride,2-(3,4-difluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-benzyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,N-(pyridin-3-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride,N-(pyridin-2-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,2-(3,4-dichlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionetrifluoroacetate,N-(2-oxopropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,2-(3-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,7-(2,2-dimethylpropionyl)-2-(3-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(2-fluorobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-(4-fluorobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-methyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-benzyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,N-methyl-2-(4-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,7-(2,2-dimethylbutyryl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3,4-dichlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3,4-dichlorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-fluorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(4-fluorobenzyl)-9-hydroxy-7-(3-methylbutyryl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride, N-methyl-2-(3,4-difluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(4-fluorobenzyl)-9-hydroxy-7-(3-methoxy-2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-5-propoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-5-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-benzyloxy-5-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-(pyridin-3-yl)acetamidehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[2,2-a]pyrazin-7-yl]-2-(pyridin-4-yl)acetamidehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-(pyridin-2-yl)acetamidehydrochloride,2-(3-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,2-(3-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]-3,3-dimethylbutyramide,2-(3-fluorobenzyl)-9-hydroxy-4-methyl-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione.hydrochloride,7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-4-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(pyridin-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,N-(furan-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,7-bromo-2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(4-dimethylaminobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]benzenesulfonamide, N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]benzylsulfonamide,N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-thiophenesulfonamide,N-(4-methanesulfonylbenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-6-(2-hydroxy-3,3-dimethylbutyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-[2-(3-chlorobenzyl)-9-hydroxy-4-methyl-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide,2-(4-fluorobenzyl)-9-hydroxy-6-methoxymethyl-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(4-fluorobenzyl)-9-hydroxy-7-(3-methoxy-2,2-dirnethylpropionyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(4-methoxypyrimidin-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamidehydrochloride,6-(3,3-dimethyl-2-oxobutyl)-7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,N-(4-acetylaminobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2-hydroxyethyl)-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3,4-dichlorobenzyl)-9-hydroxy-4-(1-hydroxypropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-(3-hydroxypropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-(1-hydroxy-2-methylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,2-(3,4-dichlorobenzyl)-9-hydroxy-4-phenethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione, 2-(4-fluorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dionehydrochloride,2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dionehydrochloride,2-(3-chlorobenzyl)-9-hydroxy-4-methyl-2H-pyrido[1,2-d][1,2,4]triazine-1,8-dione,2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-2,8-dione,7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dionesodium salt,N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamidesodium salt, and2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dionesodium salt,or a pharmaceutically acceptable salt thereof.
[26] A pharmaceutical composition comprising a nitrogen-containingfused ring compound of any of claims 1 to 25, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
[27] An anti-HIV agent comprising a nitrogen-containing fusedring compound of any of claims 1 to 25 or a pharmaceuticallyacceptable salt thereof as an active ingredient.
[28] An integrase inhibitor comprising a nitrogen-containingfused ring compound of any of claims 1 to 25 or apharmaceutically acceptable salt thereof as an active ingredient.
[29] An antivirus agent comprising a nitrogen-containing fusedring compound of any of claims 1 to 25, or a pharmaceuticallyacceptable salt thereof as an active ingredient.
[30] An anti-HIV composition comprising a nitrogen-containingfused ring compound of any of claims 1 to 25, or apharmaceutically acceptable salt thereof and one or more otherkinds of anti-HIV active substances as active ingredients.
[31] An anti-HIV agent comprising a nitrogen-containing fusedring compound of any of claims 1 to 25, or a pharmaceuticallyacceptable salt thereof as an active ingredient, which is usedfor a multiple drug therapy with other anti-HIV agents.
[32] Use of a nitrogen-containing fused ring compound of any ofclaims 1 to 25, or a pharmaceutically acceptable salt thereoffor the production of an anti-HIV agent.
[33] Use of a nitrogen-containing fused ring compound of any ofclaims 1 to 25, or a pharmaceutically acceptable salt thereoffor the production of an integrase inhibitor.
[34] Use of a nitrogen-containing fused ring compound of any ofclaims 1 to 25, or a pharmaceutically acceptable salt thereoffor the production of an antivirus agent.
[35] A method for the prophylaxis or treatment of an HIVinfectious disease, which comprises administering an effectiveamount of a nitrogen-containing fused ring compound of any ofclaims 1 to 25 or a pharmaceutically acceptable salt thereof toa mammal.
[36] The method of claim 35, further comprising administering aneffective amount of at least one kind of other anti-HIV activesubstance to the mammal.
[37] A method of inhibiting integrase, which comprisesadministering an effective amount of a nitrogen-containing fusedring compound of any of claim 1 to 25 or a pharmaceutically acceptable salt thereof to a mammal.
[38] A method for the prophylaxis or treatment of a viralinfectious disease, which comprises administering an effectiveamount of a nitrogen-containing fused ring compound of any ofclaims 1 to 25 or a pharmaceutically acceptable salt thereof toa mammal.

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同族专利:

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公开号 | 公开日

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US7211572B2|2007-05-01|

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CL2004002061A1|2005-06-03|

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EP2042502A1|2009-04-01|

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ES2315700T3|2009-04-01|

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AR045367A1|2005-10-26|

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PT1544199E|2008-12-03|

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US20060052361A1|2006-03-09|

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TW200510425A|2005-03-16|

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JPWO2005016927A1|2006-10-12|

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EP1544199A4|2006-07-26|

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CA2577239A1|2005-02-24|

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DK1544199T3|2009-01-12|

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EP1544199B1|2008-10-15|

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US20080161311A1|2008-07-03|

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JP3814631B2|2006-08-30|

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PE20050361A1|2005-06-27|

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SI1544199T1|2009-04-30|

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AT411315T|2008-10-15|

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DE602004017108D1|2008-11-27|

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WO2005016927A1|2005-02-24|

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US20050054645A1|2005-03-10|

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优先权:

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申请号 | 申请日 | 专利标题

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JP2003293117||2003-08-13||

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JP2003293117||2003-08-13||

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JP2004134896||2004-04-28||

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JP2004134896||2004-04-28||

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PCT/JP2004/011869|WO2005016927A1|2003-08-13|2004-08-12|Nitrogenous condensed-ring compound and use thereof as hiv integrase inhibitor|SI200430973T| SI1544199T1|2003-08-13|2004-08-12|Nitrogenous condensed-ring compound and use thereof as hiv integrase inhibitor|

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EP08166109A| EP2042502A1|2003-08-13|2004-08-12|Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor|