Dibenzylamine compound and medicinal use thereof

专利摘要:
A dibenzylamine compound represented by the formula (1)wherein R1 and R2 are each a C1-6 alkyl group optionallysubstituted by halogen atoms and the like; R3, R4 and R5 areeach a hydrogen atom, a halogen atom and the like, or R3 and R4may form, together with carbon atoms bonded thereto, ahomocyclic or heterocyclic ring optionally havingsubstituent (s) ; A is-N(R7)(R8) and the like; ring B is an aryl group or aheterocyclic residue; R6 is a hydrogen atom, a halogen atom, anitro group, a C1-6 alkyl group and the like; n is an integer of1 to 3, a prodrug thereof and a pharmaceutically acceptablesalt thereof show selective and potent CETP inhibitoryactivity, and therefore, they can be provided as therapeuticor prophylactic agents for hyperlipidemia or arteriosclerosisand the like.
公开号:EP1533292A1
申请号:EP03791414
申请日:2003-08-29
公开日:2005-05-25
发明作者:Kimiya c/o Central Pharm. Research Inst. MAEDA；Hironobu Central Pharm. Research Inst. NAGAMORI；Hiroshi Central Pharm. Research Inst. NAKAMURA；Hisashi c/o Central Pharm. Research Inst SHINKAI；Yasunori；Suzuki；Daisuke Central Pharm. Research Inst. TAKAHASHI；Toshio Central Pharm. Research Inst. TANIGUCHI
申请人:Japan Tobacco Inc；
IPC主号:C07D213-00

专利说明:
[0001] The present invention relates to a novel CETP activityinhibitor, particularly a therapeutic agent or a prophylacticagent of arteriosclerosis or hyperlipidemia. Background Art
[0002] Regarding the relationship between arterioscleroticdiseases and serum lipoprotein, it has been considered forsome time that a certain relationship exists from the resultsof many epidemiological researches. For example, Badimon et al.(J. Clin. Invest., 85, 1234-1241 (1990)) reported thatintravenous injection of fractions containing HDL (highdensity lipoprotein) and VHDL (very high density lipoprotein)to cholesterol-loaded rabbits resulted in the observation ofnot only prevention of progression of arteriosclerotic lesionbut also regression thereof, and HDL and VHDL are consideredto have an anti-arteriosclerotic action in the relationshipbetween arteriosclerotic diseases and serum lipoprotein.
[0003] In recent years, the presence of a protein that transferslipid between blood lipoproteins, or CETP (cholesteryl estertransfer protein), has been clarified. The presence of CETPwas first pointed out in 1965 by Nichols & Smith (J. LipidRes., 6, 206, 1965), and thereafter its cDNA was cloned in1987 by Drayna et al. The molecular weight thereof is 74,000Da as glycoprotein and about 58,000 Da when sugar chain iscompletely cleaved. Its cDNA consists of 1656 residues andencodes 476 amino acids following 17 signal peptides. Sinceabout 44% thereof consists of hydrophobic amino acids, it hasextremely high hydrophobicity and is easily inactivated byoxidation. In addition, it has been confirmed that CETP isproduced in the organs such as liver, spleen, adrenal gland,adipose tissue, small intestine, kidney, skeletal muscle, heart muscle and the like, and produced in cells of the celltypes of human monocyte-derived macrophage, B lymphocyte, fatcell, small intestinal epithelial cell, CaCo2 cell, hepatocyte(exemplified by human liver cancer cell-derived cell line,HepG2 cells) and the like. Besides the above-mentioned tissues,it is present in cerebrospinal fluid and semen, and itspresence has been confirmed in culture media of humanneuroblastoma and neuroglioma cells, choroid plexus of sheepand the like.
[0004] It has been also clarified that CETP is involved in themetabolism of any lipoprotein in living organisms, and has amajor role in the reverse cholesterol transfer system. Namely,CETP has drawn attention as a mechanism for preventingaccumulation of cholesterol in peripheral cells and preventingarteriosclerosis. In fact, with regard to HDL having animportant role in this reverse cholesterol transfer system, anumber of epidemiological researches have shown that adecrease in CE (cholesteryl ester) of HDL in blood is one ofthe risk factors of coronary artery diseases. It has been alsoclarified that the CETP activity varies depending on theanimal species, wherein arteriosclerosis due to cholesterol-loadingis hardly induced in animals with lower activity, andin reverse, easily induced in animals with higher activity,and that hyper-HDL-emia and hypo-LDL (low densitylipoprotein)-emia are induced in the case of CETP deficiency,thus rendering the development of arteriosclerosis difficult,which in turn led to the recognition of the significance ofblood HDL, as well as significance of CETP that mediatestransfer of CE in HDL into blood LDL.
[0005] Free cholesterol (FC) synthesized in and secreted fromthe liver is taken up by very low density lipoprotein (VLDL).Then, due to the action of lipoprotein lipase (LPL) andhepatic triglyceride lipase (HTGL), VLDL is metabolized in blood into LDL via intermediate density lipoprotein (IDL). LDLis taken up by peripheral cells via an LDL receptor and FC issupplied to the cells. Conversely from such flow from theliver to the peripheral cells, there exists a flow ofcholesterol from peripheral cells toward the liver, which iscalled a reverse cholesterol transfer system. In other words,FC accumulated in the peripheral tissues is drawn by HDL,further esterified on HDL by the action of LCAT (lecithin-cholesterolacyltransferase) to form CE, and transferred tothe hydrophobic core part of HDL, whereby HDL matures intospheric HDL particles. CE in HDL is transferred by CETPpresent in blood to apoB-containing lipoproteins such as VLDL,IDL, LDL and the like, and in return, TG is transferred to HDLat a molar ratio of 1:1. CE transferred to apoB-containinglipoprotein is taken up by the liver via LDL receptor in theliver, thereby indirectly transferring cholesterol to theliver. Moreover, there is a mechanism in which HDL takes upapoprotein E secreted from macrophage and the like to becomeapoprotein E-containing HDL rich in CE, and then is directlytaken up by the liver via LDL receptor or remnant receptor.There also exists a path in which HDL particles are not takenup by the liver and only CE in HDL is selectively taken up byhepatocytes. Furthermore, another path exists in which HDLparticles are taken up by hepatocytes via what is called anHDL receptor in the liver.
[0006] Namely, in the state of enhanced CETP activity, since CEtransfer from HDL increases, CE in HDL decreases, and CE inVLDL, IDL and LDL increases. When take up of IDL and LDL bythe liver increases, down-regulation is imposed on the LDLreceptor, and LDL in blood increases. In contrast, in the CETPdeficient state, HDL draws cholesterol from peripheral cellswith the aid of LCAT, gradually increases its size andacquires apo E. Then, apo E-rich HDL is taken up by the liver via LDL receptor in the liver and catabolized. However, sincethis mechanism does not function sufficiently in human, largeHDL dwells in the blood. Consequently, cholesterol pool in theliver becomes smaller and up-regulation is imposed on the LDLreceptor, thereby decreasing LDL. Accordingly, selectiveinhibition of CETP can lower IDL, VLDL and LDL that promotearteriosclerosis and increase HDL that acts suppressivelythereon, and produces expectation for the provision of anunprecedented prophylactic or therapeutic agent forarteriosclerosis or hyperlipidemia.
[0007] While many attempts have been made in recent years todevelop a drug that inhibits such activity of CETP, a compoundhaving a satisfactory activity has not been developed yet.
[0008] Meanwhile, many reports have been found recently on thecompounds aiming at inhibiting such activity of CETP. Forexample, Biochemical and Biophysical Research Communications223, 42-47 (1996) discloses dithiodipyridine derivatives,substituted dithiodibenzene derivatives and the like ascompounds that inactivate CETP by modifying cysteine residue.However, this reference does not contain any description ofthe compound of the present invention, not to mention adescription suggestive thereof.
[0009] In addition, WO95/06626 discloses Wiedendiol-A andWiedendiol-B as CETP activity inhibitors. However, thispublication does not contain any description suggesting thecompound of the present invention.
[0010] Moreover, JP-B-45-11132, JP-B-45-2892, JP-B-45-2891, JP-B-45-2731and JP-B-45-2730 disclose mercaptoanilidessubstituted by higher fatty acid such as o-isostearoylaminothiophenoland the like, as a compound havingan action to prevent arteriosclerosis. However, thesepublications only mention the presence of an effect to preventarteriosclerosis and lack description of Experimental Example that support the effect, much less a description of inhibitionof CETP activity. Moreover, no description is found thatsuggests the compound of the present invention.
[0011] JP-T-2001-512416 (WO98/04528) discloses a biaryl compoundthat inhibits CETP. However, this publication has nodescription that suggests the compound of the presentinvention.
[0012] WO00/17164, WO00/17166 and WO01/40190 disclose 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolineas aCETP inhibitor. However, these publications contain nodescription that suggests the compound of the presentinvention.
[0013] On the other hand, various compounds having a structurelike the compound of the present invention have been reported.For example, JP-A-2001-106666 and WO01/10825 disclosecarbamate derivatives characterized in that phenyl group hasan oxime ether group. However, the compounds of thesepublications are compounds useful as antimicrobial agents foragriculture or gardening, and they lack a disclosure ofusefulness as a CETP activity inhibitor, or even a descriptionsuggestive thereof.
[0014] WO00/69810 discloses compounds such as 3-(4-{[N-[3-(2,6-dichlorophenyl)acryloyl]-N-(4-tert-butylbenzyl)amino]methyl}benzoylamino)propionicacid and thelike. However, the compound of this publication is useful as aglucagon antagonist, and this publication lacks a disclosureof usefulness as a CETP activity inhibitor, or even adescription suggestive thereof.
[0015] WO99/67204 discloses compounds such as 1-[N-(4-chlorobenzyl)-N-(N,N-dimethylcarbamoyl)aminomethyl]-4-guanidinomethylbenzeneand the like. However, the compound ofthis publication is useful as an analgesic, and thispublication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
[0016] WO99/44987 and US6,218,426 disclose compounds such as N-(4-tert-butylbenzyl)-N-[4-(guanidinomethyl)benzyl]benzamideand the like useful as a gonadotropin-releasing hormoneantagonist/agonist. However, this publication lacks adisclosure of usefulness as a CETP activity inhibitor, or evena description suggestive thereof.
[0017] US5,834,514 and JP-T-9-512556 (WO95/29672) disclose thathalomethylamide compounds such as N-benzyl-N-(2,4-dichlorobenzyl)chloroacetamideand the like are useful as IL-1βprotease activity inhibitors. However, these publications lacka disclosure of usefulness as a CETP activity inhibitor, oreven a description suggestive thereof.
[0018] WO97/24328 discloses 2-amino-heterocyclic compounds suchas N,N-bis(2,4-dimethoxybenzyl)-N'-(4-methoxyphenyl)urea andthe like. However, the compound of this publication is usefulas a leukotriene synthesis inhibitor and this publicationlacks a disclosure of usefulness as a CETP activity inhibitor,or even a description suggestive thereof.
[0019] WO96/10559 discloses urea derivatives such as 1-benzyl-1-[3-(pyrazol-3-yl)benzyl]-3-(2,4,6-trimethylphenyl)ureaand thelike. However, the compound of this publication is useful asan acyl-CoA:cholesterol acyltransferase inhibitor and thispublication lacks a disclosure of usefulness as a CETPactivity inhibitor, or even a description suggestive thereof.
[0020] US4,623,662 discloses that urea compounds such as 1-benzyl-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)ureaandthe like are useful as acyl-CoA:cholesterol acyltransferaseinhibitors. However, this publication lacks a disclosure ofusefulness as a CETP activity inhibitor, or even a descriptionsuggestive thereof.
[0021] US4,473,579 discloses urea compounds such as 1,1-dibenzyl-3-(2,4-dimethylphenyl)-3-phenylureaand the like. However, the compound of this publication is useful as anacyl-CoA:cholesterol acyltransferase inhibitor and thispublication lacks a disclosure of usefulness as a CETPactivity inhibitor, or even a description suggestive thereof.
[0022] US4,122,255, US4,064,125, US4,151,354 and US4,127,606disclose compounds such as N-[[2-[3-(dimethylamino)propoxy]phenyl]methyl]-3-phenyl-N-(phenylmethyl)-2-propenamideand the like. However, thecompounds of these publications are useful as antiinflammatoryagents and they lack a disclosure of usefulness as a CETPactivity inhibitor, or even a description suggestive thereof.
[0023] WO99/18066 discloses amide carboxylic acid compounds suchas ethyl 2-butyl-3-[4-[2-[N-benzyl-(4-pyridin-2-yl)amino]ethoxy]phenyl]propionateand the like having usefullipid-lowering action and the like. However, this publicationlacks a disclosure of usefulness as a CETP activity inhibitor,or even a description suggestive thereof. Moreover, thispublication lacks a disclosure of a structure such as thecompound of the present invention, or even a descriptionsuggestive thereof.
[0024] In contrast, WO00/18724 discloses a compound having astructure similar to that of the present invention and a CETPinhibitory activity. To be specific, the following formula isdisclosed.
[0025] In other words, this invention does not disclose aconcrete structure as the compound of the present invention,not to mention a description suggestive thereof. Disclosure of the Invention
[0026] The present invention aims at providing a novel compoundthat selectively inhibits the activity of CETP. The presentinvention also aims at providing a compound useful as aprophylactic or therapeutic agent of arteriosclerosis orhyperlipidemia, which increases HDL cholesterol andsimultaneously decreases LDL cholesterol and triglyceride byselectively inhibiting the activity of CETP, and which is freeof a CYP inhibitory effect.
[0027] The present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects and foundthat the compounds shown in the following [1] to [13] have aneffect to selectively inhibit the activity of CETP(hereinafter to be referred to as a CETP inhibitory effect),and are useful pharmaceutical agents, particularly,prophylactic or therapeutic agents of arteriosclerosis orhyperlipidemia. Moreover, they have found that a structuresuch as the formula (1) provides a potent CETP inhibitoryeffect, which resulted in the completion of the presentinvention. More particularly, the following [1] to [76] areprovided. [1] A dibenzylamine compound represented by the formula (1)
[0028] The definition of each substituent used in the presentspecification is as follows.
[0029] The "halogen atom" is a chlorine atom, a bromine atom, afluorine atom and the like. For R¹, R², R³, R⁴, R⁵, R⁶, R⁶⁰, R⁶¹ or R⁶², it is preferably a chlorine atom or a fluorine atom,and a preferable halogen atom as a substituent for the C_4-10cycloalkylalkyl group for R⁷, R⁸, R¹¹, R¹² or R¹³ is chlorineatom or fluorine atom.
[0030] The "C_2-6 alkenyl group" is a straight chain or optionallybranched alkenyl group having 2 to 6 carbon atoms, such asethenyl group (vinyl group), 1-propenyl group, 2-propenylgroup (allyl group), isopropenyl group, 1-butenyl group, 2-butenylgroup, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenylgroup, 2-methyl-2-propenyl group, 1-ethylvinylgroup, 1-pentenyl group, 2-pentenyl group, 3-pentenylgroup, 4-pentenyl group, 1,2-dimethyl-1-propenylgroup, 1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group,1-ethyl-2-propenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenylgroup, 2-methyl-1-butenyl group, 1-isopropylvinylgroup, 2,4-pentadienyl group, 1-hexenyl group, 2-hexenyl group,3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2,4-hexadienylgroup, 1-methyl-1-pentenyl group and the like,preferably a straight chain or optionally branched alkenylgroup having 2 to 4 carbon atoms. Particularly preferred areethenyl group, isopropenyl group and 2-methyl-2-propenyl group.
[0031] The "C_1-6 alkyl group" is a straight chain or optionallybranched alkyl group having 1 to 6 carbon atoms, such asmethyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, sec-butyl group, tert-butyl group,pentyl group, isopentyl group, neopentyl group, tert-pentylgroup, hexyl group and the like, preferably a straight chainor optionally branched alkyl group having 1 to 4 carbon atoms.Particularly preferred are methyl group, ethyl group andisopropyl group. R²⁰ and R²¹ are each preferably a methyl group.For R⁶, R⁶⁰, R⁶¹ or R⁶², it is preferably a methyl group or anethyl group, for R⁷, R⁸, R¹¹, R¹² or R¹³, it is preferably anethyl group, a propyl group or a butyl group, and for R⁹ or R¹⁰, it is preferably a methyl group or an ethyl group. Apreferable C_1-6 alkyl group as a substituent for the C_4-10cycloalkylalkyl group for R⁷, R⁸, R¹¹, R¹² or R¹³ is a methylgroup or an ethyl group. For R¹⁴, it is preferably a methylgroup or an ethyl group.
[0032] The "C_1-6 alkyl group optionally substituted by halogenatoms" is the aforementioned C_1-6 alkyl group optionallysubstituted by the aforementioned halogen atoms, such asmethyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, sec-butyl group, tert-butyl group,pentyl group, isopentyl group, neopentyl group, tert-pentylgroup, hexyl group, trifluoromethyl group, 1- or 2-chloroethylgroup, 1- or 2-bromoethyl group, 1- or 2-fluoroethyl group, 1-,2- or 3-chloropropyl group, 1-, 2- or 3-bromopropyl group, 1-,2- or 3-fluoropropyl group, 1-, 2-, 3- or 4-chlorobutyl group,1-, 2-, 3- or 4-bromobutyl group, 1-, 2-, 3- or 4-fluorobutylgroup and the like, preferably methyl group, ethyl group ortrifluoromethyl group. For R¹, R², R³, R⁴ or R⁵, it ispreferably a methyl group, an ethyl group or a trifluoromethylgroup.
[0033] The "C_1-6 alkoxy group" means a straight chain or branchedchain alkoxy group having 1 to 6 carbon atoms, such as methoxygroup, ethoxy group, propoxy group, isopropoxy group, butoxygroup, tert-butoxy group, pentyloxy group, tert-pentyloxygroup and hexyloxy group. Preferred are methoxy group, ethoxygroup, isopropoxy group, butoxy group and tert-butoxy group,which have 1 to 4 carbon atoms. Particularly preferred aremethoxy group and ethoxy group. For R⁶, R⁶⁰, R⁶¹ or R⁶², it ispreferably a methoxy group, and a preferable C_1-6 alkoxy groupas a substituent for the C_4-10 cycloalkylalkyl group for R⁷, R⁸,R¹¹, R¹² or R¹³ is a methoxy group or an ethoxy group.
[0034] The "C_1-6 alkoxy group optionally substituted by halogenatoms" is the aforementioned C_1-6 alkoxy group optionally substituted by the aforementioned halogen atoms, such asmethoxy group, ethoxy group, propoxy group, isopropoxy group,butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxygroup, hexyloxy group, trifluoromethoxy group, 1- or2-chloroethoxy group, 1- or 2-bromoethoxy group, 1- or 2-fluoroethoxygroup, 1-, 2- or 3-chloropropoxy group, 1-, 2- or3-bromopropoxy group, 1-, 2- or 3-fluoropropoxy group, 1-, 2-,3- or 4-chlorobutoxy group, 1-, 2-, 3- or 4-bromobutoxy group,1-, 2-, 3- or 4-fluorobutoxy group and the like. Preferred aremethoxy group, ethoxy group and trifluoromethoxy group. For R³,R⁴ or R⁵, it is preferably a methoxy group, an ethoxy group ora trifluoromethoxy group.
[0035] The "C_1-6 alkylthio group optionally substituted byhalogen atoms" is one wherein the C_1-6 alkylthio group isoptionally substituted by the aforementioned halogen atoms,which is exemplified by methylthio group, ethylthio group,propylthio group, isopropylthio group, butylthio group, tert-butylthiogroup, pentylthio group, tert-pentylthio group,hexylthio group, trifluoromethylthio group, 1- or 2-chloroethylthiogroup, 1- or 2-bromoethylthio group, 1- or 2-fluoroethylthiogroup, 1-, 2- or 3-chloropropylthio group, 1-,2- or 3-bromopropylthio group, 1-, 2- or 3-fluoropropylthiogroup, 1-, 2-, 3- or 4-chlorobutylthio group, 1-, 2-, 3- or 4-bromobutylthiogroup, 1-, 2-, 3- or 4-fluobutylthio group andthe like, preferably methylthio group, ethylthio group ortrifluoromethylthio group. For R³, R⁴ or R⁵, it is preferably amethylthio group, an ethylthio group or a trifluoromethylthiogroup.
[0036] The "C_4-10 cycloalkylalkyl group" is a C_1-3 alkyl groupsubstituted by C_3-7 cycloalkyl group. Here, the "C_3-7 cycloalkylgroup" means a cycloalkyl group having 3 to 7 carbon atoms,which is exemplified by cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group and cycloheptyl group. Preferred is cycloalkyl group having 3 to 6 carbon atoms,which is specifically cyclopropyl group, cyclobutyl group,cyclopentyl group or cyclohexyl group. The "C_1-3 alkyl group"means a straight chain or optionally branched alkyl grouphaving 1 to 3 carbon atoms, which is exemplified by methylgroup, ethyl group, propyl group and isopropyl group.Preferred are methyl group, ethyl group and propyl group.
[0037] Concrete examples of the "C_4-10 cycloalkylalkyl group"include cyclopropylmethyl group, cyclobutylmethyl group,cyclopentylmethyl group, cyclohexylmethyl group,cycloheptylmethyl group, cyclopentylethyl group (1- or 2-(cyclopentyl)ethylgroup), cyclohexylethyl group (1- or 2-(cyclohexyl)ethylgroup), cyclopentylpropyl group (1-, 2- or3-(cyclopentyl)propyl group) and cyclohexylpropyl group (1-,2- or 3-(cyclohexyl)propyl group). Preferred iscycloalkylalkyl group preferably having 3 to 7 carbon atoms,which is specifically cyclopropylmethyl group,cyclobutylmethyl group, cyclopentylmethyl group orcyclohexylmethyl group. A preferable C_4-10 cycloalkylalkylgroup for R⁷, R⁸, R¹¹, R¹² or R¹³ is cyclopentylmethyl group,cyclohexylmethyl group or 2-(cyclopentyl)ethyl group.
[0038] The "acyl group" includes alkylcarbonyl groups such asacetyl group, propionyl group, butyryl group, pivaloyl groupand the like; and arylcarbonyl groups such as benzoyl group,naphthoyl and the like. Preferred is acetyl group. For R⁶, R⁶⁰,R⁶¹ or R⁶², it is preferably an acetyl group, a preferable acylgroup as a substituent for the C_4-10 cycloalkylalkyl group forR⁷, R⁸, R¹¹, R¹² or R¹³ is acetyl group.
[0039] The "aryl group" is a phenyl group, a naphthyl group, abiphenyl group and the like, with preference given to a phenylgroup.
[0040] As the "heterocyclic residue", a 5- to 8-memberedaromatic heterocyclic group containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom,nitrogen atom and the like, a bicyclic or tricyclicheterocyclic group condensed therewith and the like can bementioned. Examples thereof include pyrrolyl group (1-, 2- or3-pyrrolyl group), furyl group (2- or 3-furyl group), thienylgroup (2- or 3-thienyl group), imidazolyl group (1-, 2-, 4- or5-imidazolyl group), oxazolyl group (2-, 4- or 5-oxazolylgroup), thiazolyl group (2-, 4- or 5-thiazolyl group),pyrazolyl group (1-, 3-, 4- or 5-pyrazolyl group), isoxazolylgroup (3-, 4- or 5-isoxazolyl group), isothiazolyl group (3-,4- or 5-isothiazolyl group), oxadiazolyl group (1,2,4-oxadiazol-3or 5-yl group, 1,3,4-oxadiazol-2-yl group, 1,2,5-oxadiazol-3-ylgroup), thiadiazolyl group (1,2,4-thiadiazol-3or 5-yl group, 1,3,4-thiadiazol-2-yl group, 1,2,5-thiadiazol-3-ylgroup), triazolyl group (1,2,4-triazol-1, 3, 4 or 5-ylgroup, 1,2,3-triazol-1, 2 or 4-yl group), indolyl group (1-,2-, 3-, 4-, 5-, 6- or 7-indolyl group), benzofuryl group (2-,3-, 4-, 5-, 6- or 7-benzofuryl group), benzothienyl group (2-,3-, 4-, 5-, 6- or 7-benzothienyl group), benzimidazolyl group(1-, 2-, 4-, 5-, 6- or 7-benzimidazolyl group), benzoxazolylgroup (2-, 4-, 5-, 6- or 7-benzoxazolyl group), benzothiazolylgroup (2-, 4-, 5-, 6- or 7-benzothiazolyl group), pyridylgroup (2-, 3- or 4-pyridyl group), pyridine-1-oxide group (2-,3- or 4-pyridine-1-oxide group), pyrimidinyl group (2-, 4- or5-pyrimidinyl group), tetrazolyl group (1H-tetrazol-1 or 5-ylgroup, 2H-tetrazol-2 or 5-yl group), quinolyl group (2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl group), isoquinolyl group (1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl group) and the like.
[0041] As the "homocyclic ring", for example, an optionallycondensed 3- to 7-membered carbon ring such as C_6-10 arene (C_6-10aryl) (e.g., benzene (phenyl), naphthalene (naphthyl) and thelike), C_3-7 cycloalkane (cycloalkyl) (e.g., cyclopropane(cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane(cycloheptyl) etc.), C_3-7 cycloalkene (C_3-7 cycloalkenyl group)(e.g., cyclopropene (cyclopronyl), cyclobutene (cyclobutenyl),cyclopentene (cyclopentenyl), cyclohexene (cyclohexenyl),cycloheptene (cycloheptenyl) etc.) and the like, and the likeare used. The parenthesis following each name of thehomocyclic ring shows a homocyclic group corresponding to thehomocyclic ring.
[0042] As the substituent that the above-mentioned homocyclicring may have, for example, (1) a C_1-6 alkyl group optionallysubstituted by halogens (particularly, C_1-6 alkyl groupsubstituted by halogens is preferable), (2) a C_3-10 cycloalkylgroup, (3) a C_2-10 alkenyl group, (4) a C_2-10 alkynyl group, (5)a C_6-10 aryl group, (6) a C_7-20 aralkyl group, (7) a nitro group,(8) a hydroxy group, (9) a mercapto group, (10) a oxo group,(11) a thioxo group, (12) a cyano group, (13) a carbamoylgroup, (14) a carboxyl group, (15) a C_1-6 alkoxycarbonyl group(e.g., methoxycarbonyl group, ethoxycarbonyl group etc.), (16)a sulfo, (17) a halogen atom, (18) a C_1-6 alkoxy group, (19) aC_6-10 aryloxy group (e.g., phenoxy group etc.), (20) a C_1-6acyloxy group (e.g., acetoxy, propionyloxy), (21) a C_1-6alkylthio group (e.g., methylthio group, ethylthio group, n-propylthiogroup, isopropylthio group, n-butylthio group,tert-butylthio group etc.), (22) a C_6-10 arylthio group (e.g.,phenylthio group etc.), (23) a C_1-6 alkylsulfinyl group (e.g.,methylsulfinyl group, ethylsulfinyl group etc.), (24) a C_6-10arylsulfinyl group (e.g., phenylsulfinyl group etc.), (25) aC_1-6 alkylsulfonyl group (e.g., methylsulfonyl group,ethylsulfonyl group etc.), (26) a C_6-10 arylsulfonyl group (e.g.,phenylsulfonyl group etc.), (27) an amino group, (28) a C_1-6acylamino group (e.g., acetylamino group, propionylamino groupetc.), (29) a mono- or di-C_1-4 alkylamino group (e.g.,methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, dimethylamino group,diethylamino group etc.), (30) a C_3-8 cycloalkylamino group(e.g., cyclopropylamino group, cyclobutylamino group,cyclopentylamino group, cyclohexylamino group etc.), (31) a C_6-10arylamino group (e.g., anilino etc.), (32) a C_1-6 alkanoylgroup (e.g., formyl group, acetyl group, hexanoyl group etc.),(33) C_6-10 arylcarbonyl group (e.g., benzoyl group etc.), (34) a5- or 6-membered heterocyclic group containing, besides carbonatom, 1 to 4 heteroatoms selected from oxygen, sulfur,nitrogen and the like (e.g., 2- or 3-thienyl group, 2- or 3-furylgroup, 3-, 4- or 5-pyrazolyl group, 2-, 4- or 5-thiazolylgroup, 3-, 4- or 5-isothiazolyl group, 2-, 4- or 5-oxazolylgroup, 3-, 4- or 5-isoxazolyl group, 2-, 4- or 5-imidazolylgroup, 1,2,3- or 1,2,4-triazolyl (1,2,4-triazol-1,3, 4 or 5-yl group, 1,2,3-triazol-1, 2 or 4-yl group), 1H or2H-tetrazolyl (1H-tetrazol-1 or 5-yl group, 2H-tetrazol-2 or5-yl group), 2-, 3- or 4-pyridyl group, 2-, 4- or 5-pyrimidylgroup, 3- or 4-pyridazinyl group, quinolyl group (2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl group), isoquinolyl group (1-, 3-, 4-,5-, 6-, 7- or 8-isoquinolyl group), indolyl group (1-, 2-, 3-,4-, 5-, 6- or 7-indolyl group) etc.) and the like can bementioned. The number of substitution is 1 to 6, preferably 1to 3, more preferably 1 or 2.
[0043] Preferable examples of the "homocyclic ring optionallyhaving a substituent" formed by R³ and R⁴ or R⁴ and R⁵ togetherwith carbon atoms bonded thereto are C_3-7 cycloalkane andbenzene, and more preferable examples are cyclopentane andcyclohexane.
[0044] As the "heterocyclic ring", a 5- to 8-memberedheterocyclic group containing, besides carbon atom, 1 to 4heteroatoms selected from oxygen atom, sulfur atom, nitrogenatom and the like, and a bicyclic or tricyclic heterocyclicgroup condensed therewith and the like can be mentioned. Specific examples of the heterocyclic ring include (1) a 5-memberedheterocyclic ring containing, besides carbon atom, 1to 4 heteroatoms selected from oxygen atom, sulfur atom,nitrogen atom and the like, such as thiophene (thienyl group),furan (furyl group), pyrrole (pyrrolyl group), pyrroline(pyrrolinyl group), pyrrolidine (pyrrolidinyl group), 1,3-dioxole(1,3-dioxolyl group), oxazole (oxazolyl group),thiazole (thiazolyl group), pyrazole (pyrazolyl group),imidazole (imidazolyl group), imidazoline (imidazolinyl group),isoxazole (isoxazolyl group), isothiazole (isothiazolyl group),furazan (furazanylgroup), 1,2,3-thiadiazole (1,2,3-thiadiazolylgroup), 1,2,5-thiadiazole (1,2,5-thiadiazolylgroup), 1,2,3-triazole (1,2,3-triazolyl group), 1,2,3-triazolidine(triazolidinyl group) and the like, (2) a 6-memberedheterocyclic ring containing, besides carbon atom, 1to 4 heteroatoms selected from oxygen atom, sulfur atom,nitrogen atom and the like, such as pyridine (pyridyl group),pyrimidine (pyrimidinyl group), thiomorpholine(thiomorpholinyl group), morpholine (morpholinyl group),1,2,3-triazine, 1,2,4-triazine (triazinyl group), piperidine(piperidinyl group), pyrane (pyranyl group), thiopyrane(thiopyranyl group), 1,4-oxazine (1,4-oxazinyl group), 1,4-dioxane(1,4-dioxanyl group), 1,4-thiazine (1,4-thiazinylgroup), 1,3-thiazine (1,3-thiazinyl group), piperazine(piperazinyl group), oxotriazine (oxotriazinyl group),pyridazine (pyridazinyl group), pyrazine (pyrazinyl group) andthe like can be mentioned. As the bicyclic or tricycliccondensed heterocyclic ring, a bicyclic or tricyclic condensedheterocyclic ring containing, besides carbon atom, 1 to 4heteroatoms selected from oxygen atom, sulfur atom, nitrogenatom and the like, such as benzofuran (benzofuryl group),benzothiazole (benzothiazolyl group), benzoxazole(benzoxazolyl group), tetrazolo[1,5-b]pyridazine (tetrazolo[1,5-b]pyridazinyl group), triazolo[4,5-b]pyridazine(triazolo[4,5-b]pyridazinyl group), benzimidazole(benzimidazolyl group), quinoline (quinolyl group),isoquinoline (isoquinolyl group), cinnoline (cinnolinyl group),phthalazine (phthalazinyl group), quinazoline (quinazolinylgroup), quinoxaline (quinoxalinyl group), indolizine(indolizinyl group), indole (indolyl group), quinolizine(quinolizinyl group), 1,8-naphthyridine. (1,8-naphthyridinylgroup), pteridine (pteridinyl group), dibenzofuran(dibenzofuranyl group), carbazole (carbazolyl group), acridine(acrydinyl group), phenanthridine (phenanthridinyl group),chromane (chromanyl group), benzoxazine (benzoxazinyl group),phenazine (phenazinyl group), phenothiazine (phenothiazinylgroup), phenoxazine (phenoxazinyl group) and the like can bementioned. The parenthesis following each name of theheterocyclic ring shows a heterocyclic group corresponding tothe heterocyclic ring.
[0045] As the substituent that the above-mentioned heterocyclicring may have, for example, (1) a C_1-6 alkyl group, (2) a C_2-6alkenyl group, (3) a C_2-6 alkynyl group, (4) a C_3-6 cycloalkylgroup, (5) a cycloalkenyl group, (6) a C_7-11 aralkyl group, (7)a C_6-14 aryl group, (8) a C_1-6 alkoxy group, (9) a C_6-14 aryloxygroup (e.g., phenoxy group etc.), (10) a C_1-6 alkanoyl group(e.g., formyl group, acetyl group, propionyl group, n-butyrylgroup, iso-butyryl group etc.), (11) a C_6-14 arylcarbonyl group(e.g., benzoyl group etc.), (12) a C_1-6 alkanoyloxy group (e.g.,formyloxy group, acetyloxy group, propionyloxy group, n-butyryloxygroup, iso-butyryloxy group etc.), (13) a C_6-14arylcarbonyloxy group (e.g., benzoyloxy group etc.), (14) acarboxyl group, (15) a C_1-6 alkoxycarbonyl group (e.g.,methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonylgroup, iso-propoxycarbonyl group, n-butoxycarbonyl group,isobutoxycarbonyl group, tert-butoxycarbonyl group etc.), (16) a carbamoyl group, (17) a N-mono-C_1-4 alkylcarbamoyl group (e.g.,N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoylgroup, N-isopropylcarbamoyl group, N-butylcarbamoylgroup etc.), (18) an N,N-di-C_1-4 alkylcarbamoylgroup (e.g., N,N-dimethylcarbamoyl group, N,N-diethylcarbamoylgroup, N,N-dipropylcarbamoyl group, N,N-dibutylcarbamoyl groupetc.), (19) a cyclic aminocarbonyl group (e.g., 1-aziridinylcarbonylgroup, 1-azetidinylcarbonyl group, 1-pyrrolizinylcarbonylgroup, 1-piperidinylcarbonyl group, N-methylpiperazinylcarbonylgroup, morpholinocarbonyl groupetc.), (20) a halogen atom, (21) a C_1-6 alkyl group optionallysubstituted by halogen atoms (e.g., chloromethyl group,dichloromethyl group, trifluoromethyl group, trifluoroethylgroup etc.), (22) an oxo group, (23) an amidino group, (24) animino group, (25) an amino group, (26) a mono- or di-C_1-4alkylamino group (e.g., methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group,dimethylamino group, diethylamino group, dipropylamino group,diisopropylamino group, dibutylamino group etc.), (27) a 3- to6-membered cyclic amino group optionally containing, besidescarbon atom and one nitrogen atom, 1 to 3 heteroatoms selectedfrom oxygen atom, sulfur atom, nitrogen atom and the like(e.g., aziridinyl group, azetidinyl group, pyrrolizinyl group,pyrrolinyl group, pyrrolyl group, imidazolyl group, pyrazolylgroup, imidazolidinyl group, piperidino group, morpholinogroup, dihydropyridyl group, pyridyl group, N-methylpiperazinylgroup, N-ethylpiperazinyl group etc.), (28)a C_1-6 alkanoylamino group (e.g., formamide group, acetamidegroup, trifluoroacetamide group, propionylamide group,butyrylamide group, isobutyrylamide group etc.), (29) abenzamide group, (30) a carbamoylamino group, (31) a N-C_1-4alkylcarbamoylamino group (e.g., N-methylcarbamoylamino group,N-ethylcarbamoylamino group, N-propylcarbamoylamino group, N-isopropylcarbamoylamino group, N-butylcarbamoylamino groupetc.), (32) a N,N-di-C_1-4 alkylcarbamoylamino group (e.g., N,N-dimethylcarbamoylaminogroup, N,N-diethylcarbamoylamino group,N,N-dipropylcarbamoylamino group, N,N-dibutylcarbamoylaminogroup etc.), (33) a C_1-3 alkylenedioxy group (e.g.,methylenedioxy group, ethylenedioxy group etc.), (34) a -B(OH)₂,(35) a hydroxy group, (36) an epoxy group (-O-), (37) a nitrogroup, (38) a cyano group, (39) a mercapto group, (40) a sulfogroup, (41) a sulfino group, (42) a phosphono group, (43) asulfamoyl group, (44) a C_1-6 alkylsulfamoyl group (e.g., N-methylsulfamoylgroup, N-ethylsulfamoyl group, N-propylsulfamoylgroup, N-isopropylsulfamoyl group, N-butylsulfamoylgroup etc.), (45) a di-C_1-6 alkylsulfamoyl group(e.g., N,N-dimethylsulfamoyl group, N,N-diethylsulfamoyl group,N,N-dipropylsulfamoyl group, N,N-dibutylsulfamoyl,group etc.),(46) a C_1-6 alkylthio group (e.g., methylthio group, ethylthiogroup, propylthio group, isopropylthio group, n-butylthiogroup, sec-butylthio group, tert-butylthio group etc.), (47) aphenylthio group, (48) a C_1-6 alkylsulfinyl group (e.g.,methylsulfinyl group, ethylsulfinyl group, propylsulfinylgroup, butylsulfinyl group etc.), (49) a phenylsulfinyl group,(50) a C_1-6 alkylsulfonyl group (e.g., methylsulfonyl group,ethylsulfonyl group, propylsulfonyl group, butylsulfonyl groupetc.), (51) a phenylsulfonyl group and the like can bementioned. The number of substitution is 1 to 6, preferably 1to 3, more preferably 1 or 2.
[0046] Preferable examples of the "heterocyclic ring optionallyhaving a substituent" formed by R³ and R⁴ or R⁴ and R⁵ togetherwith carbon atoms bonded thereto are thiophene, furan, pyrrole,pyrroline, oxazole, thiazole, pyrazole, imidazole, imidazoline,isoxazole, isothiazole, furazan, 1,2,3-thiadiazole, 1,2,5-thiadiazole,1,2,3-triazole, 1,2,3-triazine, 1,2,4-triazine,1,2,3-triazolidine, 2,2-difluoro-1,3-dioxole and 2,2,3,3-tetrafluoro-1,4-dioxane.
[0047] In the above-mentioned embodiments, the substituent ofthe "homocyclic ring optionally having substituents" and thesubstituent of the "heterocyclic ring optionally havingsubstituents" are preferably selected from the groupconsisting of (1) C_1-6 alkyl group optionally substituted byhalogen atoms, (2) nitro group, (3) hydroxy group, (4)mercapto group, (5) cyano group, (6) carbamoyl group, (7)carboxyl group, (8) C_1-6 alkoxycarbonyl group, (9) sulfo group,(10) halogen atom, (11) C_1-6 alkoxy group, (12) C_1-6 alkylthiogroup, (13) C_1-6 alkylsulfinyl group, (14) C_1-6 alkylsulfonylgroup, (15) amino group, (16) mono- or di-C_1-4 alkylamino group,(17) C_1-6 alkanoyl group and (18) C_1-6 alkanoyloxy group.
[0048] The "pharmaceutically acceptable salt" may be any as longas it forms a nontoxic salt with the aforementioned compoundrepresented by the formula (1). Examples thereof include, butare not limited to, salts with various inorganic acids such ashydrochloride, hydrobromide, hydroiodide, sulfate, nitrate,phosphate, carbonate, hydrogen carbonate, perchlorate and thelike; salts with organic acids such as formate, acetate,trifluoroacetate, propionate, oxalate, glycolate, succinate,lactate, maleate, hydroxymaleate, methylmaleate, fumarate,adipate, tartrate, malate, citrate, benzoate, cinnamate,ascorbate, salicylate, 2-acetoxybenzoate, nicotinate,isonicotinate and the like; sulfonates such asmethanesulfonate, ethanesulfonate, isethionate,benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate andthe like; salts with acidic amino acid such as aspartate,glutamate and the like; alkali metal salts such as sodium salt,potassium salt and the like; alkaline earth metal salts suchas magnesium salt, calcium salt and the like; ammonium salt;salts with organic base such as trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt andthe like; salts with amino acid such as lysin salt, argininesalt and the like; and the like. In some cases, the salt maybe a water-containing product, hydrate or solvate with alcoholand the like.
[0049] In addition, the above-mentioned compound represented bythe formula (1) may have various isomers. For example, E formand Z form are present as geometric isomers, and when anasymmetric carbon atom exists, enantiomer and diastereomer asstereoisomers based thereon exist, and a tautomer can exist.Accordingly, the present invention encompasses all of theseisomers and mixtures thereof.
[0050] The compound of the present invention encompasses prodrugcompounds and metabolites.
[0051] By the "prodrug compound" is meant a derivative of thecompound of the present invention, which has a chemically ormetabolically decomposable group and which, afteradministration to the body, restores to the original compoundto show its inherent efficacy, including a complex and a saltfree of covalent bond.
[0052] As the prodrug compound of the compound represented bythe formula (1) of the present invention, a compound whereinthe carboxyl group of the compound represented by the formula(1) is modified by ethyl group, pivaloyloxymethyl group, 1-(acetyloxy)ethylgroup, 1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethylgroup, carboxylmethyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, phenyl group, o-tolylgroup and the like; a compound wherein the hydroxylgroup of the compound represented by the formula (1) ismodified by acetyl group, propionyl group, isobutyryl group,pivaloyl group, benzoyl group, 4-methylbenzoyl group,dimethylcarbamoyl group or sulfo group; a compound wherein theamino group of the compound represented by the formula (1) is modified by 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, and the like can be mentioned. Best Mode for Embodying the Invention
[0053] Now, various substituents and substitution sites aredescribed in more detail in the following.
[0054] R¹ is preferably a C_1-6 alkyl group optionally substitutedby halogen atoms, more preferably a trifluoromethyl group.
[0055] R² is preferably a halogen atom, a C_1-6 alkyl groupoptionally substituted by halogen atoms or a cyano group, morepreferably a trifluoromethyl group or a cyano group.
[0056] R³ and R⁴ are each preferably a hydrogen atoms, a halogenatom, a C_1-6 alkyl group optionally substituted by halogen atoms,a C_1-6 alkoxy group optionally substituted by halogen atoms, aC_1-6 alkylthio group optionally substituted by halogen atoms orR³ and R⁴ form a homocyclic ring together with carbon atomsbonded thereto.
[0057] R⁵ is preferably a hydrogen atom.
[0058] R⁶ is preferably a hydrogen atom or a C_1-6 alkyl group,more preferably a hydrogen atom, a methyl group or an ethylgroup.
[0059] n is preferably 0, 1 or 2.
[0060] Ring B and (R⁶)_n are each preferably
[0061] A is preferably -N(R⁷)(R⁸), more preferably that whereinR⁷ is a C_1-6 alkyl group and R⁸ is a C_4-10 cycloalkylalkyl groupoptionally substituted by -(CH₂)_r-COOR¹⁰ (wherein r and R¹⁰ areas defined above) or a C_1-6 alkyl group substituted by carboxylgroup.
[0062] Preferable examples of the compound of the presentinvention (1) are as follows: 1. N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine, 2. 3-{[N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile, 3. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine, 4. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride, 5. N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine, 6. N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)aminehydrochloride, 7. N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine, 8. 5-{N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino}pentanoicacid hydrochloride, 9. methyl trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylate, 10. 3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile, 11. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-ethyl-2H-tetrazol-5-yl)amine, 12. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-[1,2,4]triazol-3-yl)amine, 13. 3-({N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-phenylamino}methyl)-5-trifluoromethylbenzonitrile, 14. 3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(4,5-dimethyl-thiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile, 15. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(thiazol-2-yl)aminehydrochloride, 16. 3-({N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(thiazol-2-yl)amino}methyl)-5-trifluoromethylbenzonitrilehydrochloride, 17. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(oxazol-2-yl)aminehydrochloride, 18. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methylthiazol-2-yl)aminehydrochloride, 19. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4-methylthiazol-2-yl)aminehydrochloride, 20. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4,5-dimethylthiazol-2-yl)aminehydrochloride, 21. 3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(5-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride, 22. 3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(4-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride, 23. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4-methyloxazol-2-yl)aminehydrochloride, 24. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methylisothiazol-5-yl)aminehydrochloride, 25. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methylisoxazol-3-yl)aminehydrochloride, 26. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methylisoxazol-5-yl)aminehydrochloride, 27. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-3-yl)aminehydrochloride, 28. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-4-yl)aminehydrochloride, 29. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]thiadiazol-2-yl)aminehydrochloride, 30. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]oxadiazol-2-yl)aminehydrochloride, 31. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-pyridin-3-ylaminehydrochloride, 32. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-pyridin-2-ylaminehydrochloride, 33. N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(N'-cyclopentylmethyl-N'-ethylamino)-5-trifluoromethylbenzyl]-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride, 34. 3-{[N-[2-(N'-cyclopentylmethyl-N'-ethylamino)-5-trifluoromethylbenzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride, 35. methyl 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoatehydrochloride, 36. methyl 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-ylmethyl)-N-ethylamino]pentanoatehydrochloride, 37. methyl 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoatehydrochloride, 38. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 39. 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 40. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 41. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 42. methyl trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylatehydrochloride, 43. methyl trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylatehydrochloride, 44. trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 45. trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 46. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,2,4]oxadiazol-3-yl)amine hydrochloride, 47. methyl trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylatehydrochloride, 48. trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 49. methyl trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylate, 50. trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 51. trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 52. trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 53. trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 54. trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 55. methyl 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoatehydrochloride, 56. 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(3-methyl-isoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 57. 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 58. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 59. trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 60. trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid, 61. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methyl-[1,2,4]thiadiazol-5-yl)amine, 62. 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]inethyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 63. methyl 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoatehydrochloride, 64. methyl 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoatehydrochloride, 65. 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride, 66. 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacid hydrochloride, 67. trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 68. trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 69. trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 70. trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid, 71. trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 72. trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 73. 2-(5-{N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]amino}tetrazol-2-yl)ethanolhydrochloride, 74. methyl 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoatehydrochloride, 75. methyl 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride, 76. 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride, 77. 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride, 78. 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride, 79. 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride, 80. 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride, 81. 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride, 82. trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid, 83. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoicacid hydrochloride, 84. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoicacid hydrochloride, 85. 5-[N-(2-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoicacid hydrochloride, 86. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoicacidhydrochloride, 87. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, 88. 5-{N-[6-({N'-[3,5-bis(trifluoromethyl)benzyl]-N'-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}pentanoicacid hydrochloride, 89. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoicacidhydrochloride, 90. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-2,2-dimethylpentanoicacid hydrochloride, 91. 6-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]hexanoicacid hydrochloride, 92. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride, 93. trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 94. (1-{2-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]ethyl}cyclopentyl)aceticacid hydrochloride, 95. trans-4-({N-[6-({N'-[3,5-bis(trifluoromethyl)benzyl]-N'-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}methyl)cyclohexanecarboxylicacid, 96. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 97. (1-{2-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]ethyl}cyclopentyl)aceticacid, 98. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 99. trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthal-en-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 100. trans-4-({N-[3-({N'-[3,5-bis(trifluoromethyl)benzyl]-N'-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-ethylamino}methyl)cyclohexanecarboxylicacid hydrochloride, 101. 1-{3-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]propyl}cyclohexanecarboxylicacid hydrochloride, 102. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoicacid, 103. 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride, 104. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride, 105. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride, 106. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 107. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride, 108. 5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride, 109. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]inethyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 110. 6-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]hexanoicacidhydrochloride, 111. trans-(4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 112. 6-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-4,4-dimethylhexanoicacid hydrochloride, 113. 6-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylhexanoicacid hydrochloride, 114. 5-,[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-4,4-dimethylpentanoicacid hydrochloride, 115. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 116. 6-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-4,4-dimethylhexanoicacid hydrochloride, 117. 6-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-4,4-dimethylhexanoicacidhydrochloride, 118. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 119. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride, 120. 6-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-5,5-dimethylhexanoicacid hydrochloride, 121. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexanecarboxylic acid hydrochloride, 122. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-isobutylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 123. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid amide, 124. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid methylamide, 125. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid dimethylamide, 126. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-chlorophenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 127. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 128. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(m-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 129. trans-4-{[N-(2-{[N'-(3,5-dichlorobenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 130. trans-4-{[N-ethyl-N-(2-{[N'-(2-methyl-2H-tetrazol-5-yl)-N'-(3-methyl-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylic acidhydrochloride, 131. trans-4-{[N-(2-{[N'-(3-chloro-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 132. trans-4-{[N-ethyl-N-(2-{[N'-(2-methyl-2H-tetrazol-5-yl)-N'-(3-nitro-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylicacidhydrochloride, 133. trans-(4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride, 134. trans-(4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 135. trans-3-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)propionicacid hydrochloride, 136. trans-(4-{[N-(7-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride, 137. trans-(4-{[N-(7-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 138. trans-2-(4-{[N-(7-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)acetamide hydrochloride, 139. trans-N-[3,5-bis(trifluoromethyl)benzyl]-N-{2-[N'-ethyl-N'-(4-(methoxymethyl)cyclohexylmethyl)amino]-5-trifluoromethoxybenzyl}-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride, 140. trans-2-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)ethanolhydrochloride, 141. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride, 142. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 143. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 144. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexylmethyl)phosphonicacid, 145. trans-4-{[N-(2-{[N'-(3-bromo-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 146. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride, 147. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride, 148. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride, 149. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-methoxyphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 150. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl]methanolhydrochloride, 151. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4,5-dimethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 152. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylthiophenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 153. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacidhydrochloride, 154. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride, 155. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacidhydrochloride, 156. trans-4-({N-[2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-(2,2,2-trifluoroethyl)phenyl]-N-ethylamino}methyl)cyclohexanecarboxylic acid hydrochloride, 157. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride, 158. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride, 159. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-ethylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 160. trans-4-{[N-(2-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, 161. trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-isopropenylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid, 162. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid dihydrochloride, 163. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluorbmethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 164. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 165. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride, 166. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid, 167. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid, 168. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid methanesulfonate, 169. ethyl trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate, 170. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid, 171. trans-(4-{[N-(2-{[N'-(3-methyl-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid, 172. trans-(4-{[N-(2-{[N'-(3-methyl-5-trifluoromethylbenzyl)-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid, 173. ethyl cis-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate, 174. {4-[2-(2-{[N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)butyl]cyclohexyl}aceticacid and 175. 5-[2-({N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-methyl-2H-tetrazol-5-yl]amino}methyl)-5-methyl-4-trifluoromethylphenoxy]heptanoicacid.
[0063] Of the compounds recited above, the compound shown beloware particularly preferable. 115. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 118. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 142. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 143. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride, 154. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride, 157. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride, 158. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride, 166. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid, 167. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid and 168. trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid methanesulfonate.
[0064] The compound of the present invention, a prodrug thereofand a pharmaceutically acceptable salt thereof have superiorCETP inhibitory activity in mammals (e.g., human, monkey,bovine, horse, dog, cat, rabbit, rat, mouse and the like), andcan be used as CETP activity inhibitors. In addition,utilizing the superior CETP inhibitory activity of thecompound of the present invention, a prodrug thereof and apharmaceutically acceptable salt thereof, they are useful aspharmaceutical agents effective for the prophylaxis ortreatment of the diseases in which CETP is involved (e.,g.,hyperlipidemia, arteriosclerosis, atherosclerosis, peripheralvascular disease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia,hypertriglyceridemia, familial hypercholesterolemia,cardiovascular disorder, angina, ischemia, heart ischemia,thrombosis, cardiac infarction, reperfusion injury, angioplasty restenosis, hypertension, diabetic vascularcomplications, obesity or endotoxemia etc.), particularly asprophylactic or therapeutic agents for hyperlipidemia orarteriosclerotic diseases.
[0065] When the compound represented by the formula (1) of thepresent invention, a prodrug thereof or a pharmaceuticallyacceptable salt thereof is used as a pharmaceuticalpreparation, it is generally admixed with a pharmacologicallyacceptable carrier, excipient, diluent, filler, disintegrant,stabilizer, preservative, buffer, emulsifier, aromatic,coloring agent, sweetening agent, thickening agent, corrigent,dissolution aids, and other additives, which are known per se,specifically water, vegetable oil, alcohol such as ethanol andbenzyl alcohol, polyethylene glycol, glycerol triacetategelatin, carbohydrates such as lactose, starch and the like,magnesium stearate, talc, lanolin, petrolatum and the like,and can be administered orally or parenterally in the form oftablet, pill, powder, granule, suppository, injection, eyedrop, liquid, capsule, troche, aerosol, elixir, suspension,emulsion, syrup and the like.
[0066] While the dose of the pharmaceutical agent of thepresent invention varies depending on the kind and severity ofthe disease, the compound to be administered andadministration route, age, sex and body weight of patients andthe like, it is generally about 1-1000 mg, particularly about50 mg-800 mg in the amount of the compound represented by theformula (1) of the present invention, a prodrug thereof or apharmaceutically acceptable salt thereof per day for an adultby oral administration.
[0067] The pharmaceutical agent of the present invention may beadministered alone or concurrently with a differentprophylactic or therapeutic agent for hyperlipidemia and/or aprophylactic or therapeutic agent for arteriosclerotic diseases, or may be used concurrently with a differentpharmaceutical agent (e.g., therapeutic agent for obesity,therapeutic agent for diabetes, therapeutic agent forhypertension, therapeutic agent for arteriosclerosis,therapeutic agent for coronary artery disease etc.).Particularly, concurrent use with a different therapeuticagent for hyperlipidemia (statin pharmaceutical agent) isexpected to provide an extremely superior synergistic effectof particularly remarkable suppression of blood cholesterol.
[0068] As used herein, by "concurrent use" means a combined useof the compound of the present invention, a prodrug thereof ora pharmaceutically acceptable salt thereof with a differentpharmaceutical agent, such as a therapeutic agent forhyperlipidemia, wherein the mode of use thereof is notparticularly limited. For example, it includes both theadministration of a pharmaceutical composition containing thecompound of the present invention, a prodrug thereof or apharmaceutically acceptable salt thereof and a differentpharmaceutical agent, and the simultaneous or staggeredadministration of respective preparations produced separatelywithout mixing.
[0069] While the dose of the different pharmaceutical agent tobe used concurrently varies depending on the kind and severityof the disease, administration route, age, sex and body weightof patients and the like, it is generally about 1-1000 mg,particularly about 50 mg-800 mg thereof per day for an adultby oral administration.
[0070] As a therapeutic agent for hyperlipidemia to be usedconcurrently with the pharmaceutical agent of the presentinvention, statin pharmaceutical agents such as lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin,cerivastatin and the like can be mentioned.
[0071] As a therapeutic agent for obesity to be used concurrently with the pharmaceutical agent of the presentinvention, mazindol and the like can be mentioned.
[0072] As a therapeutic agent for diabetes to be usedconcurrently with the pharmaceutical agent of the presentinvention, insulin preparations, sulfonylureas (e.g.,glibenclamide, tolbutamide, glyclopyramide, acetohexamide,glimepiride, tolazamide, gliclazide etc.), insulinsecretagogues (e.g., nateglinide etc.), sulfonamides (e.g.,glybuzole etc.), biguanides (e.g., metformin hydrochloride,buformin hydrochloride etc.), α glucosidase inhibitors (e.g.,voglibose, acarbose etc.), insulin sensitizers (e.g.,pioglitazone hydrochloride etc.) and the like can be mentioned.
[0073] As a therapeutic agent for hypertension to be usedconcurrently with the pharmaceutical agent of the presentinvention, loop diuretics (e.g., furosemide sustained-releasepreparation etc.), angiotensin converting enzyme inhibitors(e.g., captopril, captopril sustained-release preparation,enalapril maleate, alacepril, delapril hydrochloride,cilazapril, lisinopril, benazepril hydrochloride, imidaprilhydrochloride, temocapril hydrochloride, quinaprilhydrochloride, trandrapril, perindopril erbumine etc.),angiotensin II receptor antagonists (e.g., losartan potassium,candesartan cilexetil etc.), Ca antagonists (e.g., nicardipinehydrochloride, nicardipine hydrochloride sustained-releasepreparation, nilvadipine, nifedipine, nifedipine sustained-releasepreparation, benidipine hydrochloride, diltiazemhydrochloride, diltiazem hydrochloride sustained-releasepreparation, nisoldipine, nitrendipine, manidipinehydrochloride, barnidipine hydrochloride, efonidipinehydrochloride, amlodipine besylate, felodipine, cilnidipine,aranidipine etc.), β blockers (e.g., propranolol hydrochloride,propranolol hydrochloride sustained-release preparation,pindolol, pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, carteololhydrochloride sustained-release preparation, bunitrololhydrochloride, bunitrolol hydrochloride sustained-releasepreparation, atenolol, acebutolol hydrochloride, metoprololtartrate, metoprolol tartrate sustained-release preparation,nipradilol, penbutolol sulfate, tilisolol hydrochloride,carvedilol, bisoprolol fumarate, betaxolol hydrochloride,celiprolol hydrochloride, bopindolol malonate, bevantololhydrochloride etc.), α,β blockers (e.g., labetalolhydrochloride, arotinolol hydrochloride, amosulalolhydrochloride etc.), α blockers (e.g., prazosin hydrochloride,terazosin hydrochloride, doxazosin mesylate, bunazosinhydrochloride, bunazosin hydrochloride sustained-releasepreparation, urapidil, phentolamine mesylate etc.) and thelike can be mentioned.
[0074] Moreover, the pharmaceutical agent of the presentinvention can be administered not only to humans but also toother mammals (e.g., monkey, bovine, horse, dog, cat, rabbit,rat, mouse and the like).
[0075] Now, one embodiment of the production method of thedibenzylamino compound represented by compound (1) isexplained, but the production method of the present inventionis not limited to this example.
[0076] When the reaction to be mentioned below is carried out,functional groups at positions other than the reaction sitemay be protected beforehand as necessary and may bedeprotected at a suitable stage.
[0077] Moreover, the reaction in each step may be carried outaccording to a conventional method, wherein isolation andpurification are performed by appropriately selecting orcombining conventional methods, such as crystallization,recrystallization, column chromatography, preparative HPLC andthe like. Conventional Production Method
[0078] The production method of the compound represented by theformula (1) is exemplarily shown in the following
[0079] This step is directed to a general reductive amination.The compound represented by the formula (2) is reacted with acompound represented by the formula (3) in the presence of areducing agent in a solvent to give a compound represented bythe formula (4).
[0080] As the solvent to be used for the reaction, for example,ether solvents such as diethyl ether, tetrahydrofuran (THF),dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xyleneand the like; halogenated solvents such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and thelike; alcohol solvents such as methanol, ethanol, isopropylalcohol, tert-butanol and the like; ester solvents such asethyl acetate, methyl acetate, butyl acetate and the like;polar solvents such as acetic acid, N,N-dimethylformamide andthe like; and the like can be mentioned, which can be usedalone or in combination. Preferable solvents in this reactionare chloroform and dichloromethane.
[0081] As the reducing agent, sodium triacetoxyborohydride,sodium cyanoborohydride, sodium borohydride and the like canbe mentioned. A preferable reducing agent in this reaction issodium triacetoxyborohydride. Step 1-2
[0082] This step is directed to a general alkylation. Acompound represented by the formula (4) is reacted with acompound represented by the formula (5) in a solvent in thepresence of a base to give one of the object compounds, whichis represented by the formula (1-a).
[0083] As the solvent to be used for the reaction, for example,ether solvents such as diethyl ether, tetrahydrofuran (THF),dioxane, 1,2-dimethoxyethane, diglyme and the like;hydrocarbon solvents such as benzene, toluene, hexane, xyleneand the like; alcohol solvents such as methanol, ethanol,isopropyl alcohol, tert-butanol and the like; ester solventssuch as ethyl acetate, methyl acetate, butyl acetate and thelike; polar solvents such as acetone, N,N-dimethylformamide,dimethyl sulfoxide and the like; and the like can be mentioned,which can be used alone or in combination. A preferablesolvent in this reaction is N,N-dimethylformamide.
[0084] As the base, for example, alkali metal hydrides (e.g.,sodium hydride, potassium hydride etc.); alkali metal alkoxides (e.g., sodium ethoxide, sodium methoxide, potassiumtert-butoxide etc.); alkyllithiums (e.g., n-butyllithium, sec-butyllithiumetc.); alkali metal amides (e.g., lithiumdiisopropylamide, sodium amide, lithium bistrimethylsilylamideetc.); alkali metal carbonates (e.g., sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate etc.); alkali metal hydroxides (e.g.,lithium hydroxide, sodium hydroxide, potassium hydroxideetc.); alkali metal phosphates (e.g., sodium phosphate,potassium phosphate etc.); and organic bases (e.g.,triethylamine, pyridine, N-methylmorpholine etc.) can bementioned, with preference given to sodium hydride andpotassium tert-butoxide.
[0085] The obtained object compound may be subjected to a salt-formingreaction to give a desired salt. Production Method 2Step 2-1
[0086] This step is directed to a general reductive amination.A compound represented by the formula (6) is reacted with acompound represented by the formula (3) in a solvent in thepresence of a reducing agent to give a compound represented bythe formula (7).
[0087] As the solvent, for example, ether solvents such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,diglyme and the like; hydrocarbon solvents such as benzene,toluene, hexane, xylene and the like; halogenated solventssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, tert-butanol and thelike; ester solvents such as ethyl acetate, methyl acetate,butyl acetate and the like; polar solvents such as N,N-dimethylformamideand the like; and the like can be mentioned,which can be used alone or in combination. Preferable solvents in this reaction are dichloromethane and toluene.
[0088] As the reducing agent, sodium triacetoxyborohydride,sodium cyanoborohydride, sodium borohydride, lithium hydride,aluminum hydride and the like can be mentioned. A preferablereducing agent in this reaction is sodium borohydride.
[0089] As a different method, the formula (6) is reacted withthe formula (3) to once give a Schiff base, which is followedby a reduction. For a reaction to form a Schiff base,azeotropic dehydration may be conducted in a solvent such asbenzene, toluene, ethanol and the like without catalyst or inthe presence of an acid catalyst such as hydrochloric acid,acetic acid and the like, or a method using a dehydratingagent such as molecular sieves and the like in an aproticsolvent such as methylene chloride, toluene and the like maybe employed. Step 2-2
[0090] A compound represented by the formula (8), which isobtained by treating the formula (2) by a general reduction,is reacted with thionyl chloride in a solvent such as toluene,tetrahydrofuran, chloroform and the like to give a compoundwherein hydroxyl group of the formula (8) is chlorinated. Next,a similar reaction as in Step 1-2 using the obtained compoundand a compound represented by the formula (7) gives one of theobject compounds, which is represented by the formula (1-a). Production Method 3Step 3-1
[0091] This step is directed to a general reductive amination.A compound represented by the formula (2) is reacted with acompound represented by the formula (9) in a solvent in thepresence of a reducing agent to give a compound represented bythe formula (10).
[0092] As the solvent, for example, ether solvents such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene,toluene, hexane, xylene and the like; halogenated solventssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, tert-butanol and thelike; ester solvents such as ethyl acetate, methyl acetate,butyl acetate and the like; polar solvents such as N,N-dimethylformamideand the like; and the like can be mentioned,which can be used alone or in combination. A preferablesolvent in this reaction is dichloromethane.
[0093] As the reducing agent, sodium triacetoxyborohydride,sodium cyanoborohydride, sodium borohydride and the like canbe mentioned. A preferable reducing agent in this reaction issodium triacetoxyborohydride. Step 3-2
[0094] This step is directed to a general nucleophilicsubstitution reaction. In a similar manner as in Step 1-2, acompound represented by the formula (10) is reacted with acompound represented by the formula (11) to give one of theobject compounds, which is represented by the formula (1-a).
[0095] Besides such method comprising directly reacting acompound having ring B, which is represented by the formula(11), there is a method comprising forming ring B on thenitrogen atom of compound (10) by a known method. As anexample of this method, the following production method 3' andproduction method 3" are shown. Production Method 3'
[0096] When
[0097] A compound represented by the formula (10) is reacted with compound (12) in a solvent. The obtained residue isreacted with hydrazine hydrate in a solvent in the presence ofan acid to give a compound represented by the formula (1-b),which is one of the object compounds.
[0098] As the solvent to be used for the first reaction, forexample, ether solvents such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, diglyme and the like;hydrocarbon solvents such as benzene, toluene, hexane, xyleneand the like; halogenated solvents such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and thelike; ester solvents such as ethyl acetate, methyl acetate,butyl acetate and the like; polar solvents such as N,N-dimethylformamideand the like; and the like can be mentioned,which can be used alone or in combination. A preferablesolvent in this reaction is dichloromethane.
[0099] As the solvent to be used for the next reaction, forexample, ether solvents such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, diglyme and the like;hydrocarbon solvents such as benzene, toluene, hexane, xyleneand the like; halogenated solvents such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and thelike; alcohol solvents such as methanol, ethanol, isopropylalcohol, tert-butanol and the like; ester solvents such asethyl acetate, methyl acetate, butyl acetate and the like;polar solvents such as N,N-dimethylformamide, dimethylsulfoxide and the like; and the like can be mentioned, whichcan be used alone or in combination. A preferable solvent inthis reaction is 1,2-dimethoxyethane.
[0100] As the acid to be used for the reaction, for example,inorganic acids such as hydrochloric acid, sulfuric acid,nitric acid and the like; organic acids such astrifluoroacetic acid, trichloroacetic acid, acetic acid,methanesulfonic acid, p-toluenesulfonic acid and the like; and a mixture thereof can be mentioned, with preference given tomethanesulfonic acid. Production Method 3"
[0101] When
[0102] A compound represented by the formula (10) is reactedwith cyanogen bromide in a solvent in the presence of a base,and the obtained residue is reacted with hydroxylamine in asolvent. The obtained residue is reacted with an acylatingagent, such as acid chloride represented by the formula (13)and the like, in a solvent to give a compound represented bythe formula (1-c), which is one of the object compounds.
[0103] As the solvent to be used for the first reaction, forexample, alcohol solvents such as methanol, ethanol, isopropylalcohol, tert-butanol and the like; ether solvents such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,diglyme and the like; hydrocarbon solvents such as benzene,toluene, hexane, xylene and the like; halogenated solventssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like; ester solvents such as ethylacetate, methyl acetate, butyl acetate and the like; polarsolvents such as N,N-dimethylformamide and the like; and thelike can be mentioned, which can be used alone or incombination. A preferable solvent in this reaction is methanol.
[0104] As the base to be used for the first reaction, forexample, alkali metal carbonates (e.g., sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate etc.); alkali metal phosphates (e.g.,sodium phosphate, potassium phosphate etc.); and organic bases(e.g., triethylamine, pyridine, N-methylmorpholine etc.) can be mentioned, with preference given to sodium hydrogencarbonate.
[0105] As the solvent to be used for the next reaction, forexample, ether solvents such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, diglyme and the like;hydrocarbon solvents such as benzene, toluene, hexane, xyleneand the like; halogenated solvents such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and thelike; alcohol solvents such as methanol, ethanol, isopropylalcohol, tert-butanol and the like; polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide and the like; andthe like can be mentioned, which cam be used alone or incombination. A preferable solvent in this reaction is dioxane.
[0106] As the solvent to be used for the final reaction, forexample, ether solvents such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, diglyme and the like;hydrocarbon solvents such as benzene, toluene, hexane, xyleneand the like; halogenated solvents such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and thelike; ester solvents such as ethyl acetate, methyl acetate,butyl acetate and the like; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide and the like; and thelike can be mentioned, which can be used alone or incombination. A preferable solvent in this reaction is pyridine.
[0107] In addition, A, B and R¹ to R⁶ may be further subjectedto conversion of a functional group according to a knownmethod, after synthesis of compound (1) in the above-mentionedproduction method.
[0108] As a functional group conversion reaction, for example,when the terminal of substituent A is an ester, the obtainedcompound (1-a) is subjected to a conventional ester hydrolysis,whereby a compound having a carboxyl group as the terminal ofsubstituent A can be easily obtained. As the solvent to be used for this ester hydrolysis reaction, for example, ethersolvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,diglyme and the like; alcohol solvents suchas methanol, ethanol, isopropyl alcohol, tert-butanol and thelike, and water can be mentioned, which may be used alone orin combination. Similarly, as the base to be used for thisester hydrolysis reaction, metal hydroxides such as sodiumhydroxide, potassium hydroxide, lithium hydroxide and the like,and the like can be mentioned.
[0109] In addition, a method exists which comprises, afterdeprotection of protected hydroxyl group at the terminal ofsubstituent A, conversion to cyano group, carboxyl group andthe like.
[0110] A compound represented by the formula (2), which is astarting material of the above-mentioned production method,can be produced according to a conventionally known method. Inthe following, some examples thereof are explained. Production Method 4
[0111]
[0112] Aniline represented by the formula (15) is reacted withan acid halide and the like in the presence or absence of abase under cooling to heating in an organic solvent, water, or without solvent, whereby a compound represented by the formula(16) can be synthesized (Step 4-1). The compound representedby the formula (16) is reacted with a reducing agent such aslithium aluminum hydride, Red-Al, sodium borohydride and thelike under cooling to heating in an organic solvent, whereby acompound represented by the formula (17) can be synthesized(Step 4-2). The compound represented by the formula (17) isreacted with alkyl halide and the like in the presence orabsence.of a base under cooling to heating in an organicsolvent or water, or without solvent, whereby a compoundrepresented by the formula (18) can be synthesized (Step 4-3).The compound represented by the formula (18) is reacted usinga Vilsmeier reagent prepared from phosphorus oxychloride andN,N-dimethylformamide and the like under cooling to heating inan organic solvent or without solvent, whereby a compoundrepresented by the formula (2-a), which is one of the desiredstarting materials, can be synthesized (Step 4-4). Production Method 5
[0113]
[0114] Phenol represented by the formula (19) is reacted withalcohol represented by the formula; (R¹¹)(R¹²)(R¹³)COH (whereinR¹¹, R¹² and R¹³ are as defined above) in the presence oftriphenylphosphine using a condensing agent such as diethylazodicarboxylate and the like under cooling to heating in anorganic solvent or water, or without solvent, whereby acompound represented by the formula (20) can be synthesized(Step 5-1). The compound represented by the formula (20) is reacted using a Vilsmeier reagent prepared from phosphorusoxychloride and N,N-dimethylformamide and the like undercooling to heating in an organic solvent or without solvent,whereby a compound represented by the formula (2-b), which isone of the desired starting materials, can be synthesized(Step 5-2). Production Method 6
[0115]
[0116] Halobenzene represented by the formula (21) andbutyllithium are reacted in an organic solvent under coolingto room temperature and a lithio form generated is treatedwith ketone, aldehyde and the like, whereby a compoundrepresented by the formula (22) can be synthesized (Step 6-1).The compound represented by the formula (22) is hydrogenatedin the presence of a catalyst such as palladium hydroxide andthe like at room temperature or under heating in an organicsolvent or water, whereby a compound represented by theformula (23) can be synthesized (Step 6-2). The compoundrepresented by the formula (23) is reacted using a brominatingagent such as bromosuccinimide and the like under cooling toheating in an organic solvent or without solvent, whereby acompound represented by the formula (24) can be synthesized (Step 6-3). The compound represented by the formula (24) andbutyllithium are reacted in an organic solvent under coolingto room temperature and a lithio form generated is treatedwith N,N-dimethylformamide and the like, whereby a compoundrepresented by the formula (2-c), which is one of the desiredstarting materials, can be synthesized (Step 6-4). Production Method 7
[0117]
[0118] A fluorobenzene compound represented by the formula (25)and LDA, butyllithium and the like are reacted in an organicsolvent under cooling to room temperature and a lithio formgenerated is treated with N,N-dimethylformamide and the like,whereby a compound represented by the formula (26) can besynthesized (Step 7-1). The compound represented by theformula (26) is reacted with an amine represented by theformula; (R₇) (R₈)NH in the presence of a base such as potassiumcarbonate and the like under cooling to heating in an organicsolvent or without solvent, whereby a compound represented bythe formula (2-d), which is one of the desired startingmaterials, can be synthesized (Step 7-2).
[0119] The present invention is explained in more detail inthe following by referring to Examples, which are not to beconstrued as limitative. Examples Example 1N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)aminea) N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine
[0120] To a solution (10 ml) of 3-(N-cyclopentylmethyl-N-ethylamino)-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde(333mg) and 5-amino-2-methyltetrazole (231 mg) in chloroform wasadded sodium triacetoxyborohydride (745 mg) with stirring atroom temperature, and acetic acid (13 µl) was addedsuccessively. The reaction solution was stirred overnight.andsodium borohydride (50 mg) and methanol (3 ml) were added. Themixture was further stirred for 2 hr. The reaction solutionwas washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated brine, and the organic layerwas dried over sodium sulfate. Sodium sulfate was filtered offand the filtrate was concentrated. The obtained residue waspurified by column chromatography (n-hexane:ethyl acetate=6:1→ 3:1) to give the title compound (254 mg, 59%).¹HNMR(CDCl₃, 400MHz) δ: 1.01(t, J=7.1Hz, 3H), 1.10-1.30(m, 2H),1.30-1.62(m, 4H), 1.67-1.82(m, 6H), 1.93-2.10(m, 1H), 2.63-2.77(m,4H), 2.81(d, J=7.1Hz, 2H), 2.94(q, J=7.1Hz, 2H),4.14(s, 3H), 4.51(d, J=5.8Hz, 2H), 5.35-5.50(brs, 1H), 6.87(s,1H), 7.03(s, 1H). b) N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine
[0121] To a solution (2 ml) of N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine(121 mg) obtained in Example 1a) in N,N-dimethylformamide (DMF) was added sodium hydride (16mg) with stirring at room temperature. The reaction solutionwas stirred for 1 hr and 3,5-bis(trifluoromethyl)benzyl bromide (73 µl) was added. The mixture was further stirredovernight. Water was added to the reaction solution and themixture was extracted with ethyl acetate. The extract waswashed successively with water and saturated brine and theorganic layer was dried over sodium sulfate. Sodium sulfatewas filtered off and the filtrate was concentrated. Theobtained residue was purified by column chromatography (n-hexane:ethylacetate=10:1) to give the title compound (102 mg,52%) (see Table 1). Example 23-{[N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrilea) 3-bromomethyl-5-trifluoromethylbenzonitrile
[0122] To a solution (10 ml) of 3-hydroxymethyl-5-trifluoromethylbenzonitrile(1.00 g) and carbon tetrabromide(1.81 g) in dichloromethane was added triphenylphosphine (1.37g) with stirring under ice-cooling, and the mixture wascontinuously stirred for 30 min. The reaction solution wasconcentrated and the obtained residue was purified by columnchromatography (n-hexane:ethyl acetate=9:1) to give the titlecompound (1.11 g, 84%).¹HNMR(CDCl₃, 400MHz) δ: 4.50(s, 2H), 7.85(s, 1H), 7.87(s, 2H). b) 3-{[N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile
[0123] To a solution (2 ml) of N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine(132 mg) obtained in Example 1a) in DMF was added sodium hydride (17 mg) with stirring atroom temperature. The reaction solution was stirred for 1 hrand 3-bromomethyl-5-trifluoromethylbenzonitrile (114 mg)obtained in Example 2 b) was added. The mixture was further stirred overnight.
[0124] Water was added to the reaction solution and the mixturewas extracted with ethyl acetate. The extract was washedsuccessively with water and saturated brine and the organiclayer was dried over sodium sulfate. Sodium sulfate wasfiltered off and the filtrate was concentrated. The obtainedresidue was purified by column chromatography (n-hexane:ethylacetate=6:1) to give the title compound (86 mg, 44%) (seeTable 1). Example 3N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine
[0125] In a similar manner as in Example 1, the title compoundwas obtained (see Table 1). Example 4N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride
[0126] To a solution (12 ml) of N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine(550 mg) obtained in Example 3 in n-hexane was added dropwise1N hydrochloric acid-diethyl ether (0.76 ml) with stirring atroom temperature. The precipitated solid was collected byfiltration and dried to give the title compound (332 mg) (seeTable 1). Example 5N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine
[0127] To a solution (1 ml) of a compound obtained in a similarmanner as in.Example 1, N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-triphenylmethyl-2H-tetrazol-5-yl)amine (75 mg), in ethyl acetate was added dropwise 4Nhydrochloric acid-ethyl acetate (3 ml) with stirring at roomtemperature. The mixture was stirred at room temperature for1.5 hr and 1N aqueous sodium hydroxide, then aqueous citricacid solution were added. The mixture was extracted with ethylacetate and the extract was washed successively with water andsaturated brine. The organic layer was dried over sodiumsulfate. Sodium sulfate was filtered off and the filtrate wasconcentrated. The obtained residue was purified using apreparative TLC plate (n-hexane:ethyl acetate=2:1) to give thetitle compound (24 mg, 46%) (see Table 1). Example 6N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)aminehydrochloridea) N-cyclopentylmethyl-N-{6-[[3,5-bis(trifluoromethyl)benzylamino]methyl]indan-5-yl}-ethylamine
[0128] To a solution (20 ml) of 6-(N-cyclopentylmethyl-N-ethylamino)indane-5-carbaldehyde(1.09 g) and 3,5-bis(trifluoromethyl)benzylamine(1.26 g) in dichloromethanewas added sodium triacetoxyborohydride (1.70 g) with stirringat room temperature. The reaction solution was stirredovernight. The reaction solution was washed successively withsaturated aqueous sodium hydrogen carbonate, water andsaturated brine, and the organic layer was dried over sodiumsulfate. Sodium sulfate was filtered off and the filtrate wasconcentrated. The obtained residue was purified by columnchromatography (n-hexane:ethyl acetate=6:1) to give the titlecompound (1.65 g, 83%).¹HNMR(CDCl₃, 300MHz) δ: 0.95(t, J=7.1Hz, 3H), 1.04-1.22(m, 2H),1.35-1.78(m, 6H), 1.90-2.17 (m, 3H), 2.78(d, J=7.4Hz, 2H),2.75-2.95 (m, 6H), 3.84(s, 2H), 3.88(s, 2H), 7.07(s, 1H), 7.12(s, 1H), 7.75(s,1H), 7.83(s, 2H). b) N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine
[0129] To a solution (3 ml) of N-cyclopentylmethyl-N-{6-[[3,5-bis(trifluoromethyl)benzylamino]methyl]indan-5-yl}-ethylamine(150 mg) obtained in Example 6 a) and 2-chloropyrimidine (69mg) in toluene was added triethylamine (0.17 ml) with stirringat room temperature. The reaction solution was refluxed withstirring overnight and concentrated. The obtained residue waspurified using a preparative TLC plate (n-hexane:ethylacetate=6:1) to give the title compound (68 mg, 39%).¹HNMR(CDCl₃, 400MHz) δ: 0.92(t, J=7.1Hz, 3H), 0.97-1.12(m, 2H),1.30-1.60(m, 6H), 1.83-2.08(m, 3H), 2.80-2.93(m, 8H), 4.86(s,2H), 5.06(s, 2H), 6.59(t, J=4.7Hz, 1H), 6.91(s, 1H), 7.04(s,1H), 7.66(s, 2H), 7.71(s, 1H), 8.36(d,J=4.7Hz,2H). c) N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)aminehydrochloride
[0130] In a similar manner as in Example 4, the title compound(50 mg) was obtained from N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine(68 mg)obtained in Example 6 b) (see Table 2). Example 7N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine
[0131] To a solution (20 ml) of N-cyclopentylmethyl-N-{6-[[3,5-bis(trifluoromethyl)benzylamino]methyl]indan-5-yl}-ethylamine(500 mg) obtained in Example 6 a) in dichloromethane was addeddiketene (85 µl) with stirring under ice-cooling. The reactionsolution was stirred for 2 hr. The reaction solution wasconcentrated and a part (250 mg) of the obtained residue was dissolved in dimethoxyethane (0.7 ml) and methanesulfonic acid(0.56 ml) and then hydrazine hydrate (0.21 ml) were addeddropwise with stirring under ice-cooling. The reactionsolution was stirred at room temperature for 5 days andsaturated aqueous sodium hydrogen carbonate was added. Themixture was extracted with ethyl acetate and washedsuccessively with water and saturated brine. The organic layerwas dried over sodium sulfate. Sodium sulfate was filtered offand the filtrate was concentrated. The obtained residue waspurified using a preparative thin layer chromatography (TLC)plate (n-hexane:ethyl acetate=4:1) to give the title compound(58 mg) (see Table 2). Example 85-{N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino}pentanoicacid hydrochloridea) methyl 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoate
[0132] To a suspension (10 ml) of methyl 5-(N-{6-[N'-(3,5-bis(trifluoromethyl)benzylamino)methyl]indan-5-yl}-N-ethylamino)pentanoate(500 mg) obtained in a similar manner asin Example 6 a) and sodium hydrogen carbonate (160 mg) inmethanol was added cyanogen bromide (165 mg) with stirring atroom temperature and the stirring was continued for 2 hr.
[0133] The reaction solution was diluted with ethyl acetate andwashed successively with water and saturated brine. Theorganic layer was dried over sodium sulfate. Sodium sulfatewas filtered off and the filtrated was concentrated. Theobtained residue was dissolved in 1,4-dioxane (5 ml). Theretowas added aqueous hydroxylamine solution (50%, 0.14 ml) andthe mixture was stirred at room temperature for 5 hr. Thereaction solution was concentrated and the obtained residue was dissolved in pyridine (10 ml). Acetyl chloride (0.1 ml)was added with stirring under ice-cooling. The stirring wascontinued at room temperature for 30 min, and at 130°C for 3 hr.The reaction solution was concentrated and the obtainedresidue was purified by column chromatography (n-hexane:ethylacetate=4:1) to give the title compound (178 mg, 31%).¹HNMR(CDCl₃, 300MHz)δ: 0.88(t, J=7.0Hz, 3H), 1.25-1.60(m, 4H),1.95-2.10(m, 2H), 2.20(t, J=7.3Hz, 2H), 2.49(s, 3H), 2.70-2.90(m,8H), 4.56(s, 2H), 4.72(s, 2H), 6.99(s, 1H), 7.02(s,1H), 7.65(s, 2H), 7.72(s, 1H). b) 5-{N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino}pentanoicacid hydrochloride
[0134] To a solution (5 ml) of methyl 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoate(178 mg)obtained in Example 8 a) in tetrahydrofuran-methanol (THF-MeOH4:1) was added aqueous sodium hydroxide solution (4N, 2 ml)with stirring at room temperature. The reaction solution wasstirred overnight and water was added. The mixture wasextracted with ethyl acetate and the extract was washedsuccessively with water and saturated brine. The organic layerwas dried over sodium sulfate and sodium sulfate was filteredoff. The filtrate was concentrated and the obtained residuewas purified by column chromatography (n-hexane:ethylacetate=2:1). To a solution (7 ml) of the obtained compound inn-hexane was added dropwise 1N hydrochloric acid-diethyl ether(0.3 ml) with stirring at room temperature. The precipitatedsolid was collected by filtration and dried to give the titlecompound (158 mg, 86%) (see Table 2). Example 9methyl trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylatea) 5-{[3,5-bis(trifluoromethyl)benzyl]amino}-2-methyl-2H-tetrazole
[0135] A solution (70 ml) of 3,5-bis(trifluoromethyl)benzaldehyde(6.71 g) and 5-amino-2-methyltetrazole(3.30 g) in toluene was heated under refluxfor 4 hr. The reaction solution was concentrated and theobtained residue was dissolved in ethanol (70 ml), and sodiumborohydride (2.10 g) was added with stirring at,roomtemperature. The reaction solution was stirred at roomtemperature for 30 min, and saturated aqueous ammoniumchloride was added. The mixture was extracted with ethylacetate. The extract was washed successively with water andsaturated brine. The organic layer was dried over sodiumsulfate and sodium sulfate was filtered off. The filtrate wasconcentrated and the obtained residue was recrystallized fromisopropanol - water (3:7, 50 ml) to give the title compound.¹HNMR(CDCl₃,300MHz) δ: 4.16(s,3H), 4.66(d,J=6.3Hz2H),4.92(brs,1H), 7.79(s,1H), 7.83(s,2H). b) methyl trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylate
[0136] To a solution (5 ml) of methyl trans-4-{[N-ethyl-N-(2-hydroxymethyl-4-trifluoromethoxyphenyl)amino]methyl}cyclohexylcarboxylate(330mg) in chloroform was added thionyl chloride (0.074 ml) withstirring under ice-cooling, and the stirring was continued for10 min. The reaction solution was treated with aqueous.sodiumhydrogen carbonate, extracted with ethyl acetate and washedsuccessively with water and saturated brine. The organic layerwas dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residuewas dissolved in DMF (3 ml). This solution was added dropwiseto a solution (3 ml) of 5-[[3,5-bis(trifluoromethyl)benzyl]amino]-2-methyl-2H-tetrazole(331mg) obtained in Example 9 a) and sodium hydride (51 mg) in DMFwith stirring at room temperature. The stirring was continuedfor 15 min and saturated aqueous ammonium chloride was added.The mixture was extracted with ethyl acetate. The extract waswashed successively with water and saturated brine. Theorganic layer was dried over sodium sulfate and sodium sulfatewas filtered off. The filtrate was concentrated and theobtained residue was purified by column chromatography (n-hexane:ethylacetate=4:1) to give the title compound (366 mg,62%) (see Table 2). Example 169ethyl trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetatea) 2-fluoro-4-methyl-5-trifluoromethylbenzaldehyde
[0137] To a suspension (200 ml) of 5-fluoro-2-iodotoluene(110.6 g) and copper iodide (76.2 g) in N-methylmorpholine wasadded dropwise methyl fluorosulfonyl(difluoro)acetate (150 g)with stirring at 120°C over 2 hr. The stirring was continuedat the same temperature for 3.5 hr and the reaction solutionwas distilled under atmospheric pressure to give a yellowliquid. This was diluted with hexane (300 ml) and washed withsaturated brine. The organic layer was dried over sodiumsulfate and sodium sulfate was filtered off. The obtainedhexane solution was added dropwise over 1.5 hr to a mixture oftetrahydrofuran (300 ml) and 1.0 M solution (600 ml) of s-butyllithiumin hexane, which had been cooled to -78°C andstirred. The stirring was continued for 1 hr and N,N-dimethylformamide(57 ml) was added dropwise. After completion of the dropwise addition, 2N aqueous hydrochloric acid (600ml) was added and the mixture was allowed to warm to roomtemperature. This was extracted with hexane and washed withwater and saturated brine. The organic layer was dried oversodium sulfate and sodium sulfate was filtered off. Thefiltrate was concentrated to give the title compound (61.54 g,52%).¹HNMR(CDCl₃; 300MHz)δ: 2.56(s, 3H), 7.14(d, J=10:7Hz, 1H),8.15(d, J=6.8Hz, 1H), 10.32(s, 1H). b) ethyl trans-8{4-[(N-ethylamino)methyl]cyclohexyl}acetateb-1) trans-4-(ethoxycarbonylmethyl)cyclohexanecarboxylic acid
[0138] To a solution (600 ml) of ethyl 4-oxocyclohexanecarboxylate(150 g) in ethanol was added sodiumhydroxide (38.8 g) with stirring at room temperature. Thereaction solution was stirred for 1 hr and ethyldiethylphosphonoacetate (192 ml) was added. To this reactionsolution was added dropwise 21% sodium ethoxide/ethanolsolution (363 ml) with stirring under ice-cooling over 1 hr.The stirring was continued for 1 hr and acetic acid (126 ml)was added. Then ammonium formate (111 g) and palladium carbon(5%, 15 g) were added and the mixture was stirred at 60°C for 6hr with heating. The reaction solution was allowed to returnto room temperature and insoluble materials were filtered offthrough celite. The filtrate was concentrated and the obtainedresidue was diluted with ethyl acetate. The mixture was washedsuccessively with 2N aqueous hydrochloric acid, water andsaturated brine. The organic layer was dried over sodiumsulfate and sodium sulfate was filtered off. The filtrate wasconcentrated to give a crudely purified product (180.4 g) ofthe title compound. b-2) ethyl trans-[4-(N-ethylcarbamoyl)cyclohexyl]acetate
[0139] To a solution (200 ml) of the crudely purified product(180.4 g) of trans-4-(ethoxycarbonylmethyl)cyclohexanecarboxylic acid obtained inb-1) in tetrahydrofuran was added thionyl chloride (74 ml)with stirring at room temperature. The reaction solution wasstirred for 3 hr and concentrated to give an acid chloride. Asolution (80 ml) of the above-mentioned acid chloride intetrahydrofuran was added dropwise to tetrahydrofuran (250 ml)and 70% aqueous ethylamine (250 ml) with stirring under ice-cooling.This reaction solution was stirred for 30 min andwater (800 ml) was added. The mixture was extracted with ethylacetate and the extract was washed successively with water andsaturated brine. The organic layer was dried over sodiumsulfate and sodium sulfate was filtered off. The filtrate wasconcentrated and the obtained residue was recrystallized fromhexane-ethyl acetate to give the title compound (78.9 g, yieldfrom ethyl 4-oxocyclohexanecarboxylate 37%).¹HNMR(CDCl₃, 300MHz)δ: 0.90-1.10(m, 2H), 1.13(t, J=7.3Hz, 3H),1.25(t, J=7.1Hz, 3H), 1.40-1.60(m, 2H), 1.72-1.95(m, 5H),1.99(m, 1H), 2.19(d, J=6.8Hz, 2H), 3.28(m, 2H), 4.13(q,J=7.1Hz, 2H), 5.39 (brs, 1H). b-3) ethyl trans-8{4-[(N-ethylamino)methyl]cyclohexyl}acetate
[0140] To a suspension (800 ml) of ethyl trans-[4-(N-ethylcarbamoyl)cyclohexyl]acetate(100 g) and sodiumborohydride (75.2 g) in tetrahydrofuran was added dropwiseacetic acid (114 ml) over 1 hr with stirring under reflux, andthe reaction solution was further stirred for 2 hr. Thereaction solution was quenched by dropwise addition of water(200 ml) with stirring under ice-cooling. 1.5N Aqueous sodiumhydroxide (1000 ml) was added. The mixture was extracted withethyl acetate and the extract was washed successively withwater and saturated brine. The organic layer was dried oversodium sulfate and sodium sulfate was filtered off. Thefiltrate was concentrated and the obtained residue wasdissolved in ethanol (500 ml). 4N Hydrochloric acid-ethyl acetate (125 ml) was added dropwise with stirring at roomtemperature, and the stirring was continued for 20 hr. Thereaction mixture was diluted with ethyl acetate and washedsuccessively with 2N aqueous sodium hydroxide, water andsaturated brine. The organic layer was dried over sodiumsulfate and sodium sulfate was filtered off. The filtrate wasconcentrated to give the title compound (81.9 g, 87%).¹HNMR(CDCl₃, 300MHz)δ: 0.82-1.08(m, 4H), 1.10(t, J=7.1Hz, 3H),1.25(t, J=7.1Hz, 3H), 1.37(m, 1H), 1.66-1.88(m, 5H), 1.99(m,1H), 2.18(d, J=6.8Hz, 2H), 2.44(d, J=6.6Hz, 2H), 2.62(q,J=7.1Hz, 2H), 4.12(q, J=7.1Hz, 2H). c) ethyl trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetatec-1) ethyl trans-(4-{[N-ethyl-N-(2-hydroxymethyl-5-methyl-4-trifluoromethylphenyl)amino]methyl}cyclohexyl)acetatep-toluenesulfonate
[0141] A solution (470 ml) of 2-fluoro-4-methyl-5-trifluoromethylbenzaldehyde(47.03 g), ethyl trans-{4-[(N-ethylamino)methyl]cyclohexyl}acetate(57.05 g) and potassiumcarbonate (94.5 g) in toluene was heated under reflux for 48hr. The reaction solution was allowed to return to roomtemperature and washed successively with water, aqueouspotassium hydrogen sulfate and saturated brine. The organiclayer was dried over magnesium sulfate and magnesium sulfatewas filtered off. Ethanol (100 ml) was added to the obtainedsolution and sodium borohydride (4.31 g) was added withstirring at room temperature. The reaction solution wasstirred for 1 hr and aqueous ammonium chloride (200 ml) wasadded to allow for partitioning. The organic layer was washedsuccessively with water and saturated brine, and dried oversodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was dissolvedin diethyl ether (1060 ml), and p-toluenesulfonic acid hydrate(43.4 g) was added with stirring at room temperature. Thestirring was continued for 2 hr. The precipitated crystalswere collected by filtration and dried to give the titlecompound (120 g, 32%).¹HNMR(CDCl₃, 300MHz)δ: 0.70-1.14(m, 4H), 1.21(t, J=7.1Hz, 3H),1.23(t, J=7.1Hz, 3H), 1.42(m, 1H), 1.50-1.78(m, 4H), 1.93(m,1H), 2.09(d, J=6.7Hz, 2H), 2.36(s, 3H), 2.54(s, 3H), 3.10-4.15(m, 4H), 4.09(q, J=7.1Hz, 2H), 4.85-5.25(m, 2H), 7.07(d,J=8.0Hz, 2H), 7.33(s, 1H), 7.54(s, 1H), 7.77(d, J=8.0Hz, 2H),11.57(brs, 1H). c-2) ethyl trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate
[0142] A solution of ethyl trans-(4-{[N-ethyl-N-(2-hydroxymethyl-5-methyl-4-trifluoromethylphenyl)amino]methyl}cyclohexyl)acetatep-toluenesulfonate(120 g) and sodium hydrogen carbonate (32.3g) in toluene-water (480-480 ml) was stirred at roomtemperature for 30 min and partitioned. The organic layer waswashed successively with water and saturated brine and driedover magnesium sulfate. Magnesium sulfate was filtered off andthe resulting solution was added dropwise to a solution (360ml) of thionyl chloride (17.65 ml) in toluene with stirringunder ice-cooling. The stirring was continued at roomtemperature for 30 min and pyridine (33 ml) was added to thereaction solution. The mixture was washed successively withwater and saturated brine. The organic layer was dried oversodium sulfate and sodium sulfate was filtered off. Thefiltrate was concentrated and potassium t-butoxide (27.5 g)was added to a solution (900 ml) of the obtained residue and 5-{[3,5-bis(trifluoromethyl)benzyl]amino}-2-methyl-2H-tetrazole(69.7 g) obtained in Example 9 a) in N,N-dimethylformamidewith stirring at room temperature. Thestirring was continued for 2 hr and saturated aqueous ammoniumchloride was added. The mixture was extracted with ethylacetate and the extract was washed successively with water andsaturated brine. The organic layer was dried over sodiumsulfate and sodium sulfate was filtered off. The filtrate wasconcentrated and the obtained residue was purified by columnchromatography (n-hexane:ethyl acetate=4:1) to give the titlecompound (118 g, 80%) (see Table 34). Example 170trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid
[0143] To a solution (326 ml) of ethyl trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate(118 g) in ethanol wasadded 4N aqueous sodium hydroxide solution (163 ml) withstirring at room temperature. The reaction solution wasstirred at 60°C for 2 hr and aqueous citric acid was added withstirring under ice-cooling for neutralization. The mixture wasextracted with ethyl acetate and the extract was washedsuccessively with water and saturated brine. The organic layerwas dried over sodium sulfate and sodium sulfate was filteredoff. The filtrate was concentrated. The obtained residue waspurified by column chromatography (n-hexane:ethyl acetate=2:1)to give the title compound (104 g, 92%) (see Table 34). Example 142trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride
[0144] To a solution (1.5 ml) of trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid (130 mg) in ether wasadded 1N hydrochloric acid-ether (0.20 ml) with stirring atroom temperature. The precipitated solid was collected byfiltration and dried to give the title compound (128 mg, 94%)(see Table 29). Example 168trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid methanesulfonate
[0145] To a solution (580 ml) of trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid (96.3 g) in ethylacetate was added methanesulfonic acid (13.56 ml) withstirring at room temperature. The stirring was continued for15 hr and the precipitated solid was collected by filtrationand dried to give an ethyl acetate solvate of methanesulfonate.This was suspended in heptane-ethyl acetate (3:1, 990 ml) andthe suspension was stirred with heating at 80°C for 20 hr,allowed to return to room temperature, filtered and dried togive the title compound (91.0 g, 83%) (see Table 34).
[0146] In a similar manner as in Examples 1-9, 142, 168, 169and 170, the compounds of Examples 10-141 and 143-167 wereobtained. These are shown in Tables 1-34 together withExamples 1-9, 142, 168, 169 and 170.
[0147] The compounds shown in Table 35 can be produced in asimilar manner.
[0148] The following tests were performed for the CETP activityinhibitory effect of the compound of the present invention. Preparation of Donor Lipoprotein
[0149] Potassium bromide (KBr) was added to plasma (40 mL) ofhealthy subject and the mixture was adjusted to have aspecific density d=1.125 g/mL. The mixture was subjected todensity gradient centrifugation (227,000×g, 4°C, 17 hr) and afraction showing a specific density of d>1.125 g/mL (HDL₃fraction) was harvested. The obtained fraction was dialyzedagainst PBS solution [10 mmol/L Na₂HPO₄; 10 mmol/L NaH₂PO₄; 0.15mol/L NaCl; 1 mol/L EDTA (pH 7.4)]. Then, tritium-labeledcholesterol (37 MBq) was dissolved in 95% ethanol, graduallyadded to the above-mentioned HDL₃ fraction with stirring andincubated at 37°C for 18 hr. [By this operation, tritium-labeledcholesterol was esterified by the action of lecithinacyl transferase (LCAT) present on the HDL₃ surface and takenup into HDL₃ as tritium-labeled cholesteryl ester ([³H]CE)].After incubation, KBr was added, the mixture was adjusted tohave a specific density d=1.21 g/mL, subjected to densitygradient centrifugation (227,000xg, 4°C, 17 hr) and a fractionof specific density d>1.21 g/mL was harvested. The obtainedfraction was dialyzed against the aforementioned PBS solutionto give HDL₃ incorporating [³H]CE ([³H]CE-HDL₃, specificdensity: 1.125<d<1.21, specific activity: 10,000 dpm/µL), whichwas used as a donor lipoprotein. Experimental Example 1: inhibitory effect in vitro on CETPactivity in total plasma
[0150] The donor lipoprotein obtained above was added to plasmaof healthy subject to prepare a [³H]CE-HDL₃-containing plasma(1,000 dpm/µL). The compound was dissolved in dimethylformamide. A solution of the compound or a solvent alone (2µL) and the [³H]CE-HDL₃-containing plasma (100 µL) were addedinto a microtube, and this was incubated at 37°C or 4°C for 4hr. After ice-cooling, TBS solution [100 µL, 20 mmol/L Tris;0.15 mol/L NaCl (pH 7.4)] containing 1 mol/L magnesiumchloride and 2% dextran sulfate was added to each microtubeand the mixture was thoroughly stirred. After keeping at 4°Cfor 30 min, the mixture was centrifuged (10,000xg, 4°C, 10 min),and the radioactivity in the obtained supernatant (HDLfraction) was measured with a scintillation counter. Thedifference in the measurement values obtained by incubation ofsolvent alone at 4°C and 37°C was taken as CETP activity, andthe proportion of decrease in the difference in themeasurement values of specimen was taken as percent inhibitionof CETP activity. The concentration of the compound necessaryfor inhibiting the CETP activity by 50% was calculated as anIC₅₀ value. The results are shown in the following. Example No. IC₅₀ (µM) Example No. IC₅₀ (µM) 1 0.23 2 0.08 3 0.24 4 0.18 7 0.27 8 0.63 10 0.23 11 0.63 12 0.25 13 0.5826 0.47 27 0.58 28 0.44 33 0.56 34 0.22 35 0.35 36 0.34 37 0.80 38 0.47 39 0.88 40 0.39 41 0.51 42 0.70 43 0.55 44 0.36 45 0.49 46 0.39 51 0.41 52 0.37 53 0.70 54 0.79 55 0.77 58 0.715 59 0.43 60 0.78 63 0.64 64 0.75 65 0.29 66 0.87 67 0.26 68 0.28 69 0.34 70 0.54 71 0.44 72 0.39 73 0.19 74 0.40 75 0.41 The IC₅₀ values in Table show average values. Example No. IC₅₀ (µM) Example No. IC₅₀ (µM) 76 0.29 77 0.54 78 0.32 79 0.89 80 0.43 81 0.33 82 0.59 86 0.94189 0.69 91 0.56 92 0.19 93 0.76 96 0.31 98 0.30 99 0.53 102 0.59 103 0.43 104 0.35 105 0.60 107 0.56 108 0.25 109 0.16 111 0.19 114 0.28 115 0.09 118 0.09 119 0.13 120 0.28 121 0.23 122 0.24 127 0.37 129 0.61 131 0.17 135 0.22 137 0.14 138 0.16 140 0.12 141 0.12 142 0.06 143 0.10 The IC₅₀ values in Table show average values. Experimental Example 2: inhibitory effect exo vivo on CETPactivity in total plasma of normal hamster
[0151] The compound of the present invention was suspended in0.5% methyl cellulose solution and orally administered once toa healthy hamster with a plastic gavage needle. Blood wastaken at 2 or 4 hr after the administration and CETP activityin plasma was measured according to the following method.
[0152] The donor lipoprotein obtained above was added tohamster plasma (100 µL) to prepare [³H]CE-HDL₃-containingplasma (ca. 1,000 dpm/µL). The [³H]CE-HDL₃-containing plasmawas dispensed to two microtubes by 25 µL each, and one wasincubated at 37°C and the other was incubated at 4°C for 4 hr each. After ice-cooling, TBS solution (50 µL) containing 1mol/L magnesium chloride and 2% dextran sulfate was added toeach microtube and the mixture was thoroughly stirred. Afterkeeping at 4°C for 30 min, the mixture was centrifuged(10,000×g, 4°C, 20 min), and the radioactivity in the obtainedsupernatant (HDL fraction) was measured with a liquidscintillation counter. The radioactivity of the [³H]CE-HDL₃-containingplasma was measured with a liquid scintillationcounter, and taken as the total radioactivity. The transferrate of [³H]CE was calculated from the following formula usingthe total radioactivity (Total count), radioactivity by 37°Cincubation (37°C count) and radioactivity by 4°C incubation (4°Ccount) of the sample of each individual and taken as the CETPactivity.CETP activity (transfer ratio (%)) = {[(4°C count)-(37°C count)]/(Total count)}×100
[0153] The CETP activity inhibitory ratio of each compoundadministration group based on the CETP activity of the solventadministration group as 100% was calculated from the followingformula and expressed in %.CETP activity inhibitory ratio (%) = 100-[(CETP activity of each compound administration group)/(CETP activity of solvent administration group)×100]
[0154] The results are shown in the following. compound Dose (mg/kg) CETP activity (%) 2 (hr later) 4 (hr later) 35 30 37.8 - 36 30 33.3 - 37 30 45.4 - 38 30 79.4 - 39 30 49.6 -40 30 59.5 - 41 30 36.0 - 89 10 77.7 - 91 10 44.7 - 92 10 46.9 - 96 10 41.1 - 98 10 43.3 - 107 10 41.9 - 108 10 53.8 - 109 10 42.8 - 115 3 - 62.1 118 3 - 55.4 142 3 - 71.6 143 3 - 42.2 154 3 - 64.2 157 3 - 80.4 158 3 - 55.6 The CETP activity inhibitory ratios in Table show average values. Experimental Example 3: blood HDL cholesterol increasingeffect in normal hamster
[0155] To the plasma (40 µL) obtained from the above-mentionedanimal at 4 or 8 hr after the administration was added 15%polyethylene glycol solution (40 µL) and the mixture wasthoroughly stirred. After keeping at room temperature for 10min, the mixture was centrifuged (10,000×g, 4°C, 20 min) andthe cholesterol content (HDL cholesterol content) of theobtained supernatant (HDL fraction) was measured. The increaseratio of the HDL cholesterol content of each compoundadministration group when the HDL cholesterol content of the solvent administration group as 100% was calculated from thefollowing formula and expressed in %.HDL cholesterol increase ratio (%)= [(HDL cholesterol content of each compound administration group/HDL cholesterol content of solvent administration group)×100]-100
[0156] The results are shown in the following. compound Dose (mg/kg) HDL cholesterol increase content (%) 4 (hr later) 8 (hr later) 115 3 23.3 30.7 118 3 21.1 31.7 142 3 20.3 31.9 143 3 17.0 21.3 154 3 13.3 22.4 157 3 17.9 27.1 158 3 14.8 23.7 The HDL cholesterol increase ratios in Table show average values. Experimental Example 4: concomitant use test
[0157] For the experiment, 10-week-old male Japanese whiterabbits (manufactured by KITAYAMA LABES Co., Ltd.) were used.The animal was acclimated on normal food (RC-4, manufacturedby Oriental Bio-Service Co.) and fasted for 24 hr and a highcholesterol food (0.25% cholesterol-added RC-4, manufacturedby Oriental Bio-Service Co.) was given by 100 g/day per rabbit(preliminary feeding) for 3 days. On the next day of day 3 ofpreliminary feeding, blood was taken from the auricular arterybefore feeding, and the animals were grouped by 6 rabbits pergroup based on the parameters (HDL cholesterol content, totalcholesterol content, triglyceride content) of plasma and body weight.
[0158] Foods were prepared (manufactured by Oriental Bio-ServiceCo.) by adding simvastatin (0.002%), compound (0.2%)of Example 168, or simvastatin (0.002%) + compound (0.2%) ofExample 168 to a high cholesterol food, and each food wasgiven to the grouped animals by 100 g/day per rabbit for 15days. At 8 hr after feeding on day 15, the total blood wastaken from the carotid artery under anesthesia, HDLcholesterol content, total cholesterol content and ApoA-Icontent in plasma were measured. The arteriosclerosis indexwas calculated from [(total cholesterol content-HDLcholesterol content)/HDL cholesterol content]. Furthermore,the HDL₃ fraction was separated from plasma byultracentrifugation and the cholesterol content of thefraction was measured. In Table, arteriosclerotic index, ApoA-Icontent and HDL₃ cholesterol content are shown based on thevalue of the control group as 100%. group Arteriosclerotic index (%) ApoA-I content (%) HDL₃ cholesterol content (%) control 100 100 100 simvastatin 53 114 128 compound of Example 168 82 114 141 Simvastatin + compound of Example 168 37 150 170 Industrial Applicability
[0159] From the foregoing test results and the like, the compound and a salt thereof of the present invention havesuperior CETP activity inhibitory effect. Therefore, they candecrease IDL, VLDL and LDL that promote arteriosclerosis andincrease HDL that acts suppressively. As a result, they areuseful as prophylactic or therapeutic agents forhyperlipidemia. In addition, they are useful as prophylacticor therapeutic agents for arteriosclerotic disease and thelike.
[0160] Moreover, concurrent use of the compound of the presentinvention with a different therapeutic agent forhyperlipidemia (statin pharmaceutical agent) is expected topromote increase in HDL cholesterol, decrease arterioscleroticindex particularly remarkably, and show extremely superiorsynergistic effect. Therefore, it is clear that the compoundof the present invention can be used concurrently with adifferent pharmaceutical agent, particularly other therapeuticagents for hyperlipidemia, arteriosclerosis, coronary arterydisease, obesity, diabetes or hypertension.
[0161] This application is based on patent application Nos.255604/2002 and 1071610/2003 filed in Japan, the contents ofwhich are hereby incorporated by reference.

权利要求:
Claims (76)
[1] A dibenzylamine compound represented by the formula (1)
[2] The dibenzylamine compound of claim 1wherein R³, R⁴ and R⁵ are the same or different and each is a hydrogenatom, a halogen atom, a C_1-6 alkyl group optionallysubstituted by halogen atoms or a C_1-6 alkoxy groupoptionally substituted by halogen atoms, or R³ and R⁴or R⁴ and R⁵ may form, together with a carbon atombonded thereto, a homocyclic ring optionally havingsubstituent(s) or a heterocyclic ring optionallyhaving substituent(s); R⁷ and R⁸ are the same or different and each is a hydrogenatom, a C_1-6 alkyl group (wherein C_1-6 alkyl group isoptionally substituted by phenyl group or -COOR⁹(wherein R⁹ is a hydrogen atom or a C_1-6 alkyl group))or a C_4-10 cycloalkylalkyl group (wherein C_4-10cycloalkylalkyl group is optionally substituted by 1to 3 substituents from halogen atom, nitro group,amino group, hydroxyl group, cyano group, acyl group,C_1-6 alkoxy group, C_1-6 alkyl group or -COOR¹⁰ (whereinR¹⁰ is a hydrogen atom or a C_1-6 alkyl group)); R¹¹, R¹² and R¹³ are the same or different and each is a hydrogenatom, a C_1-6 alkyl group (wherein C_1-6 alkyl group isoptionally substituted by phenyl group or -COOR⁹(wherein R⁹ is as defined above) or a C_4-10cycloalkylalkyl group (wherein C_4-10 cycloalkylalkylgroup is optionally substituted by 1 to 3substituents from halogen atom, nitro group, aminogroup, hydroxyl group, cyano group, acyl group, C_1-6 alkoxy group, C_1-6 alkyl group or -COOR¹⁰ (wherein R¹⁰is as defined above)); R⁶ is a hydrogen atom, a halogen atom, a nitro group,an amino group, a hydroxyl group, a cyano group, anacyl group, a C_1-6 alkoxy group or a C_1-6 alkyl group(wherein C_1-6 alkyl group is optionally substituted byhydroxyl group or -COOR¹⁴ (wherein R¹⁴ is a hydrogenatom or a C_1-6 alkyl group)), or a prodrug thereof or a pharmaceutically acceptable saltthereof.
[3] The dibenzylamine compound of claim 1 or 2, wherein R¹ is aC_1-6 alkyl group substituted by a halogen atom, or a prodrugthereof or a pharmaceutically acceptable salt thereof.
[4] The dibenzylamine compound of claim 3, wherein R¹ is atrifluoromethyl group, or a prodrug thereof or apharmaceutically acceptable salt thereof.
[5] The dibenzylamine compound of claim 1, 3 or 4, wherein ringB and (R⁶)_n are each
[6] The dibenzylamine compound of claim 5, wherein ring B and(R⁶)_n are each
[7] The dibenzylamine compound of claim 6, wherein ring B and(R⁶)_n are each
[8] The dibenzylamine compound of any of claim 1 and claims 3to 7, wherein A is -N(R⁷) (R⁸) (wherein R⁷ and R⁸ are as definedin claim 1) or a prodrug thereof or a pharmaceuticallyacceptable salt thereof.
[9] The dibenzylamine compound of claim 8, wherein R⁷ is a C_1-6 alkyl group or a prodrug thereof or a pharmaceuticallyacceptable salt thereof.
[10] The dibenzylamine compound of claim 9, wherein R⁶ is a C_1-6alkyl group or a prodrug thereof or a pharmaceuticallyacceptable salt thereof.
[11] The dibenzylamine compound of claim 1, which is selectedfrom the group consisting ofN-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine,3-{[N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrzol-5-yl)amine,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride,N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine,N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)aminehydrochloride,N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine,5-{N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino}pentanoicacid hydrochloride,methyl trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylate, 3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-ethyl-2H-tetrazol-5-yl)amine,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-[1,2,4]triazol-3-yl)amine,3-({N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-phenylamino}methyl)-5-trifluoromethylbenzonitrile,3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(4,5-dimethyl-thiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(thiazol-2-yl)aminehydrochloride,3-({N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(thiazol-2-yl)amino}methyl)-5-trifluoromethylbenzonitrilehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(oxazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methylthiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4-methylthiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4,5-dimethylthiazol-2-yl)amine hydrochloride,3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(5-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride,3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(4-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4-methyloxazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methylisothiazol-5-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methylisoxazol-3-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methylisoxazol-5-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-3-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-4-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]thiadiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]oxadiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-pyridin-3-ylamine hydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-pyridin-2-ylaminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(N'-cyclopentylmethyl-N'-ethylamino)-5-trifluoromethylbenzyl]-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride,3-{[N-[2-(N'-cyclopentylmethyl-N'-ethylamino)-5-trifluoromethylbenzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride,methyl 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoatehydrochloride,methyl 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-ylmethyl)-N-ethylamino]pentanoatehydrochloride,methyl 5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoatehydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,methyl trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylate hydrochloride,methyl trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylatehydrochloride,trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,2,4]oxadiazol-3-yl)aminehydrochloride,methyl trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylatehydrochloride,trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,methyl trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylate,trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride, trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,methyl 5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoatehydrochloride,5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol=3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methyl-[1,2,4]thiadiazol-5-yl)amine,5-[N-(6-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride, methyl 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoatehydrochloride,methyl 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoatehydrochloride,5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacid hydrochloride,trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(3-1-[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid,trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,trans-4-{[N-(3-{[N'-(3-cyanb-5-trifluoromethylbenzyl)-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,2-(5-{N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]amino}tetrazol-2-yl)ethanolhydrochloride,methyl 5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoatehydrochloride,methyl 5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoatehydrochloride,5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydroriaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride,5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride,5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride,5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacidhydrochloride,5-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,5-[N-(3-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoicacid hydrochloride,trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(2-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoicacid hydrochloride,5-{N-[6-({N'-[3,5-bis(trifluoromethyl)benzyl]-N'-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}pentanoicacid hydrochloride,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoicacid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-2,2-dimethylpentanoicacid hydrochloride,6-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]hexanoic acid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride,trans-4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,(1-{2-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]ethyl}cyclopentyl)aceticacid hydrochloride,trans-4-({N-[6-({N'-[3,5-bis(trifluoromethyl)benzyl]-N'-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}methyl)cyclohexanecarboxylicacid,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,(1-{2-[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]ethyl}cyclopentyl)aceticacid,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(3-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-({N-[3-({N'-[3,5-bis(trifluoromethyl)benzyl]-N'-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-ethylamino}methyl)cyclohexanecarboxylic acid hydrochloride,1-{3-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]propyl}cyclohexanecarboxylicacid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoicacid,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride,5-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoicacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,6-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]hexanoicacid hydrochloride, trans-(4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,6-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-4,4-dimethylhexanoicacid hydrochloride,6-[N-(6-{[N'-[3,5-bis-(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylhexanoicacid hydrochloride,5-[N-(6-{[N'-[3,5-bis(trifluoromethyl)-benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-4,4-dimethylpentanoicacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,6-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-4,4-dimethylhexanoicacid hydrochloride,6-[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-4,4-dimethylhexanoicacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride,6-[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-5,5-dimethylhexanoicacid hydrochloride, trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-isobutylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid amide,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid methylamide,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid dimethylamide,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-chlorophenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(m-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(2-{[N'-(3,5-dichlorobenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-ethyl-N-(2-{[N'-(2-methyl-2H-tetrazol-5-yl)-N'-(3-methyl-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylic acidhydrochloride,trans-4-{[N-(2-{[N'-(3-chloro-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-ethyl-N-(2-{[N'-(2-methyl-2H-tetrazol-5-yl)-N'-(3-nitro-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylicacidhydrochloride,trans-(4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride,trans-(4-{[N-(6-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-3-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)propionicacid hydrochloride,trans-(4-{[N-(7-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride,trans-(4-{[N-(7-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-2-(4-{[N-(7-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)acetamide hydrochloride,trans-N-[3,5-bis(trifluoromethyl)benzyl]-N-{2-[N'-ethyl-N'-(4-(methoxymethyl)cyclohexylmethyl)amino]-5-trifluoromethoxybenzyl}-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride,trans-2-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)ethanolhydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexylmethyl)phosphonicacid,trans-4-{[N-(2-{[N'-(3-bromo-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride, trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-methoxyphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl)methanolhydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4,5-dimethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylthiophenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacidhydrochloride,trans-4-({N-[2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-(2,2,2-trifluoroethyl)phenyl]-N-ethylamino}methyl)cyclohexanecarboxylic acid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-ethylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(2-{[N'-(3-cyano-5-trifluoromethylbenzyl)-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid hydrochloride,trans-4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(4-isopropenylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylicacid,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid dihydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(triflupromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid methanesulfonate,ethyl trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetateandtrans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacidor a prodrug thereof or a pharmaceutically acceptable saltthereof.
[12] The dibenzylamine compound of claim 1, which is selectedfrom the group consisting oftrans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid hydrochloride,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)aceticacid,trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)aceticacid andtrans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid methanesulfonateor a prodrug thereof or a pharmaceutically acceptable saltthereof.
[13] The dibenzylamine compound of claim 2, which is selectedfrom the group consisting ofN-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine,3-{[N-[3-(N'-cyclopentylmethyl-N'-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride,N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine,N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)aminehydrochloride,N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine,3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(2-ethyl-2H-tetrazol-5-yl)amine,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-[1,2,4]triazol-3-yl)amine, 3-({N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-phenylamino}methyl)-5-trifluoromethylbenzonitrile,3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(4,5-dimethyl-thiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(thiazol-2-yl)aminehydrochloride,3-({N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(thiazol-2-yl)amino}methyl)-5-trifluoromethylbenzonitrilehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(oxazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methylthiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4-methylthiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4,5-dimethylthiazol-2-yl)aminehydrochloride,3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(5-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride,3-{[N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-N-(4-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrilehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(4-methyloxazol-2-yl)amine hydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methylisothiazol-5-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methylisoxazol-3-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(3-methylisoxazol-5-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-3-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-4-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]thiadiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]oxadiazol-2-yl)aminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-pyridin-3-ylaminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N'-cyclopentylmethyl-N'-ethylamino)indan-5-ylmethyl]-pyridin-2-ylaminehydrochloride,N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(N'-cyclopentylmethyl-N'-ethylamino)-5-trifluoromethylbenzyl]-(2-methyl-2H-tetrazol-5-yl)aminehydrochloride and3-{[N-[2-(N'-cyclopentylmethyl-N'-ethylamino)-5-trifluoromethylbenzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochlorideor a prodrug thereof or a pharmaceutically acceptable saltthereof.
[14] A pharmaceutical composition comprising the dibenzylaminecompound of any of claims 1 to 13 or a prodrug thereof or apharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
[15] A CETP activity inhibitor comprising a dibenzylaminecompound of any of claims 1 to 13 or a prodrug thereof or apharmaceutically acceptable salt thereof as an activeingredient.
[16] A therapeutic agent or a prophylactic agent forhyperlipidemia, which comprises a dibenzylamine compound ofany of claims 1 to 13 or a prodrug thereof or apharmaceutically acceptable salt thereof as an activeingredient.
[17] A method for treating or preventing hyperlipidemia, whichcomprises administering a dibenzylamine compound of any ofclaims 1 to 13 or a prodrug thereof or a pharmaceuticallyacceptable salt thereof to a mammal.
[18] Use of a dibenzylamine compound of any of claims 1 to 13or a prodrug thereof or a pharmaceutically acceptable saltthereof for the production of a therapeutic agent or aprophylactic agent for hyperlipidemia.
[19] A therapeutic agent or a prophylactic agent forarteriosclerosis, which comprises a dibenzylamine compound ofany of claims 1 to 13 or a prodrug thereof or a pharmaceutically acceptable salt thereof as an activeingredient.
[20] A method for treating or preventing arteriosclerosis,which comprises administering a dibenzylamine compound of anyof claims 1 to 13 or a prodrug thereof or a pharmaceuticallyacceptable salt thereof to a mammal.
[21] Use of a dibenzylamine compound of any of claims 1 to 13or a prodrug thereof or a pharmaceutically acceptable saltthereof for the production of a therapeutic agent or aprophylactic agent for arteriosclerosis.
[22] The pharmaceutical composition of claim 14, which is usedin combination with a different therapeutic agent forhyperlipidemia.
[23] The pharmaceutical composition of claim 22, wherein thedifferent therapeutic agent for hyperlipidemia is a statinpharmaceutical agent.
[24] The pharmaceutical composition of claim 23, wherein thestatin pharmaceutical agent is at least one pharmaceuticalagent selected from the group consisting of lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin andcerivastatin.
[25] The pharmaceutical composition of claim 14, which is usedin combination with a different therapeutic agent for obesity.
[26] The pharmaceutical composition of claim 25, wherein thedifferent therapeutic agent for obesity is mazindol.
[27] The pharmaceutical composition of claim 14, which is usedin combination with a different therapeutic agent for diabetes.
[28] The pharmaceutical composition of claim 27, wherein thedifferent therapeutic agent for diabetes is at least onepharmaceutical agent selected from the group consisting of aninsulin preparation, a sulfonylurea, an insulin secretagogue,a sulfonamide, a biguanide, an α glucosidase inhibitor and aninsulin sensitizer.
[29] The pharmaceutical composition of claim 28, wherein thedifferent therapeutic agent for diabetes is at least onepharmaceutical agent selected from the group consisting ofinsulin, glibenclamide, tolbutamide, glyclopyramide,acetohexamide, glimepiride, tolazamide, gliclazide,nateglinide, glybuzole, metformin hydrochloride, buforminhydrochloride, voglibose, acarbose and pioglitazonehydrochloride.
[30] The pharmaceutical composition of claim 14, which is usedin combination with a different therapeutic agent forhypertension.
[31] The pharmaceutical composition of claim 30, wherein thedifferent therapeutic agent for hypertension is at least onepharmaceutical agent selected from the group consisting of aloop diuretic, an angiotensin converting enzyme inhibitor, anangiotensin II receptor antagonist, a Ca antagonist, a βblocker, an α,β blocker and an α blocker.
[32] The pharmaceutical composition of claim 31, wherein thedifferent therapeutic agent for hypertension is at least onepharmaceutical agent selected from the group consisting of.a furosemide sustained-release preparation, captopril, acaptopril sustained-release preparation, enalapril maleate,alacepril, delapril hydrochloride, cilazapril, lisinopril,benazepril hydrochloride, imidapril hydrochloride, temocaprilhydrochloride, quinapril hydrochloride, trandrapril,perindopril erbumine, losartan potassium, candesartancilexetil, nicardipine hydrochloride, a nicardipinehydrochloride sustained-release preparation, nilvadipine,nifedipine, a nifedipine sustained-release preparation,benidipine hydrochloride, diltiazem hydrochloride, a diltiazemhydrochloride sustained-release preparation, nisoldipine,nitrendipine, manidipine hydrochloride; barnidipinehydrochloride, efonidipine hydrochloride, amlodipine besylate,felodipine, cilnidipine, aranidipine, propranololhydrochloride, a propranolol hydrochloride sustained-releasepreparation, pindolol, a pindolol sustained-releasepreparation, indenolol hydrochloride, carteolol hydrochloride,a carteolol hydrochloride sustained-release preparation,bunitrolol hydrochloride, a bunitrolol hydrochloridesustained-release preparation, atenolol, acebutololhydrochloride, metoprolol tartrate, a metoprolol tartratesustained-release preparation, nipradilol, penbutolol sulfate,tilisolol hydrochloride, carvedilol, bisoprolol fumarate,betaxolol hydrochloride, celiprolol hydrochloride, bopindololmalonate, bevantolol hydrochloride, labetalol hydrochloride,arotinolol hydrochloride, amosulalol hydrochloride, prazosinhydrochloride, terazosin hydrochloride, doxazosin mesylate,bunazosin hydrochloride, a bunazosin hydrochloride sustained-releasepreparation, urapidil and phentolamine mesylate.
[33] The therapeutic agent or a prophylactic agent of claim 16,which aims at the treatment or prophylaxis of hyperlipidemiaand which is used in combination with a different therapeutic agent for hyperlipidemia.
[34] The therapeutic agent or a prophylactic agent of claim 33,wherein the different therapeutic agent for hyperlipidemia isa statin pharmaceutical agent.
[35] The therapeutic agent or a prophylactic agent of claim 34,wherein the statin pharmaceutical agent is at least onepharmaceutical agent selected from the group consisting oflovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin and cerivastatin.
[36] The therapeutic agent or a prophylactic agent of claim 16,which aims at the treatment or prophylaxis of hyperlipidemiaand which is used in combination with a different therapeuticagent for obesity.
[37] The therapeutic agent or a prophylactic agent of claim 36,wherein the different therapeutic agent for obesity ismazindol.
[38] The therapeutic agent or a prophylactic agent of claim 16,which aims at the treatment or prophylaxis of hyperlipidemiaand which is used in combination with a different therapeuticagent for diabetes.
[39] The therapeutic agent or a prophylactic agent of claim 38,wherein the different therapeutic agent for diabetes is atleast one pharmaceutical agent selected from the groupconsisting of an insulin preparation, a sulfonylurea, aninsulin secretagogue, a sulfonamide, a biguanide, an αglucosidase inhibitor and an insulin sensitizer.
[40] The therapeutic agent or a prophylactic agent of claim 39,wherein the different therapeutic agent for diabetes is atleast one pharmaceutical agent selected from the groupconsisting of insulin, glibenclamide, tolbutamide,glyclopyramide, acetohexamide, glimepiride, tolazamide,gliclazide, nateglinide, glybuzole, metformin hydrochloride,buformin hydrochloride, voglibose, acarbose and pioglitazonehydrochloride.
[41] The therapeutic agent or a prophylactic agent of claim 16,which aims at the treatment or prophylaxis of hyperlipidemiaand which is used in combination with a different therapeuticagent for hypertension.
[42] The therapeutic agent or a prophylactic agent of claim 41,wherein the different therapeutic agent for hypertension is atleast one pharmaceutical agent selected from the groupconsisting of a loop diuretic, an angiotensin convertingenzyme inhibitor, an angiotensin II receptor antagonist, a Caantagonist, a β blocker, an α,β blocker and an α blocker.
[43] The therapeutic agent or a prophylactic agent of claim 42,wherein the different therapeutic agent for hypertension is atleast one pharmaceutical agent selected from the groupconsisting of a furosemide sustained-release preparation, acaptopril, captopril sustained-release preparation, enalaprilmaleate, alacepril, delapril hydrochloride, cilazapril,lisinopril, benazepril hydrochloride, imidapril hydrochloride,temocapril hydrochloride, quinapril hydrochloride, trandrapril,perindopril erbumine, losartan potassium, candesartancilexetil, nicardipine hydrochloride, a nicardipinehydrochloride sustained-release preparation, nilvadipine,nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazemhydrochloride sustained-release preparation, nisoldipine,nitrendipine, manidipine hydrochloride, barnidipinehydrochloride, efonidipine hydrochloride, amlodipine besylate,felodipine, cilnidipine, aranidipine, propranololhydrochloride, a propranolol hydrochloride sustained-releasepreparation, pindolol, a pindolol sustained-releasepreparation, indenolol hydrochloride, carteolol hydrochloride,a carteolol hydrochloride sustained-release preparation,bunitrolol hydrochloride, a bunitrolol hydrochloridesustained-release preparation, atenolol, acebutololhydrochloride, metoprolol tartrate, a metoprolol tartratesustained-release preparation, nipradilol, penbutolol sulfate,tilisolol hydrochloride, carvedilol, bisoprolol fumarate,betaxolol hydrochloride, celiprolol hydrochloride, bopindololmalonate, bevantolol hydrochloride, labetalol hydrochloride,arotinolol hydrochloride, amosulalol hydrochloride, prazosinhydrochloride, terazosin hydrochloride, doxazosin mesylate,bunazosin hydrochloride, a bunazosin hydrochloride sustained-releasepreparation, urapidil and phentolamine mesylate.
[44] The method of claim 17, which aims at the treatment orprophylaxis of hyperlipidemia and which is used in combinationwith a different therapeutic agent for hyperlipidemia.
[45] The method of claim 44, wherein the different therapeuticagent for hyperlipidemia is a statin pharmaceutical agent.
[46] The method of claim 45, wherein the statin pharmaceuticalagent is at least one pharmaceutical agent selected from thegroup consisting of lovastatin, simvastatin, pravastatin,fluvastatin, atorvastatin and cerivastatin.
[47] The method of claim 17, which aims at the treatment orprophylaxis of hyperlipidemia and which is used in combinationwith a different therapeutic agent for obesity.
[48] The method of claim 47, wherein the different therapeuticagent for obesity is mazindol.
[49] The method of claim 17, which aims at the treatment orprophylaxis of hyperlipidemia and which is used in combinationwith a different therapeutic agent for diabetes.
[50] The method of claim 49, wherein the different therapeuticagent for diabetes is at least one pharmaceutical agentselected from the group consisting of an insulin preparation,a sulfonylurea, an insulin secretagogue, a sulfonamide, abiguanide, an α glucosidase inhibitor and an insulinsensitizer.
[51] The method of claim 50, wherein the different therapeuticagent for diabetes is at least one pharmaceutical agentselected from the group consisting of insulin, glibenclamide,tolbutamide, glyclopyramide, acetohexamide, glimepiride,tolazamide, gliclazide, nateglinide, glybuzole, metforminhydrochloride, buformin hydrochloride, voglibose, acarbose andpioglitazone hydrochloride.
[52] The method of claim 17, which aims at the treatment orprophylaxis of hyperlipidemia and which is used in combinationwith a different therapeutic agent for hypertension.
[53] The method of claim 52, wherein the different therapeuticagent for hypertension is at least one pharmaceutical agentselected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin IIreceptor antagonist, a Ca antagonist, a β blocker, an α,βblocker and an α blocker.
[54] The method of claim 53, wherein the different therapeuticagent for hypertension is at least one pharmaceutical agentselected from the group consisting of a furosemide sustained-releasepreparation, captopril, a captopril sustained-releasepreparation, enalapril maleate, alacepril, delaprilhydrochloride, cilazapril, lisinopril, benazeprilhydrochloride, imidapril hydrochloride, temocaprilhydrochloride, quinapril hydrochloride, trandrapril,perindopril erbumine, losartan potassium, candesartancilexetil, nicardipine hydrochloride, a nicardipinehydrochloride sustained-release preparation, nilvadipine,nifedipine, a nifedipine sustained-release preparation,benidipine hydrochloride, diltiazem hydrochloride, a diltiazemhydrochloride sustained-release preparation, nisoldipine,nitrendipine, manidipine hydrochloride, barnidipinehydrochloride, efonidipine hydrochloride, amlodipine besylate,felodipine, cilnidipine, aranidipine, propranololhydrochloride, a propranolol hydrochloride sustained-releasepreparation, pindolol, a pindolol sustained-releasepreparation, indenolol hydrochloride, carteolol hydrochloride,a carteolol hydrochloride sustained-release preparation,bunitrolol hydrochloride, a bunitrolol hydrochloridesustained-release preparation, atenolol, acebutololhydrochloride, metoprolol tartrate, a metoprolol tartratesustained-release preparation, nipradilol, penbutolol sulfate,tilisolol hydrochloride, carvedilol, bisoprolol fumarate,betaxolol hydrochloride, celiprolol hydrochloride, bopindololmalonate, bevantolol hydrochloride, labetalol hydrochloride,arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate,bunazosin hydrochloride, a bunazosin hydrochloride sustained-releasepreparation, urapidil and phentolamine mesylate.
[55] The therapeutic agent or a prophylactic agent of claim 19,which aims at the treatment or prophylaxis of arteriosclerosisand which is used in combination with a different therapeuticagent for hyperlipidemia.
[56] The therapeutic agent or a prophylactic agent of claim 55,wherein the different therapeutic agent for hyperlipidemia isa statin pharmaceutical agent.
[57] The therapeutic agent or a prophylactic agent of claim 56,wherein the statin pharmaceutical agent is at least onepharmaceutical agent selected from the group consisting oflovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin and cerivastatin.
[58] The therapeutic agent or a prophylactic agent of claim 19,which aims at the treatment or prophylaxis of arteriosclerosisand which is used in combination with a different therapeuticagent for obesity.
[59] The therapeutic agent or a prophylactic agent of claim 58,wherein the different therapeutic agent for obesity ismazindol.
[60] The therapeutic agent or a prophylactic agent of claim 19,which aims at the treatment or prophylaxis of arteriosclerosisand which is used in combination with a different therapeuticagent for diabetes.
[61] The therapeutic agent or a prophylactic agent of claim 60,wherein the different therapeutic agent for diabetes is atleast one pharmaceutical agent selected from the groupconsisting of an insulin preparation, a sulfonylurea, aninsulin secretagogue, a sulfonamide, a biguanide, an αglucosidase inhibitor and an insulin sensitizer.
[62] The therapeutic agent or a prophylactic agent of claim 61,wherein the different therapeutic agent for diabetes is atleast one pharmaceutical agent selected from the groupconsisting of insulin, glibenclamide, tolbutamide,glyclopyramide, acetohexamide, glimepiride, tolazamide,gliclazide, nateglinide, glybuzole, metformin hydrochloride,buformin hydrochloride, voglibose, acarbose and pioglitazonehydrochloride.
[63] The therapeutic agent or a prophylactic agent of claim 19,which aims at the treatment or prophylaxis of arteriosclerosisand which is used in combination with a different therapeuticagent for hypertension.
[64] The therapeutic agent or a prophylactic agent of claim 63,wherein the different therapeutic agent for hypertension is atleast one pharmaceutical agent selected from the groupconsisting of a loop diuretic, an angiotensin convertingenzyme inhibitor, an angiotensin II receptor antagonist, a Caantagonist, a β blocker, an α,β blocker and an α blocker.
[65] The therapeutic agent or a prophylactic agent of claim 64,wherein the different therapeutic agent for hypertension is atleast one pharmaceutical agent selected from the groupconsisting of a furosemide sustained-release preparation,captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride,cilazapril, lisinopril, benazepril hydrochloride, imidaprilhydrochloride, temocapril hydrochloride, quinaprilhydrochloride, trandrapril, perindopril erbumine, losartanpotassium, candesartan cilexetil, nicardipine hydrochloride, anicardipine hydrochloride sustained-release preparation,nilvadipine, nifedipine, a nifedipine sustained-releasepreparation, benidipine hydrochloride, diltiazem hydrochloride,a diltiazem hydrochloride sustained-release preparation,nisoldipine, nitrendipine, manidipine hydrochloride,barnidipine hydrochloride, efonidipine hydrochloride,amlodipine besylate, felodipine, cilnidipine, aranidipine,propranolol hydrochloride, a propranolol hydrochloridesustained-release preparation, pindolol, a pindolol sustained-releasepreparation, indenolol hydrochloride, carteololhydrochloride, a carteolol hydrochloride sustained-releasepreparation, bunitrolol hydrochloride, a bunitrololhydrochloride sustained-release preparation, atenolol,acebutolol hydrochloride, metoprolol tartrate, a metoprololtartrate sustained-release preparation, nipradilol, penbutololsulfate, tilisolol hydrochloride, carvedilol, bisoprololfumarate, betaxolol hydrochloride, celiprolol hydrochloride,bopindolol malonate, bevantolol hydrochloride, labetalolhydrochloride, arotinolol hydrochloride, amosulalolhydrochloride, prazosin hydrochloride, terazosin hydrochloride,doxazosin mesylate, bunazosin hydrochloride, a bunazosinhydrochloride sustained-release preparation, urapidil andphentolamine mesylate.
[66] The method of claim 20, which aims at the treatment orprophylaxis of arteriosclerosis and which is used incombination with a different therapeutic agent forhyperlipidemia.
[67] The method of claim 66, wherein the different therapeuticagent for hyperlipidemia is a statin pharmaceutical agent.
[68] The method of claim 67, wherein the statin pharmaceuticalagent is at least one pharmaceutical agent selected from thegroup consisting of lovastatin, simvastatin, pravastatin,fluvastatin, atorvastatin and cerivastatin.
[69] The method of claim 20, which aims at the treatment orprophylaxis of arteriosclerosis and which is used incombination with a different therapeutic agent for obesity.
[70] The method of claim 69, wherein the different therapeuticagent for obesity is mazindol.
[71] The method of claim 20, which aims at the treatment orprophylaxis of arteriosclerosis and which is used incombination with a different therapeutic agent for diabetes.
[72] The method of claim 71, wherein the different therapeuticagent for diabetes is at least one pharmaceutical agentselected from the group consisting of an insulin preparation,a sulfonylurea, an insulin secretagogue, a sulfonamide, abiguanide, an α glucosidase inhibitor and an insulinsensitizer.
[73] The method of claim 72, wherein the different therapeuticagent for diabetes is at least one pharmaceutical agentselected from the group consisting of insulin, glibenclamide,tolbutamide, glyclopyramide, acetohexamide, glimepiride,tolazamide, gliclazide, nateglinide, glybuzole, metforminhydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
[74] The method of claim 20, which aims at the treatment orprophylaxis of arteriosclerosis and which is used incombination with a different therapeutic agent forhypertension.
[75] The method of claim 74, wherein the different therapeuticagent for hypertension is at least one pharmaceutical agentselected from the group consisting of a loop diuretic, anangiotensin converting enzyme inhibitor, an angiotensin IIreceptor antagonist, a Ca antagonist, a β blocker, an α,βblocker and an α blocker.
[76] The method of claim 75, wherein the different therapeuticagent for hypertension is at least one pharmaceutical agentselected from the group consisting of a furosemide sustained-releasepreparation, captopril, a captopril sustained-releasepreparation, enalapril maleate, alacepril, delaprilhydrochloride, cilazapril, lisinopril, benazeprilhydrochloride, imidapril hydrochloride, temocaprilhydrochloride, quinapril hydrochloride, trandrapril,perindopril erbumine, losartan potassium, candesartancilexetil, nicardipine hydrochloride, a nicardipinehydrochloride sustained-release preparation, nilvadipine,nifedipine, a nifedipine sustained-release preparation,benidipine hydrochloride, diltiazem hydrochloride, a diltiazemhydrochloride sustained-release preparation, nisoldipine,nitrendipine, manidipine hydrochloride, barnidipinehydrochloride, efonidipine hydrochloride, amlodipine besylate,felodipine, cilnidipine, aranidipine, propranololhydrochloride, a propranolol hydrochloride sustained-releasepreparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride,a carteolol hydrochloride sustained-release preparation,bunitrolol hydrochloride, a bunitrolol hydrochloridesustained-release preparation, atenolol, acebutololhydrochloride, metoprolol tartrate, a metoprolol tartratesustained-release preparation, nipradilol, penbutolol sulfate,tilisolol hydrochloride, carvedilol, bisoprolol fumarate,betaxolol hydrochloride, celiprolol hydrochloride, bopindololmalonate, bevantolol hydrochloride, labetalol hydrochloride,arotinolol hydrochloride, amosulalol hydrochloride, prazosinhydrochloride, terazosin hydrochloride, doxazosin mesylate,bunazosin hydrochloride, a bunazosin hydrochloride sustained-releasepreparation, urapidil and phentolamine mesylate.

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同族专利:

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AU2003261826B2|2006-02-02|

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ES2277142T3|2007-07-01|

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CZ2004627A3|2004-10-13|

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AU2003261826A1|2004-03-19|

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WO2004020393A1|2004-03-11|

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RU2004119546A|2005-08-10|

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IL161559A|2009-12-24|

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US20050059810A1|2005-03-17|

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NO20042584L|2004-06-18|

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KR100634195B1|2006-10-16|

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US7807701B2|2010-10-05|

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HK1077567A1|2006-04-13|

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AT353870T|2007-03-15|

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MXPA04005350A|2004-09-27|

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EP1829858A2|2007-09-05|

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CN1289467C|2006-12-13|

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US20080146620A1|2008-06-19|

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CA2464846C|2010-04-06|

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EP1533292B1|2007-02-14|

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CN1617850A|2005-05-18|

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TR200401413T1|2005-06-21|

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NZ532494A|2006-03-31|

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EP1533292A4|2005-11-02|

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SK2332004A3|2004-12-01|

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CA2464846A1|2004-03-11|

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ZA200403137B|2005-06-29|

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IL161559D0|2004-09-27|

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RU2293078C2|2007-02-10|

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DK1533292T3|2007-06-04|

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SI1533292T1|2007-08-31|

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DE60311821T2|2007-10-31|

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US7332514B2|2008-02-19|

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BR0306208A|2004-10-13|

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KR20040075908A|2004-08-30|

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NO328886B1|2010-06-07|

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EP1829858A3|2007-10-03|

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PT1533292E|2007-05-31|

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DE60311821D1|2007-03-29|

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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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JP2002255604||2002-08-30||

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JP2002255604||2002-08-30||

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JP2003107161||2003-04-10||

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JP2003107161||2003-04-10||

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PCT/JP2003/011041|WO2004020393A1|2002-08-30|2003-08-29|Dibenzylamine compound and medicinal use thereof|EP07003011A| EP1829858A3|2002-08-30|2003-08-29|Dibenzylamine compounds and pharmaceutical use thereof|

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SI200330767T| SI1533292T1|2002-08-30|2003-08-29|Dibenzylamine compound and medicinal use thereof|