Quinolinone derivative, method for preparing the same, and anti-allergic agent

专利摘要:
The present invention relates to a simple method for preparing a quinolinonederivative, which is effective as a medicine, e.g., as an agent for treating allergic diseases andthe like; novel amide derivatives effective as an intermediate in the method; novelquinolinone derivatives obtained according to the method; and an anti-allergic agentcontaiirng a quinolinone derivative and/or physiological salt of the same as the activeingredients. The quinolinone derivative is expressed by the following general formula (II);and the method is characterized in that an amide derivative, expressed by the followinggeneral formula (I), is reacted with a basic agent, followed by intramolecular ring formation:   General Formula (I)   [wherein, R1 represents a hydrogen atom, an alkyl group, an alkyl group containing ahydroxyl group, an alkenyl group, or an aryl group; R2 represents an alkyl group, an alkenylgroup, an aryl group, or an aralkyl group; R3 represents a reactive carboxyl group; and R4 toR7 represent, respectively and independently, a hydrogen atom, a hydroxyl group, an alkylgroup, an alkoxy group, an alkenyl group, an alkenyloxy group, an aryl group, an aryloxygroup, an aralkyloxy group, a R8R9N group (wherein, R8 and R9 represent, respectively andindependently, a hydrogen atom, an alkyl group, an aikenyl group, an aralkyl group, or anacyl group), a nitro group, or a R10OOC group (wherein, R10 represents a hydrogen atom, analkyl group, an alkenyl group, an aryl group, or an aralkyl group)].   General Formula (II)   [wherein, R1, R2 and R4 to R7 represent, respectively, the same constituents asdescribed in general formula (I)].
公开号:EP0927718A1
申请号:EP98122554
申请日:1998-12-02
公开日:1999-07-07
发明作者:Hidetsugu Takagaki；Shinobu Yamaguchi；Masayoshi Abe；Mitsuru Sakai；Osamu Misumi
申请人:Dainippon Ink and Chemicals Co Ltd；
IPC主号:C07D215-00

专利说明:
[0001] The present invention relates to a simple method for preparing a quinolinonederivative, which is effective as a medicine, e.g., as a agent for treating allergic diseases andthe like; novel amide derivatives effective as an intermediate in said method; novelquinolinone derivatives obtained by means of said method; and a anti-allergic agentcontaining a quinolinone derivative and/or physiological salt of the same as the activeingredients. Background Art
[0002] The inventors of the present invention have found that a quinolinone derivativehaving a substituent group at the 7-position and physiological salts thereof are effectiveagainst both immediate-type hypersensitivity reactions and delayed-type hypersensitivityreactions, being extremely useful as a drug with few side effects, as disclosed in JapanesePatent Application, First Application No. Hei 09-100267 and Japanese Patent Application,First Application No. Hei 09-255659. A method for preparing such a quinolinone derivativewas disclosed in both Japanese Patent Application, First Application No. Hei 09-100267 andJapanese Patent Application, First Application No. Hei 09-255659, as shown below.
[0003] However, in the preparation method disclosed in these documents, in particular, whenpreparing a compound having a substituent group at the 3-position, it was necessary toproceed along a complex reaction pathway involving the steps of introducing a protectinggroup, de-protecting, introducing a substituent group, ad then de-protecting again. Thus, themethod was not necessarily satisfactory for industrial application.
[0004] Examples of other quinolinone derivatives ad methods for preparing the same,include Monatsh. Chem., 98(1), pp. 100-104, 1967, which discloses infrared absorptionspectrum data for 3-methoxy-4-hydroxy-2(1H)-quinolinone, 3-ethoxy-4-hydroxy-2(1H)-quinolinone,and 3,4-dimethoxy-2(1H)-quinolinone, as quinolinone compounds having substituent groups at the 3- and 4-positions of the nitrogen-containing ring of quinolinone,while lacking substituent groups on the aromatic group ring.
[0005] Monatsh.Chem., 99(6), pp. 2157-2166, 1968, also discloses a method for preparing3,4-dihydroxy-2(1H)-quinolinone and 3,4-dihydroxy-1-phenyl-2(1H)-quinolinone.
[0006] Additionally, Liebigs Ann. Chem., 9, PP. 1545-1551,1973, discloses a method forpreparing 3,4-dihydroxy-1-phenyl-2(1H)quinolinone ad 3,4-diacetoxy-1-phenyl-2(1H)-quinolinone.
[0007] Furthermore, Chem. Ber. 106, pp. 1537-1548, 1973, discloses a method for preparing3,4-dihydroxy-1-methyl-2(1H)-quinolinone, and Z. Naturforsch., B; Anorg. Chem., Org.Chem., 33B (4) pp. 429-432, 1978, discloses a method for preparing 3,4-dihydroxy-1-phenyl-2(1H)-quinolinone.
[0008] Monatsh.Chem., 115(2), pp. 231-242, 1984, discloses a method for preparing 3,4-dihydroxy-2(1H-quinolinone,3-methoxy-4-hydroxy-2(1H)-quinolinone, 3-ethoxy-4-hydroxy-2(1H)-quinolinone,3-propoxy-4-hydroxy-2(1H)-quinolinone, 3-trifluoroacetoxy-4-hydroxy-2(1H)-quinolinone,3-acetoxy-4-hydroxy-2(1H)-quinolinone, 3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,and 3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone.
[0009] Phosphorus and Sulfur, 21(1), pp. 47-52, 1984, discloses 3,4-dihydroxy-2(1H)-quinolinone3-dimethylphosphate, 3-hydroxy-4-methoxy-2(1H)-quinolinone 3-dimethylphosphate,3,4-dihydroxy-2(1H)-quinolinone 3-diethylphosphate, 3,4-dihydroxy-2(1H)-quinolinone3-diisopropylphosphate, and N-methyls of these compounds.
[0010] FEBS Lett., 246(1-2), pp. 113-116, 1989, discloses a method for preparing 3,4-dihydroxy-2(1H)-quinolinone.Phytochemistry, 28(5), pp. 1517-1519, 1989, discloses 3,4-dimethoxy-2(1H)-quinolinoneand 3,4-dimethoxy-1-methyl-2(1H)-quinolinone as extracts ofClausena anisata.
[0011] As compounds having substituent groups on the aromatic ring of a quinolinone,Indian J Chem., Sect. B, 15B(5), pp. 440-444, 1977, discloses 3,4-dimethoxy-2(1H)-quinolinone,8-methoxy-3-methoxy-4-hydroxy-1-methyl-2(1H)quinolinone, and a methylether thereof, 8-methoxy-3,4-dimethoxy-1-methyl-2(1H)-quinolinone as compounds obtainedfrom the bark of Chloroxylon swietenia DC.
[0012] Additionally, Indian J. Chem., Sect. B, 22B(12), pp. 1254-1256, 1983, discloses amethod for preparing 8-methoxy-3-methoxy-4-hydroxy-2(1H)-quinolinone and 8-methoxy-3,4-dimethoxy-1-methyl-2(1H)-quinolinone.
[0013] Additionally, J Heterocyclic Chem., 22, pp. 1087-1088, 1985, discloses a method forpreparing 3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone and 8-methoxy-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone.
[0014] Journal of Natural Products, 58(4), pp. 574-576, 1995, discloses 8-methoxy-3,4-dihydroxy-2(1H)-quinolinoneas a component obtained from Eriostemon gardneri. However,as described above, only methoxy groups are known as substituent groups for the aromaticgroup rings of quinolinone derivatives.
[0015] In addition, US Patent No. 5378694 (corresponding to WO 92/04328 and JapanesePatent Application, Second Publication No. Hei 6-502845) describes quinolinone derivativeshaving a carbonyl group as the 3-position substituent group, and a hydroxyl group or analkoxy group as the 4-position substituent group; the anti-viral activities and anti-hypertensiveactivities of these compounds are also described therein.
[0016] Moreover, US Patent No. 5412104 (corresponding to WO 92/04327 and JapanesePatent Application, Second Publication No. Hei 7-110853) describes quinolinone derivativeshaving a substituent group containing a carbonyl group as the 3-position substituent group,and an alkoxy group, a carbonyloxy group or a amino group as the 4-position substituentgroup, along with the anti-viral activities of these compounds; European Patent No. 0459561A2 discloses 2,4-dioxotetrahydroquinoline derivatives, wherein the 3-position substituentgroup is a substituent group containing a carbonyl group and the 4-position group is a 4-ketonetautomer.
[0017] European Patent Application, Publication No. 0481676 A1 discloses a quinolinonederivative having a aromatic group with a substituent group as the 3-position substituentgroup and a hydroxyl group as the 4-position substituent group; US Patent No. 4,124,587discloses a quinolinone derivative having a sulfinyl group as the 3-position substituent groupand a hydroxyl group as the 4-position substituent group; and US Patent No. 4127574discloses a quinolinone derivative having a sulfonyl group as the 3-position substituent groupand a hydroxyl group as the 4-position substituent group.
[0018] WO 96/04288 discloses 5,7-dimethyl-4-hydroxy-2(1H)-quinolinone and 5,7-dichloro-4-hydroxy-2(1H)-quinolinone;Furthermore, US Patent No. 5179107 and US Patent No.5190956 abstractly describe a extremely wide range of quinolinone derivatives havingsubstituent groups on the aromatic group ring and having oxygens directly bonded to the 3-and4-positions.
[0019] These US patent publications disclose quinolinone derivatives having thecharacteristic that the substituent groups at the 3- and 4-positions are identical substituentgroups, and disclose that these derivatives have anti-viral activity. SUMMARY OF THE INVENTION
[0020] In consideration of the aforementioned, the present invention provides a simplemethod for preparing a quinolinone derivative which is effective as a medicine, e.g., as ananti-allergic agent; novel amide derivatives effective as an intermediate in said method; novelquinolinone derivatives obtained according to said method; and an anti-allergic agentcontaining a quinolinone derivative and/or physiological salt thereof as the active ingredients.The inventors of the present invention have found that various desirable quinolinonederivatives are efficiently obtained by means of using an amide derivative, expressed bygeneral formula (I), as an intermediate, and promoting the intramolecular ring formation ofthe amide derivative using an alkali compound. Furthermore, these aforementionedquinolinone derivatives are extremely useful as anti-allergic agents.
[0021] In other words, the present invention comprises: (1) A method for preparing a quinolinone derivative, expressed by the followinggeneral formula (II), characterized in that a amide derivative, expressed by the followinggeneral formula (I), is reacted with a basic agent, followed by intramolecular ring formation;
[0022] In the following, the preferred embodiments of the present invention will be describedin detail.
[0023] In general formula (I) of the present invention, R₁ represents a hydrogen atom, analkyl group, a alkyl group containing a hydroxyl group, a alkenyl group, or an aryl group;and R₂ represents an alkyl group, an alkenyl group, an aryl group, or an aralkyl group.
[0024] As for R₁, the alkyl group may be either a straight-chain or branched-chain alkylgroup, examples of which include a methyl group, ethyl group, propyl group, isopropyl group,n-butyl group, s-butyl group, n-pentyl group, hexyl group, n-heptyl group, octyl group, andthe like. The alkyl group should preferably have 1 to 9 carbon atoms, more preferably 1 to 7carbon atoms.
[0025] The alkyl group containing a hydroxyl group may be either a straight-chain orbranched-chain alkyl group, examples of which may include a compound containing onehydroxyl group such as a hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropylgroup, 4-hydroxybutyl group, 6-hydroxypentyl group, 1-hydroxyetyl group, and the like, anda compound containing two hydroxyl groups such as a 1,2-dihydroxyethyl group, 2,3-dihydroxypropylgroup, and the like.
[0026] The alkenyl group may be either a straight-chain or branched-chain alkenyl group,examples of which include a vinyl group, propenyl group, hexenyl group, octenyl group,prenyl group, and the like. The alkenyl group should preferably have 2 to 9 carbon atoms,and more preferably 3 to 7 carbon atoms. Examples of the aryl group may include a furylgroup, pyridyl group, phenyl group, and substituted phenyl group. Examples of thesubstituted phenyl group may include a p-methylphenyl group, p-methoxyphenyl group, p-hydroxyphenylgroup, 3,4-dimethoxyphenyl group, and the like. Among the aforementioned,however, a phenyl group is preferred.
[0027] Examples of the aralkyl group may include a benzyl group, and a substituted benzylgroup (such as a p-methoxybenzyl group, p-hydroxybenzyl group, 3,5-dimethyl benzyl group,and the like); but of the aforementioned a benzyl group is preferred.
[0028] As for R₂, the alkyl group may be either a straight-chain or branched-chain alkylgroup, examples of which include a methyl group, ethyl group, propyl group, isopropyl group,n-butyl group, s-butyl group, n-pentyl group, hexyl group, n-heptyl group, octyl group, n-decylgroup, and the like. The alkyl group should preferably have 1 to 10 carbon atoms, andmore preferably have 1 to 8 carbon atoms.
[0029] The alkenyl group may be either a straight-chain or branched-chain alkenyl group,examples of which include a vinyl group, propenyl group, hexenyl group, octenyl group,geranyl group, and the like. The alkenyl group should preferably have 2 to 10 carbon atoms,and more preferably have 3 to 8 carbon atoms. Examples of the aryl group may include afuryl group, pyridyl group, phenyl group, and a substituted-phenyl group. Examples of thesubstituted-phenyl group include a p-methylphenyl group, p-methoxyphenyl group, p-hydroxyphenylgroup, 3,4-dimethoxyphenyl group, and the like. However, among theaforementioned, a phenyl group is preferred.
[0030] Examples of the aralkyl group may include a benzyl group, and substituted benzylgroup (such as a p-methoxybenzyl group, p-hydroxybenzyl group, 3,5-dimethyl benzyl group,and the like). However, among the aforementioned, a benzyl group is preferred.
[0031] In general formula (I) of the present invention, R₃ represents a reactive carboxylgroup, more specifically, a carboxyl group that is reactive with a carbon anion. Examplesmay include a carboxyl group, carboxylic acid ester group, carboxylic acid thioester group,halide carboxylate, and the like; however, among the aforementioned a carboxylic acid estergroup is preferred.
[0032] In general formula (I) of the present invention, R₄ to R₇ represent, respectively andindependently, a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, analkenyl group, an alkenyloxy group, a aryl group, a aryloxy group, an aralkyloxy group, aR₈R₉N group (wherein, R₈ and R₉ represent, respectively and independently, a hydrogen atom,an alkyl group, an alkenyl group, a aralkyl group, or an acyl group), a nitro group, or aR₁₀OOC group (wherein, R₁₀ represents a hydrogen atom, an alkyl group, an alkenyl group,an aryl group, or a aralkyl group).
[0033] The alkyl group, alkenyl group, aryl group, and aralkyl group represent the sameconstituents as described above. In addition, the alkyl group, alkenyl group and aralkylgroup contained respectively in the alkyloxyl group, alkenyloxyl group, and aralkyloxy group,similarly represent the same constituents as described above.
[0034] In general formula (I) of the present invention, the acyl group in R₈ and R₉ mayinclude both an alkenoyl group represented by an acetyl group, propionyl group, butyrylgroup, and the like, and a benzoyl group. The benzoyl group may have a substituent group,and examples of such include a p-hydroxybenzoyl group, p-methoxybenzoyl group, 2,4-dihydroxybenzoylgroup, 2,4-dimethoxybenzoyl group, and the like.
[0035] In addition, a cinnamoyl group and substituted cinnamoyl group may also be included.Examples of the substituted cinnamoyl group include a 2-hydroxycinnamoyl group, 3-hydroxycinnamoylgroup, 4-hydroxycinnamoyl group, 3,4-dihydroxycinnamoyl group, 4-hydroxy-3-methoxycinnamoylgroup, 3-hydroxy-4-methoxycinnamoyl group, 3,5-dimethoxy-4-hydroxycinnamoylgroup, 3,4,5-trimethoxycinnamoyl group, and the like.
[0036] In general formula (I) of the present invention, R₁₀ represents an alkyl group, analkenyl group, an aryl group, or an aralkyl group, each of which represents the sameconstituents as described above.
[0037] In the following, a method for preparing the quinolinone derivatives according to thepresent invention will be explained.
[0038] The quinolinone derivatives, expressed by general formula (II) in the presentinvention, can be prepared by means of the reaction pathway described below.
[0039] R₁ to R₇ in the chemical formula of the reaction pathway are defined in the samemanner as described above. The preparation method according to the present invention ischaracterized in that an amide derivative, expressed by general formula (I), and a basic agentare reacted with each other, followed by intramolecular ring formation. The basic agentemployed in the present invention may include various compounds such as alkali metals,alkali metal alkoxides, alkaline earth metal alkoxides, alkali metal hydrides, alkaline earthmetal hydrides, alkali metal amides, and the like.
[0040] Examples of the alkali metal may include sodium, potassium, and the like; Examplesof the alkali metal alkoxides may include basic agents such as sodium methoxide, sodiumethoxide, sodium t-butoxide, potassium t-butoxide, and the like; and examples of the alkalineearth metals may include magnesium methoxide, magnesium ethoxide, magnesium t-butoxide,calcium methoxide, calcium ethoxide, calcium t-butoxide, barium methoxide,barium ethoxide, barium t-butoxide, and the like.
[0041] Examples of the alkali metal hydrides may include lithium hydride, sodium hydride,potassium hydride, and the like; and examples of the alkaline earth metal hydride mayinclude calcium hydride, and the like. In addition, examples of the alkali metal amides mayinclude lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithiumbis(trimethylsilyl) amide, sodium bis(trimethylsilyl) amide, potassium bis(trimethlsilyl)amide, and the like.
[0042] Among these, alkali metal alkoxides and alkali metal amides are especially preferredas a basic agent.
[0043] In addition, the amount of the basic agent necessary for ring formation is generally 1to 5 times, preferably 2 to 3 times, greater in moles than an amide derivative with which abasic agent is reacted. For example, when sodium hydride, potassium t-butoxide, or lithiumdiisopropylamide is used as a basic agent, the amount of 2 times greater in moles than anamide derivative is, in general, sufficient.
[0044] However, even if a compound, in which a hydrogen atom is substituted for a nitrogenatom, is used at 4 times greater in moles than the amide derivative, ring formation does notoccur as intended. Thus, it is critical that R₁ comprise the substituent group according to thepresent invention described above. For example, if 2-[(methoxyacetyl)amino]-4-nitro-benzoicether is reacted with 4 times the amount in moles of sodium hydride in THF, ringformation does not occur.
[0045] On the other hand, when R₁ is a methyl group, that is, a compound in which an ethylgroup is substituted at the position of a nitrogen atom (ethyl 2-[N-ethyl-(methoxyacetyl)amino]-4-nitro-benzoate),a desired quinolinone derivative can be obtainedefficiently by means of using 2 times the amount in moles of sodium hydride under the sameconditions. When R₂ is a hydrogen atom, ring formation does not occur as intended.
[0046] Reactions in the preparation method according to the present invention may occur inan organic solvent that does not hinder such reactions. Examples of the organic solvent mayinclude hydrocarbon solvents such as a benzene, toluene, and the like; alcohol solvents suchas a methanol, ethanol, propanol, isopropanol, t-butanol, and the like; ethers solvents such asa diethylether, tetrahydrofuran, 1,2-dimethoxyethane, and the like; and amide solvents suchas a N,N-dimethylformamide, 1-methyl-2-pyrrolidine, and the like.
[0047] The preferable organic solvent differs depending on the type of basic agent employed.For example, alcohol solvents are generally preferred when using alkali metal alkoxides, whereas ammonia can be used as a solvent in case of alkali metal amides such as lithiumamide, sodium amide, and potassium amide.
[0048] The reaction temperature differs depending on the type of basic agent and reactionsolvent employed, but is generally between -80°C to 100°C, and preferably -50°C to 50°C.The reaction time is usuaily 1 to 5 hours.
[0049] The amide derivative of the present invention can be prepared by means of amidationof an amine derivative, expressed by general formula (III). Provided that, if A represents ahydrogen atom in the amine derivative, expressed by general formula (III), the amidederivative, expressed by general formula (I), is prepared by amidation, followed by alkylation.Substituent groups of R₄ to R₇ of the amide derivative, expressed by general formula (I), maybe previously introduced into the amine derivative, or may be introduced after amidation ofthe amine derivative, expressed by general formula (III). For example, ethyl 2-[N-methyl-(octyloxyacetyl)amino]-4-](3,5-dimethoxy-4-hydroxycinnamoyl)aminobenzoate can beprepared by reacting ethyl 2-[N-methyl-(octyloxyacetyl)amino] 4-aminobenzoate with 3,5-dimethoxy-4-hydroxycinnamicacid.
[0050] Amidation agents for amine derivatives may include either a carboxylic halide,expressed by general formula (IV), or a carboxylic acid, expressed by general formula (V).
[0051] Reactions are preferably promoted in an organic solvent in case of using the halidecarboxylate, expressed by general formula (IV). Examples of the organic solvents employedmay include hydrocarbon solvents such as benzene, toluene, xylene, and the like; etherssolvents such as a diethylether, tetrahydroluran, 1,2-dimethoxyethane, and the like; andamide solvents such as a N,N-dimethylformamide, 1-methyl-2-pyrrolidine, and the like.
[0052] In addition, although it is not particularly necessary to add an agent which promotesthe above reaction, it is possible to add an amine, as a catalyst, for example, a basic agentsuch as a triethylamine, pyridine, and the like. The reaction time differs depending on thetype of reagents employed and the reaction temperature, but is usually 30 minutes to 3 hours.The reaction temperature is -10°C to 10°C, and preferably 0°C to 50°C. Examples of thehalide carboxylate employed may include a chloride, bromide, and iodide; however, amongthe aforementioned a chloride is preferred.
[0053] Furthermore, the desired amide derivative, expressed by general formula (I), can beobtained by means of reacting with a carboxylic acid derivative, expressed by generalformula (V). In such a case, the desired amide derivative can be obtained by means of promoting reactions in an organic solvent, in the presence of an acid catalyst. Preferredorganic solvents include hydrocarbon solvents such as benzene, toluene, xylene, and the like.
[0054] Examples of the acid catalyst preferably include acids which are used in conventionalamide synthesis via dehydration, including mineral acids such as hydrochloric acid, sulfuricacid, and the like, and organic acids such as paratoluene sulfonate, methane sulfonate,triphloromethane sulfonate, and the like. It is desirable to allow this reaction to occur whileremoving water, formed during the reaction, from the group. The reaction time differsdepending on the type of reagents employed and the reaction temperature, but is usually 1 to10 hours. The reaction temperature is 50°C to 140°C, ad preferably 90°C to 120°C.
[0055] The novel amide derivative according to the present invention is expressed by generalformula (I).
[0056] Specifically, an amide derivative, expressed by the above formula, is providedwherein, R₁ is a hydrogen atom, a straight-chain or branched chain alkyl group having 1 to 9carbon atoms, a straight-chain or branched chain alkyl group containing a hydroxyl group andhaving 1 to 5 carbon atoms, a straight-chain or branched chain alkenyl group having 2 to 9carbon atoms, or an aryl group having 5 to 8 carbon atoms; R₂ is a straight-chain or branchedchain alkyl group having 1 to 10 carbon atoms, a straight-chain or branched chain alkenylgroup having 2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, or an aralkylgroup having 7 to 9 carbon atoms; and R₈ and R₉ are, respectively and independently, ahydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, or an acyl group having 2 to 12carbon atoms.
[0057] Alternatively, an amide derivative, expressed by the above formula, is providedwherein R₁ is a hydrogen atom; R₂ is a straight-chain or branched chain alkyl group having 1to 10 carbon atoms, a straight-chain or branched chain alkenyl group having 2 to 10 carbonatoms, an aryl group having 5 to 8 carbon atoms, or a aralkyl group having 7 to 9 carbonatoms; and R₈ and R₉ are, respectively ad independently, a hydrogen atom, an alkyl grouphaving 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl grouphaving 7 to 9 carbon atoms, or an acyl group having 2 to 12 carbon atoms.
[0058] More specifically, a amide derivative, expressed by the above formula, is providedwherein R₁ is either a hydrogen atom, or a straight-chain or branched-chain alkyl grouphaving 1 to 9 carbon atoms; and R₂ is a straight-chain or branched chain alkyl group having 1to 10 carbon atoms, a straight-chain or branched chain alkenyl group having 2 to 10 carbonatoms, an aryl group having 5 to 8 carbon atoms, or an aralkyl group having 7 to 9 carbonatoms.
[0059] The following compounds are illustrative examples of the thus obtained amidederivatives represented by the formula (I) of the present invention.Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-nitrobenzoate, Methyl 2-[N-methyl-N-(ethoxyacetyl)amino]-4nitrobenzoate,Ethyl 2-[N-methyl-N-(propoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-(hexyloxyacetyl)amino]-4-nitrobenzoate, Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-(decyloxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-[(2-propenyloxy)acetyl] amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-[(3-butenyloxy)acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-[(5-hexenyloxy)acetyl] amino]-4-nitrobenzoate, Ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-(phenoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-[(4-methoxyphenoxy)acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-[(4-hydroxyphenoxy)acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-methyl-N-[(3, 4-dimethylphenoxy)acetyl]amino]-4-nitrobenzoate, Ethyl 2-[N-methyl-N- (benzyloxyacetyl) amino]-4-nitrobenzoate, Ethyl 2-[N-methyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-nitrobenzoate, Ethyl 2-[N-methyl-N-[(3, 4-dimethylbenzyloxy) acetyl]amino]-4-nitrobenzoate, Methyl 2-[N-ethyl-N-(methoxyacetyl)amino]-4-nitrobenzoate,Methyl 2-[N-ethyl-N-(ethoxyacetyl)amino]-4-nitrobenzoate, Ethyl 2-[N-ethyl-N-(propoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-ethyl-N-(butoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-propyl-N-(hexyloxyacetyl)amino]-4-nitrobenzoate, Ethyl 2-[N-propyl-N-(octyloxyacetyl)amino]-4-nitrobenzoate, ethyl 2-[N-propyl-N-[(2-propenyloxy)acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-butyl-N-[(3-butenyloxy) acetyl]amino] -4- nitrobenzoate,Ethyl 2-[N-butyl-N-[(5-hexenyloxy) acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-butyl-N-(geranyloxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-butyl-N-(phenoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-butyl-N-[(4-methoxyphenoxy)acetyl] amino]-4-nitrobenzoate, Ethyl 2-[N-butyl-N-[(4-hydoroxyphenoxy)acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-hexyl-N-(benzyloxyacetyl)amino]-4-nitrobenzoate, Ethyl 2-[N-octyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-nitrobenzoate, Ethyl 2-[N-decyl-N-(butoxyacetyl)amino]-4-nitrobenzoate, Methyl 2-[N-(2-propenyl)-N-(ethoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-(3-butenyl)-N-(propoxyacetyl)amino]-4-nitrobenzoate, Ethyl 2-[N-(5-hexenyl)-N-(butoxyacetyl)amino]-4-nitrobenzoate,Ethyl 2-[N-(2-propenyl)-N-(hexyloxyacetyl) amino]-4-nitrobenzoate,Ethyl 2-[N-geranyl-N (ethoxyacetyl)amino]-4-nitrobenzoate, Ethyl 2-[N-prenyl-N-[(5-hexenyloxy)acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-benzyl-N-(benzyloxyacetyl)amino]-4-nitrobenzoate, Ethyl 2-[N-benzyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-nitrobenzoate,Ethyl 2-[N-(2-propenyl)-N-(methoxyacetyl0amino]-4-nitrobenzoate,Methyl 2-[N-methyl-N-(ethoxyacetyl)amino]-4aminobenzoate,Ethyl 2-[N-methyl-N-(propoxyacetyl)amino]-4-aminobenzoateEthyl 2-[N-methyl-N-(butoxyacetyl)amino]-4-aminobenzoate, Ethyl 2-[N-methyl-N-(hexyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N[(2-propenyloxy)acetyl]amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-[(3-butenyloxy)acetyl]amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-[(5-hexenyloxy)acetyl]amino]-4-aminobenzoate, Ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-(phenoxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-[(4-methoxyphenoxy)acetyl]amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-[(4-hydroxyphenoxy)acetyl]amino]-4-aminobenzoate, Ethyl 2-[N-methyl-N-(benzyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-aminobenzoate, Methyl 2-[N-ethyl-N-(methoxyacetyl)amino]-4-aminobenzoate,Methyl 2-[N-ethyl-N-(ethoxyacetyl)amino]-4-aminobenzoate, Ethyl 2-[N-ethyl-N-(propoxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-ethyl-N-(butoxyacetyl) amino]-4-aminobenzoate,Ethyl 2-[N-propyl-N-(hexyloxyacetyl)amino]-4-aminobenzoate, Ethyl 2-[N-propyl-N-(octyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-propyl-N-[(2-propenyloxy)acetyl]amino]-4-aminobenzoate,Ethyl 2-[N-butyl-N-[(3-butenyloxy)acetyl]amino]-4-aminobenzoate, Ethyl 2-[N-butyl-N-[(5-hexenyloxy)acetyl]amino]-4-aminobenzoate,Ethyl 2-[N-butyl-N-(geranyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-butyl-N-(phenoxyacetyl)amino]-4-aminobenzoate, Ethyl 2-[N-butyl-N-[(4-methoxyphenoxy)acetyl]amino]-4-aminobenzoate,Ethyl 2-[N-butyl-N-[(4-hydroxyphenoxy)acetyl]amino]-4-aminobenzoate, Ethyl 2-[N-hexyl-N-(benzyloxyacetyl)amino]-4-aminobenzoate, Ethyl 2-[N-octyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-aminobenzoate,Methyl 2-[N-(2-propenyl)-(ethoxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-(3-butenyl)-N-(propoxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-(5-hexenyl)-N-(butoxyacetyl)amino]-4-aminobenzoate, Ethyl 2-[N-(2-propenyl)-N-(hexyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-geranyl-N-(octyloxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-prenyl-N-[(5-hexenyloxy)acetyl]amino]-4-aminobenzoate,Ethyl 2-[N-benzyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-aminobenzoate,Methyl 2-[N-(2-hydroxyethyl)-N-(methoxyacetyl)amino]-4-aminobenzoate, Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-hexylaminobenzoate,Methyl 2-[N-methyl-N-(ethoxyacetyl)amino]-4-hexylaminobenzoate,Ethyl 2-[N-methyl-N-(propoxyacetyl)amino]-4-hexylaminobenzoate,Ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-4-hexylaminobenzoate,Ethyl 2-[N-methyl-N-(hexyloxyacetyl)amino]-4-hexylaminobenzoate, Ethyl 2- [N-methyl-N-(octyloxyacetyl)amino]-4-hexylaminobenzoate,Ethyl 2-[N-methyl-N-[(2-propenyloxy)acetyl]amino]-4-hexylaminobenzoate,Ethyl 2- [N-methyl-N-[(3-butenyloxy)acetyl]amino]-4-octylaminobenzoate,Ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-decylaminobenzoate,Ethyl 2-[N-methyl-N-[(5-hexenyloxy)acetyl]amino]-4-octylaminobenzoate, Ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-4-octylaminobenzoate,Ethyl 2- [N-methyl-N-(phenoxyacetyl)amino]-4-octylaminobenzoate,Ethyl 2-[N-methyl-N-[(4-methoxyphenoxy)acetyl]amino]-4-octylaminobenzoate, Ethyl 2-[N-methyl-N-[(hydroxyphenoxy)acetyl]amino]-4-octylaminobenzoate,Ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-vinylaminobenzoate, Ethyl 2-[N-methyl-N-(benzyloxyacetyl)amino]-4-(2-propenyl)aminobenzoate,Ethl 2-[N-methyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-(2-propenyl)aminobenzoate,Methyl 2-[N-ethyl-N-(methoxyacetyl)amino]-4-(5-hexenyl)aminobenzoate,Methyl 2-[N-ethyl-N-(ethoxyacetyl)amino]-4-(5-hexenyl)aminobenzoate, Ethyl 2-[N-ethyl-N-(propoxyacetyl)amino]-4-(5-hexenyl)aminobenzoate,Ethyl 2-[N-ethyl-N-(butoxyacetyl)amino]-4-(5-hexenyl)aminobenzoate,Ethyl 2-[N-propyl-N-(hexyloxyacetyl)amino]-4-(5-hexenyl)aminobenzoate,Ethyl 2-[N-propyl-N-(octyloxyacetyl)amino]-4-(5-hexenyl)aminobenzoate,Ethyl 2-[N-propyl-N-[(2-propenyloxy)acetyl]amino]-4-(5-hexenyl)aminobenzoate, Ethyl 2-[N-butyl-N-[(3-butenyloxy)acetyl]amino]-4-(5-hexenyl)aminobenzoate,Ethyl 2-[N-butenyl-N-[(5-hexenyloxy)acetyl]amino]-4-(5-hexenyl)aminobenzoate,Ethyl 2-[N-butyl-N-(geranyloxyacetyl)amino]-4-(5-hexenyl)aminobenzoate,Ethyl 2-[N-butyl-N-(phenoxyacetyl)amino]-4-(5-hexenyl)aminobenzoateEthyl 2-[N-butyl-N-[(4-methoxyphenoxy)acetyl]amino]-4-(5-hexenyl)aminobenzoate, Ethyl2-[N-butyl-N-[(4-hydroxyphenoxy)acetyl]amino]-4-geranylaminobenzoate, Ethyl 2-[N-hexyl-N-(benzyloxyacetyl)amino]-4-geranylaminobenzoate,Ethyl 2-[N-octyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-geranylaminobenzoate,Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-acetylaminobenzoate, Methyl 2-[N-methyl-N-(ethoxyacetyl)amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-(propoxyacetyl)amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-(hexyloxyacetyl)amino-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-acetylaminobenzoate, Ethyl 2-[N-methyl-N-[(2-propenyloxy)acetyl]amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-[(3-butenyloxy)acetyl]amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-[(5-hexenyloxy)acetyl]amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-(phenoxyacetyl)amino]-4-acetylaminobenzoate, Ethyl 2-[N-methyl-N-[(4-methoxyphenoxy)acetyl]amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-[(4-hydroxyphenoxy)acetyl]amino]-4-acetylaminobenzoate, Ethyl 2-[N-methyl-N-(benzyloxyacetyl)amino]-4-(2-propenyl)aminobenzoate,Ethyl 2-[N-methyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-acetylaminobenzoate, Methyl2-[N-(2-propenyl)-N-(ethoxyacetyl)amino]-4-acetylaminobenzoate, Ethyl 2-[N-(3-butenyl)-N-(propoxyacetyl)amino]-4-acetylaminobenzoate,Ethyl 2-[N-(5-hexenyl)-(butoxyacetyl)amino]-4-acetylaminobenzoate,Ethyl 2-[N-(2-propenyl)-N-(hexyloxyacetyl)amino]-4-acetylaminobenzoate,Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-benzoylaminobenzoate, Ethyl 2-[N-geranyl-N-(octyloxyacetyl)amino]-4-benzoylaminobenzoate,Ethyl 2-[N-prenyl-N-[(5-hexenyloxy)acetyl]amino]-4-benzoylaminobenzoate,Ethyl 2-[N-geranyl-N-(ethoxyacetyl)amino]-4-aminobenzoate,Ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-benzylaminobenzoate,Ethyl 2-[N-benzyl-N-(benzyloxyacetyl)amino]-4-benzylaminobenzoate,Ethyl 2-[N-benzyl-N-[(4-hydroxybenzyloxy)acetyl]amino]-4-benzylaminobenzoate, Methyl2-[N-methyl-N-(methoxyacetyl)amino]-4-cinnamoylaminobenzoate, Methyl 2-[N-methyl-N-(ethoxyacetyl)amino]-4-cinnamoylaminobenzoate,Ethyl 2-[N-methyl-N-(propoxyacetyl)amino]-4-(3,5-dimethoxy-4-hydroxycinnamoyl)aminobenzoate, Ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-4-(3,5-dimethoxy-4-hyroxycinnamoyl)aminobenzoate,Ethyl 2-[N-methyl-N-(hexyloxyacetyl)amino]-4-(3,5-dimethoxy-4-hydroxycinnamoyl)aminobenzoate,Ethyl 2-[N-methyl-N-(octylacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,Ethyl 2-[N-methyl-N-[(2-propenyloxy)acetyl]amino]-4-(4-hydroxycinnamoyl)aminobenzoate,Ethyl 2-[N-methyl-N-[(3-butenyloxy)acetyl]amino]-4-(3, 4-dihydroxycinnamoyl)aminobenzoate,Ethyl 2-[N-methyl-N-[(5-hexenyloxy)acetyl]amino]-4-(3-hydroxycinnamoyl)aminobenzoate,Ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-4-(3,5-dimethoxy-4-hydroxycinnamoyl)aminobenzoate, Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-(N-methyl-N-acetyl)aminobenzoate,Methyl 2-[N-methyl-N-(ethoxyacetyl)amino]-4-(N,N-dimethyl)aminobenzoate,Ethyl 2-[N-methyl-N-(propoxyacetyl)amino]-4-(N,N-dimethyl)aminobenzoate, Ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-4-(N,N-dimethyl)aminobenzoate,Ethyl 2-[N-methyl-N-[hexyloxyacetyl)amino]-4-(N,N-dimethy)aminobenzoate,Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-(N,N-dimethyl)aminobenzoate, Ethyl 2-[N-methyl-N-[(2-propenyloxy)acetyl]amino]-4-(N-methyl-N-acetyl)aminobenzoate,Ethyl 2-[N-methyl-N-[(3-butenyloxy)acetyl]amino]-4-(N-ethyl-N-acetyl)aminobenzoate,Ethyl 2-[N-methyl-N-[(5-hexenyloxy)acetyl]amino]-4-(N-ethyl-N-acetyl)aminobenzoate,Ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-4-(N-butyl-N-acetyl)aminobenzoate,Ethyl 2-[N-methyl-N-(phenoxyacetyl)amino]-4-[N-(2-propenyl)-N-acetyl]aminobenzoate,Ethyl 2-[N-methyl-N-[(4-methoxyphenoxy)acetyl]amino]-4-(N-geranyl-N-acetyl)aminobenzoate,Ethyl 2-[N-methyl[(4-hydroxyphenoxy)acetyl]amino]-4-(N-benzyl-N-acetyl)aminobenzoate,Ethyl 2-[N-methyl-N-(benzyloxy-N-acetyl)amino]-4-(N-methyl-N-benzyl)aminobenzoate,Methyl 2-[N-ethyl-N-(ethoxyacetyl)amino]-4-nitrobenzoate, Methyl 2-[N-decyl-(butoxyacetyl)amino]-4-nitrobenzoate,Methyl 2-[N-methyl-N-(decyloxyacetyl)amino]-4-nitrobenzoate,Methyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-nitrobenzoate, Methyl 2-[N-(2-puropenyl)-N-(methoxyacetyl)amino]-4-nitrobenzoate,Methyl 2-[N-(2-hydroxyethyl)-N-(methoxyacetyl)amino]-4-nitrobenzoate,Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-aminobenzoate, Methyl 2-[N-geranyl-N-(ethoxyacetyl)amino]-4-aminobenzoate,Methyl 2-[N-methyl-N-(octylacetyl)amino]-4-aminobenzoate,Methyl 2-[N-methyl-N-(benzyloxyacetyl)amino]-4-aminobenzoate, Methyl2-[N-methyl-N-(butoxyacetyl)amino]-4-aminobenzoate, Methyl 2-[N-(3-hydroxypropyl)-N-(methoxyacetyl)amino]-4-aminobenzoate,Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-benzylaminobenzoatemethyl, Methyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-benzylaminobenzoate,Methyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-acetylaminobenzoate,Methyl 2-[N-methyl-N(benzyloxyacetyl)amino]-4-methylaminobenzoate,Methyl 2-[N-ethyl-N-(3,4-dimethylbenzyloxy)acetyl]amino]-4-hexylaminobenzoate,Methyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-(N,N-dimethyl)aminobenzoate,Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-decylaminobenzoate, Methyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-vinylaminobenzoateMethyl 2-[N-methyl-N-(benzyloxyacetyl)amino]-4-hexylaminobenzoate,Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-(N,N-dimethyl)aminobenzoate,Ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-geranylaminobenzoate,Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 4, 5-trimethoxycinnamoyl)amino]-benzoate,Ethyl 2-[N-methyl-2-pyridyloxy)acetyl]amino]-4-nirobenzoate, Ethyl 2-[N-(2-furanyl)methyl-N-methoxyacetyl]amino]-4-nitrobenzoate, Ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-6-phenoxycarbonylbenzoate,Ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-6-decyloxycarbonylbenzoate, Ethyl 2-[N-(3, 5-dimethylbenzyloxy)-N-ethoxyacetyl]amino]-6-hexylaminobenzoate.
[0060] These are using synthetic intermediate of useful quinolinone derivatives as medicine,especially anti-allergic agent.
[0061] The novel quinolinone derivative, obtained by means of the preparation methodaccording to the present mvention, is a quinolinone derivative, expressed by general formula(II).
[0062] Specifically, a quinolinone derivative, expressed by the above formula, is providedwherein R₁ is a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 9carbon atoms, a straight-chain or branched-chain alkyl group containing a hydroxyl group and having 1 to 5 carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to9 carbon atoms, or an aryl group having 5 to 8 carbon atoms; R₂ is a straight-chain orbranched-chain alkyl group having 1 to 10 carbon atoms, a straight-chain or branched-chainalkenyl group having 2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, or anaralkyl group having 7 to 9 carbon atoms; R₄ to R₇ are, respectively and independently, ahydrogen atom, a hydroxyl group, a straight-chain or branched-chain alkyl group having 1 to10 carbon atoms, a straight-chain or branched-chain alkoxy group having 1 to 10 carbonatoms, a straight-chain or branched-chain alkenyl group having 2 to 10 carbon atoms, astraight-chain or branched-chain alkenyloxy group having 2 to 10 carbon atoms, an arylgroup having 5 to 8 carbon atoms, a aryloxy group having 5 to 8 carbon atoms, or anaralkyoxy group having 7 to 9 carbon atoms; R₈ and R₉ are, respectively and independently,a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to10 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, or an acyl group having 2 to12 carbon atoms; and R₁₀ is a straight-chain or branched-chain alkyl group having 1 to 10carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to 10 carbon atoms,an aryl group having 5 to 8 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms;with the exception that the following two types of compounds are not included: (i) acompound in which R₄, R₅ and R₇ are respectively hydrogen atoms; and R₆ is selected fromthe group comprising a hydrogen atom, a hydroxyl group, an alkoxy group, an alkenyloxygroup, a aralkyloxy group, a R₈R₉N group (wherein, R₈ and R₉ represent, respectively andindependently, a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group, or anacyl group), and a nitro group; and (ii) a compound in which R₄, R₅ and R₆ are respectivelyhydrogen atoms, and R₇ is a methoxy group.
[0063] More specifically, a quinolinone derivative, expressed by the above formula, isprovided, wherein R₁ is a hydrogen atom; R₂ is a straight-chain or branched-chain alkyl grouphaving 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to 10carbon atoms, an aryl group having 5 to 8 carbon atoms, or a aralkyl group having 7 to 9carbon atoms; R₄ to R₇ are, respectively ad independently, a hydrogen atom, a hydroxylgroup, a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms, a straight-chainor branched-chain alkoxy group having 1 to 10 carbon atoms, a straight-chain orbranched-chain alkenyl group having 2 to 10 carbon atoms, a straight-chain or branched-chainalkenyloxy group having 2 to 10 carbon atoms, a aryl group having 5 to 8 carbonatoms, a aryloxy group having 5 to 8 carbon atoms, or an aralkyloxy group having 7 to 9 carbon atoms; R₈ and R₉ are, respectively and independently, a hydrogen atom, an alkylgroup having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkylgroup having 7 to 9 carbon atoms, or an acyl group having 2 to 12 carbon atoms; and R₁₀ is astraight-chain or branched-chain alkyl group having 1 to 10 carbon atoms, a straight-chain orbranched-chain alkenyl group having 2 to 10 carbon atoms, an aryl group having 5 to 8carbon atoms, or an aralkyl group having 7 to 9 carbon atoms; with the exception that thefollowing two types of compounds are not included: (i) a compound in which R₄, R₅ and R₇are respectively hydrogen atoms; and R₆ is selected from the group comprising a hydrogenatom, a hydroxyl group, an alkoxy group, an alkenyloxy group, an aralkyloxy group, a R₈R₉Ngroup (wherein, R₈ and R₉ represent, respectively and independently, a hydrogen atom, analkyl group, an alkenyl group, an aralkyl group, or an acyl group), and a nitro group; and (ii)a compound in which R₄, R₅ and R₆ are respectively hydrogen atoms, and R₇ is a methoxygroup.
[0064] More specifically, a quinolinone derivative, expressed by the above formula, isprovided wherein R₁ is either a hydrogen atom, or a straight-chain or branched-chain alkylgroup having 1 to 9 carbon atoms; and R₂ is a straight-chain or branched-chain alkyl grouphaving 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to 10carbon atoms, an aryl group having 5 to 8 carbon atoms, or an aralkyl group having 7 to 9carbon atoms; with the exception that the following two types of compounds are notincluded: (i) a compound in which R₄, R₅ and R₇ are respectively hydrogen atoms; and R₆ isselected from the group comprising a hydrogen atom, a hydroxyl group, an alkoxy group, analkenyloxy group, an aralkyloxy group, a R₈R₉N group (wherein, R₈ and R₉ representrespectively and independently, a hydrogen atom, an alkyl group, an alkenyl group, anaralkyl group, or an acyl group), and a nitro group; and (ii) a compound in which R₄, R₅ andR₆ are respectively hydrogen atoms, and R₇ is a methoxy group.
[0065] The following compounds are illustrative examples of the thus obtained quinolinonederivatives represented by the formula (II) of the present invention.7-nitro-3-methoxy-4-hydroxy-1-ethyl-2(1H)-quinolinone, 5-nitro-3-methoxy-4-hydroxy-1-ethyl-2(1H)-quinolinone,6-nitro-3-methoxy-4-hydroxy-1-octy-2(1H)-quinolinone, 7-nitro-3-butoxy-4-hydroxy-1-decyl-2(1H)-quinolinone,7-nitro-3-butoxy-4-hydroxy- 1-propenyl-2(1H)quinolinone, 7-nitro-3-decyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,8-nitro-3-methoxy-4-hydroxy-1-benzyl-2(1H)-quinolinone, 7-nitro-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-nitro-3-methoxy-4-hydroxy-1-propenyl-2(1H)-quinolinone, 7-nitro-3-methoxy-4-hydroxy-1-(2-hydroxyethyl)-2(1H)quinolinone,6-nitro-3-butoxy-4-hydroxy-1-(6-hydroxyhexyl)-2(1H)-quinolinone, 7-amino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-amino-3-ethoxy-4-hydroxy-1-geranyl-2(1H)-quinolinone,5-amino-3-ethoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-amino-3-phenoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,8-amino-3-geranyloxy-4-hydroxy-1-methyl-2(1H)quinolinone,7-amino-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-amino-3-butoxy-4-hydroxy-1-(2-furylmethyl)-2(1H)-quinolinone,7-amino-3-benzyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-amino-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-amino-3-methoxy-4-hydroxy-1-(2-hydroxyethyl)-2(1H)-quinolinone,7-benzoylamino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 5-acetylamino-3-ethoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-acetylamino-3-phenoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,8-acetylamino-3-geranyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-[(4-hydroxy-3, 5-dimethoxycinnamoyl)amino]-3-octyloxy-4-hydroxy-1methyl-2(1H)-quinolinone,7-[(3, 4, 5-trirnethoxycinnnamoyl)amino]-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-acetylamino-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-benzoylamino-3-ocryloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-methylamino-3-benzyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-hexylamino-3-(3,4-dimethylbenzyloxy)-4-hydroxy-1-ethyl-2(1H)-quinolinone, 7-dimethylamino-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-benzylamino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-decylamino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-vinylamino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-(2-furylmethyl)amino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-(2-pyridylmethyl)amino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-(3, 4-dimethylbenzyl)amino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-geranylamino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-puropenylamino-3-ethoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-benzylmethylamino-3-phenoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 8-butylamino-3-geranyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-hexylamino-3-benzyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-hydroxy-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 5-hydroxy-3-ethoxy-4hydroxy-1-ethyl-2(1H)-quinolinone, 6-hydroxy-3-phenoxy-4-hydroxy-1-octyl-2(1H)-quinolinone,8-hydroxy-3-geranyloxy-4-hydroxy-1-benzyl-2(1H)-quinolinone, 7-hydroxy-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-hydroxy-3-octyloxy-4-hydroxy-1-propenyl-2(1H)-quinolinone, 7-vinyloxy-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-octyloxy-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-decyloxy-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-phenoxy-3-ethoxy-4-hydroxy-1-ethyl-2(1H)quinolinone, 5-geranyloxy-3-ethoxy-4-hydroxy-1-ethyl-2(1H)-quinolinone,6-propenyloxy-3-phenoxy-4-hydroxy-1-octyl-2(1H)-quinolinone,8-benzyloxy-3-geranyloxy-4-hydroxy-1-benzyl-2(1H)-quinolinone,7-methoxy-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-butoxy-3-octyloxy-4-hydroxy-1-propenyl-2(1H)-quinolinone,7-methyl-3-octyloxy-4-hydroxy-1-propenyl-2(1H)-quinolinone,7-hexyl-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-decyl-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-propenyl-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-geranyl-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-(3,4-dimethylbenzyl)-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-butyl-3-ethoxy-4-hydroxy-1-ethyl-2(1H)-quinolinone, 6-phnyl-3-phenoxy-4-hydroxy-1-octyl-2(1H)-quinolinone,6-propenyl-3-phenoxy-4-hydroxy-1-octyl-2(1H)-quinolinone, 8-methyl-3-geranyloxy-4-hydroxy-1-benzyl-2(1H)-quinolinone,7-methyl-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-butyl-3-octyloxy-4-hydroxy-1-propenyl-2(1H)quinolinone,5, 7-dihydroxy-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5,7-dihydroxy-3-ethoxy-4-hydroxy-1-ethyl-2(1H)quinolinone, 5,7-dimethoxy-3-phenoxy-4-hydroxy-1-octyl-2(1H)-quinolinone,5,7-dibenzyloxy-3-geranyloxy-4-hydroxy-1-benzyl-2(1H)-quinolinone,5,7 -dipuropenyloxy-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-ethoxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 5-phenoxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-propenyloxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-hydroxycarbonyl-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,7-[(3, 5-dimethoxy-4-hydroxycinnamoyl) amino]-3-octyloxy-4-hydroxy-1-methyl-2 (1H)-quinolinone,6-benzylamino-3-phenoxy-4-hydroxy-1-methyl-2 (1H)quinolinone, 6-nitro-3-butoxy-4-hydroxy-1-decyl-2(1H)-quinolinone, 6-nitro-3-butoxy-4-hydroxy-1-(6-hydroxyhexyl)-2(1H)-quinolinone, 5-amino-3-ethoxy-4-hydroxy-1-geranyl-2 (1H)-quinolinone,7-[(3,4, 5-trimethoxycinnamoyl) amino]-3-octyloxy-4-hydroxy-1-methyl-2 (1H)-quinolinone,5-methylamino-3-benzyloxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 5-hexylamino-3-(3,5-dimethylbenzyloxy)-4-hydroxy-1-ethyl-2 (1H)-quinolinone, 6-decylamino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-vinylamino-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-(3, 5-dimethylbenzylamino)-3-methoxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 6-(2-propenyloxy)-3-phenoxy-4-hydroxy-1-octyl-2(1H)-quinolinone, 7-methyl-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-(2-propenyl)-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-butyl-3-octyloxy-4-hydroxy-1-(2-propenyl)-2(1H)-quinolinone,7-nitro-3-(2-pyridyloxy)-4-hydroxy-1-methyl-2 (1H)-quinolinone, 7-nitro-3-methoxy-4-hydroxy-1-(2-furanyl)methyl-2 (1H)-qulnolinone, 5-phenoxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-decyloxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 5-hexylamino-3-ethoxy-4-hydroxy-1-(3,5-dimethylbenzyloxy)-2(1H)-quinolinone5-nitro-3-octyloxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 6-nitro-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 8-nitro-3-octyloxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 5-amino-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-amino-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 8-amino-3-octyloxy-4-hydroxy-1-methyl-2 (1H)-quinolinone,5-[(3, 5-dimethoxy-4-hydroxycinnamoyl) amino]-3-octyloxy-4-hydroxy-1-methyl-2 (1H)-quinolinone,6-[(3, 5-dimethoxy-4-hydroxycinnamoyl) amino]-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,8-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-hexylamino-5-ethyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-methoxy-3-phenoxy-4-hydroxy-1-octyl-2 (1H)-quinolinone, 6-benzyloxy-3-geranyloxy-4-hydroxy-1-benzyl-2(1H)-quinolinone, 6-propenyloxy-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,6-ethoxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 6-phenoxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-propenyloxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 6-hydroxycarbonyl-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 8-methoxy-3-phenoxy-4-hydroxy-1-octyl-2 (1H)-quinolinone, 8-benzyloxy-3-geranyloxy-4-hydroxy-1-benzyl-2 (1H)-quinolinone, 8-propenyloxy-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone8-ethoxycarbonyl-3-butoxy-4-hydroxy-1-methyl-2 (1H-quinolinone, 8-phenoxycarbonyl-3butoxy-4-hydroxy-1-methy1-2 (1H)-quinolinone, 8-propenyloxycarbonyl-3-butoxy-4-hydroxy1-methyl-2 (1H)-quinolinone, 8-hydroxycarbonyl-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,5-octyloxy-3-methoxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 6-hexyl-3-butoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 8-hexyloxy-3-hexyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 8-octyl-3-butoxy-4-hydroxy-1-methyl-2 (1H)-quinolinone, 8-methylamino-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone,8-decylamino-3-ethoxy-4-hydroxy-1-methyl-2(1H)-quinolinone
[0066] Since the 7-aminoquinolinone derivatives and physiologically acceptable salts of thepresent invention (to be referred to as "the compound of the present invention" hereinafter)have a function to inhibit both immediate and delayed type allergic reactions and low toxicityas will be described later in examples, they are useful as antiallergic agents for the treatmentor prevention of various allergic diseases.
[0067] The term "allergic diseases" as used herein means allergic diseases resulting fromexcess activation of the biological immune mechanism caused by extrinsic or intrinsicantigens, which include immediate type asthma, delayed type asthma, bronchial asthma,pediatric asthma, atopic dermatitis, allergic dermatitis, urticaria, eczema, allergicconjunctivitis, allergic rhinitis, hay fever, food allergy, allergic gastroenteritis, allergic colitis,contact dermatitis, autoimmune disease and the like.
[0068] The antiallergic agent which comprises the compound of the present invention as aactive ingredient can be adinistered orally (internal use or inhalation) or parenterally (forexample, intravenous injection, subcutaneous injection, percutaneous absorption, rectaladministration or the like). Such a pharmaceutical agent ca be made into various dosageforms according to the purpose, such as tablets, capsules, granules, fine subtilaes, powders,troches, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions,medicated syrups ad the like. These dosage forms can be prepared in accordance withknown techniques maring use of pharmaceutically acceptable carriers which are commoniyused in this type of drugs, such as excipients, bonding agents, disintegrators, lubricants,preservatives, anti-oxidative agents, isotonic agents, buffering agents, coating agents,sweetening agents, dissolving agents, bases, dispersing agents, stabilizing agents, coloringagents and the like.
[0069] Illustrative examples of these pharmaceutically acceptable carriers are listed in thefollowing.
[0070] Firstly, as excipients, the following can be listed: starch and derivatives of starch(such as dextrin, carboxymethyl starch and the like), cellulose and derivatives of cellulose(such as methylcellulose, hydroxypropylmethylcellulose and the like), sugars (such as lactose,sucrose, glucose and the like), silicic acid and silicates (such as naturally occurring aluminiumsilicate, magnesium silicate and the like), carbonates (such as calcium carbonate, magnesiumcarbonate, sodium hydrogencarbonate and the like), aluminum magnesium hydroxide,synthetic hydrotalcite, polyoxyethylene derivatives, glycerin monostearate,sorbitan monooleic acid and the like.
[0071] As bonding agents, the following can be listed: starch and starch derivatives (such asalpha starches, dextrin and the like), cellulose and derivatives of cellulose (such as ethylcellulose, sodium carboxymethyl cellulose, hydroxypropyhnethyl cellulose and the like),gum arabic, traganth, gelatin, sugars (such as glucose, sucrose and the like), ethanol,polyvinyl alcohols and the like.
[0072] As disintegrators, the following ca be listed: starch and starch derivatives (such ascarboxymethyl starch, hydroxypropyl starch and the like), cellulose and cellulose derivatives(such as sodium carboxymethyl cellulose, crystal cellulose, hydroxypropylmethyl celluloseand the like), carbonates (such as calcium carbonate, calcium hydrogencarbonate and thelike), tragath, gelatins, agar and the like.
[0073] As lubricants, the following can be listed: stearic acid, calcium stearate, magnesiumstearate, talc, silicic acid and its salts (such as light silicic anhydrides, naturally occurringaluminum silicates and the like), titanium oxide, calcium hydrogen phosphate, dry aluminumhydroxide gel, macrogol and the like.
[0074] As preservatives, the following can be listed: p-hydroxybenzoates, sulfites (such assodium sulfites, sodium pyrosulfites and the like), phosphates (such as sodium phosphates,calcium polyphosphates, sodium polyphosphates, sodium methaphosphate and the like),alcohols (such as chlorobutanol, benzyl alcohol and the like), benzalkonium chloride,benzethonium chloride, phenol, cresol, chlorocresol, dihydroacetic acid, sodiumdihydroacetate, glycerin sorbic acid, sugars and the like.
[0075] As anti-oxidative agents, the following can be listed: sulfites (such assodium sulfite,sodium hydrogen sulfite and the like), rongalite, erythorbic acid, L-ascorbic acid, cysteine, thioglycerol, butylhydroxyanisol, dibutylhydroxytoluene, propylgallic acid, ascorbylpalmitate, dl-a-tocopherol and the like.
[0076] As isotonic agents, the following can be listed: sodium chloride, sodium nitrate,potassium nitrate, dextrin, glycerin, glucose and the like.
[0077] As buffering agents, the following can be listed: sodium carbonate, hydrochloric acid,boric acid, phosphates (such as sodium hydrogenphosphate) and the like.
[0078] As coating agents, the following can be listed: cellulose derivatives (such ashydroxypropyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulosephthalate and the like), shellac, polyvinylpyrrolidone, polyvinylpyridines (such as poly-2-vinylpyridine,poly-2-vinyl-5-ethylpyridine and the like), polyvinylacetyldiethylaminoacetate, polyvinyl alcohol phthalate, methacrylate, methacrylate copolymers andthe like.
[0079] As sweetening agents, the following can be listed: sugars (such as glucose, sucrose,lactose and the like), sodium saccharin, sugar alcohols and the like.
[0080] As dissolving agents, the following can be listed: ethylenediamine, nicotinamide,sodium saccharin, citric acid, citrates, sodium benzoic acid, soaps, polyvinylpyrrolidone,polysolvates, sorbitan fatty acid esters, glycerin, propylene glycol, benzyl alcohols and thelike.
[0081] As bases, the following can be listed: fats (such as lard and the like), vegetable oils(such as olive oil, sesame oil and the like), animal oil, lanolin acid, petrolatums, paraffin, wax,resins, bentonite, glycerin, glycol oils, higher alcohols (such as stearyl alcohol, cetanol) andthe like.
[0082] As dispersing agents, the following can be listed: gum arabic, traganth, cellulosederivatives (such as methyl cellulose and the like), stearic acid polyesters, sorbitansesquioleate, aluminum monostearate, sodium alginate, polysolvates, sorbitan fatty acidesters and the like.
[0083] Lastly, as stabilizing agents, the following can be listed: sulfites (such as sodiumhydrogen sulfite and the like), nitrogen, carbon dioxide and the like.
[0084] Though the content of the compound of the present invention in these pharmaceuticalpreparations varies depending on the dosage forms, it may be contained preferably in aconcentration of from 0.01 to 100% by weight.
[0085] Dose of the antiallergic agent of the present invention can be varied over a broadrange depending on each warm-blooded animal including human and the like, to be treated, extent of each disease, doctor's judgement and the like. In general, however, it may beadministered in a dose of from 0.01 to 50 mg, preferably from 0.01 to 10 mg, as the activeingredient per day per kg body weight in the case of oral administration or in a dose of from0.01 to 10 mg, preferably from 0.01 to 5 mg, as the active ingredient per day per kg bodyweight Inthe case ofparenteral administration. The dally dose described above may be usedin one portion or in divided portions and changed optionally in accordance with the extent ofdiseases and doctor's judgement.
[0086] The following examples are intended to illustrate this invention, however theseexamples are intended to illustrate the invention and not to be construed to limit the scope ofthe invention. EXAMPLE 1Ethyl 2-[(octyloxyacetyl)amino]-4-nitrobenzoate (compound 1)
[0087] To a mixture of 20.00 g of ethyl 4-nitroanthranllate (95.15 mmol) in 60 ml of toluenewas added 19.71 g of octyloxyacetic acid (104.67 mmol) and 0.91 g of p-toluenesulfonic acidmonohydrate (4.76 mmol), and the mixture was stirred at 120°C for 6 hours. (The waterformed during the reaction process were removed as required.) After the mixture was cooledat 30°C, 0.53 g of triethylamine (5.71 mmol) was added and the mixture was concentratedunder reduced pressure. The resulting crude product was crystallized from methanol to give41.64 g of title compound (1). (yield = 93.9%) ¹H-NMR (CDCl₃, δ -TMS) 11.86 (s, 1H), 9.68 (s, 1H), 8.21 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz),4.22 (m, 2H), 4.13 (s, 2H), 3.63 (t, 2H,J=6.4 Hz), 1.80∼1.20 (m, 15H),0.88 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 3240, 2850, 1740, 1550, 1345 Elemental analysis for: C₁₉H₂₈N₂O₆Calculated (%): C 59.98; H 7.42; N 7.36; O 25.23 Found (%): C 59.75; H 7.57; N 7.26; O 25.42
[0088] To a mixture of 20.00 g of ethyl 4-nitroanthranilate (95.15 mmol) in 60 ml oftetrahydrofuran was added 21.63 g of octyloxyacetylchloride (104.67 mmol) and 11.65 g oftriethylamine (115.14 mmol) at 10°C, and the mixture was stirred at 10°C for 1 hour. Thereaction mixture was filtered and the filtrate was concentrated under reduced pressure. Theresulting crude product was crystallized from methanol to give 41.91 g of title compound (1).(yield = 94.5 %) EXAMPLE 3Ethyl 2-[(octyloxyacetyl)amino]-4-aminobenzoate (compound 2)
[0089] To a mixture of 10.00 g of ethyl 2-[(octyloxyacetyl)amino]-4-nitrobenzoate (26.28rnmol) in 58 ml of 2-methoxyethanol and 16 ml of toluene was added 6.88 g of zinc powderat 20°C. After the mixture was stirred at 10°C, 0.53 g of triethylamine (5.71 mmol) wasadded keeping the temperature below 45°C for 1 hour. Further, the mixture was stirred at80°C for 3 hours. The reaction mixture was filtered and the filtrate was added toluene andwater, and extracted with toluene. The organic layer was concentrated under reduced pressure.The resulting crude product was crystallized from heptane to give 9.07 g of title compound(2). (yield = 98.4%) ¹H-NMR (CDCl₃, δ-TMS) 11.96 (S,1H), 8.13 (s. 1H), 7.88 (d, 1H, J=8.8 Hz), 6.32 (d, 1H, J=8.8 Hz), 4.35 (t, 2H, J=5.2Hz), 4.22 (bs, 2H), 4.07 (s, 2H), 3.74 (t, 2H, J=5.2 Hz), 1.80∼1.20 (m, 15H), 0.88 (t, 3H,J=6.8 Hz) IR (KBr, cm^-1) : 3350, 2850, 1725 Elemental analysis for: C₁₉H₃₀N₂O₄Calculated (%): C 65.11; H 8.63; N 7.99; O 18.26 Found (%): C 65.23; H 8.57; N 7.86; O 18.34
[0090] To a mixture of 10.00 g of ethyl 2-[(octyloxyacetyl)amino]-4-aminobenzoate (28.53mmol) in 50 ml of N, N-dimethylformamide was cooled at 0 to 5°C. After the mixture wasadded 0.99 g of sodium ethoxide (14.27 mmol), 2.20 g of dimethyl sulfate (17.12 mmol) wasadded sat -10 to -5°C. After the mixture was stirred at -10 to -5°C for 1 hour, 0.99 g of sodium ethoxide (14.27 mmol) and 2.20 g of dimethyl sulfate (17.12 mmol) was added s at -10 to -5°C. After the mixture was stirred at -10 to -5°C for 1 hour, 0.40 g of sodium ethoxide(5.71 mmol) and 0.88 g of dimethyl sulfate (6.85 mmol) was added s at -10 to -5°C. After themixture was stirred at -10 to -5°C for 1 hour, 0.40 g of sodium ethoxide (5.71 mmol) and0.88 g of dimethyl sulfate (6.85 mmol) was added s at -10 to -5°C. After the mixture wasstirred at -10 to -5°C for 1 hour, 5.00 g of sulfuric acid (1% solution in water), 50 ml of waterand 50 ml of toluene were added, and extracted with toluene. The organic layer wasconcentrated under reduced pressure. The resulting crude product was crystallized fromtoluene to give 8.54 g of title compound (3). (yield = 80.0%) ¹H-NMR (CDCl₃, δ-TMS) 7.94 (d, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 6.32 (d, 1H, J=1.6 Hz), 4.40 (s, 2H) 4.22 (m,2H), 3.85 (m, 2H), 3.40 (m, 2H), 3.18 (s, 3H), 1.80∼1.20 (m, 15H), 0.87 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 3350, 2850, 1725 Elemental analysis for: C₂₀H₃₂N₂O₄Calculated (%): C 65.90; H 8.85; N 7.69; O 17.56 Found (%): C 65.73; H 8.77; N 7.83; O 17.67
[0091] To the mixture of 8.20 g of 3, 5-dimethoxy-4-hydroxycinnamic acid (36.2 mmol) in30 ml of tetrahydrofuran and 0.265 g of N, N-dimethylformamide was cooled at 0°C. Themixture was added 4.31 g of tionyl chloride (36.2 mmol) at 0 to 10°C. After the mixture wasstirred at 0 to 10°C for 1 hour, a solution of 12.00 g of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-aminobenzoate(32.9 mmol) in 36 ml of tetrahydrofuran was added.After the mixture was stirred at 0 to 10°C for 30 minutes, 7.80 g of pyridine (82.2 mmol) wasadded. After the mixture was stirred at 0 to 10°C for 30 minutes, 60 ml of toluene and 60 mlof water were added, and extracted with toluene. The organic layer was concentrated underreduced pressure to give a crude product. Purification of this crude product by columnchromatography on silica gel (hexane / ethyl acetate=1/2 as an eluent) gave 17.66 g of titlecompound (4). (yield = 94.0%) ¹H-NMR (d₆-DMSO, δ -TMS) 10.52 (s, 1H), 8.94 (s, 1H), 7.96 (d, 1H, J=8.8 Hz), 7.83 (d, 1H, J=2.0 Hz), 7.76 (d, 1H, J=8.8Hz), 7.57 (d, 1H, J=15.6 Hz), 6.93 (s, 2H), 6.68 (d, 1H, J=15.6 Hz), 4.24 (q, 2H),3.85 (s, 6H), 3.78 (s, 3H), 3.68 (m, 2H), 3.38 (s, 3H), 3.27 (m, 2H), 1.40∼1.10 (m, 12H), 0.83(m, 3H) IR (KBr, cm^-1) : 3350, 1745, 1680, 1225 Elemental analysis for: C₃₁H₄₂N₂O₈Calculated (%): C 65.24; H 7.42; N 4.91; O 22.42 Found (%): C 65.35; H 7.35; N 4.96; O 22.34
[0092] To the solution of 5.0 g of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-aminobenzoate(13.72 mmol) in 15 ml of ethyl acetate was added 3.0 g of acetic anhydride atroom temperature for 2 hours. The reaction mixture was filtered and the flltrate wasconcentrated under reduced pressure. The resulting crude product was crystallized from ethylacetate and hexane to give 4.73 g of title compound (5). (yield = 85.0 %) ¹H-NMR (d₆-DMSO, δ -TMS) 10.52 (s, 1H), 7.94 (d, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 6.32 (d, 1H, J=1.6 Hz), 4.24 (q,2H), 3.78 (s, 3H), 3.68 (m, 2H), 3.38 (s, 3H), 3.27 (m, 2H), 2.34 (s3H), 1.40∼1.10 (m, 12H),0.83 (m, 3H) IR (KBr, cm^-1): 3350, 1745, 1680, 1225 Elemental analysis for: C₂₂H₃₄N₂O₅Calculated (%): C 65.00; H 8.43; N 6.89; O 19.68 Found (%): C 65.12; H 8.35; N 6.96; O 19.57
[0093] In accordance with EXAMPLE 4, ethyl 2-[(methoxyacetyl)amino]-4-nitrobenzoatewas used instead of Ethyl 2-[(octyloxyacetyl)amino]-4-aminobenzoate, the title compound(6) was obtained. ¹H-NMR (CDCl₃, δ -TMS) 9.68 (s, 1H), 8.21 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 4.23 (t, 2H, J=7.2 Hz), 4.13 (s,2H), 3.78 (s, 3H), 3.56 (s, 3H), 1.15 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 2850, 1740, 1550, 1345, 1225 Elemental analysis for: C₁₃H₁₆N₂O₆Calculated (%): C 52.70; H 5.44; N 9.46; O 32.40 Found (%): C 52.55; H 5.35; N 9.44; O 32.66
[0094] In accordance with EXAMPLE 4, ethyl 2-[(decyloxyacetyl)amino]-4-nitrobenzoatewas used instead of Ethyl 2-[(octyloxyacetyl)amino]-4-aminobenzoate, the title compound(7) was obtained. ¹H-NMR (CDCl₃, δ-TMS) 9.68 (s, 1H), 8.21 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 4.22 (m, 2H), 4.13 (m, 2H),3.63 (t, 2H, J=6.4 Hz), 3.56 (s, 3H), 1.80∼1.20(m, 19H), 0.88 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 2850, 1740, 1550, 1345, 1225 Elemental analysis for: C₂₂H₃₄N₂O₆Calculated (%): C 62.54; H 8.11; N 6.63; O 22.72 Found (%): C 62.55; H 8.05; N 6.43; O 22.97
[0095] In accordance with EXAMPLE 4, ethyl 2-[(methoxyacetyl)amino]-4-benylaminobenzoatewas used instead of Ethyl 2-[(octyloxyacetyl)amino]-4-aminobenzoate,the title compound (8) was obtained. ¹H-NMR (CDCl₃, δ-TMS) 8.13 (s, 1H), 7.88 (d, 1H, J=8.8 Hz), 7.22 (m, 5H), 6.32 (d, 1H, J=8.8 Hz), 5.23 (s, 1H), 5.15(s, 2H), 4.25 (t, 2H, J=5.2 Hz), 4.07 (s, 2H), 3.74 (s, 3H), 3.58 (s, 3H), 1.22 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 3350, 2850, 1725, 1225 Elemental analysis for: C₂₀H₂₄N₂O₄Calculated (%): C 67.39; H 6.79; N 7.86; O 17.96 Found (%): C 67.55; H 6.84; N 7.83; O 17.78
[0096] In accordance with EXAMPLE 1, ethyl 4-nitro-N-decyl-athranilate and butoxyacetic acid were used instead of ethyl 4-nitroanthranilate and octyloxyacetic acid, the titlecompound (9) was obtained. ¹H-NMR (CDCl₃, δ -TMS) 9.68 (s, 1H), 8.21 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 4.22 (m, 4H), 4.13 (s, 2H), 3.63(m, 2H), 2.25∼1.20 (m, 20H), 1.23 (t, 3H, J=7.0 Hz), 0.88 (m, 6H) IR (KBr, cm^-1) : 2850, 1740, 1550, 1345 Elemental analysis for: C₂₅N₄₀N₂O₆Calculated (%): C 64.63; H 8.63; N 6.03; O 20.66 Found (%): C 64.55; H 8.84; N 6.00; O 20.61
[0097] In accordance with EXAMPLE 1, ethyl 4-nitro-N-methyl-anthranilate andmethoxyacetic acid were used instead of ethyl 4-nitroanthranilate and octyloxyacetic acid, thetitle compound (10) was obtained. ¹H-NMR (CDCl₃, δ-TMS) 8.13 (s, 1H), 7.88 (d, 1H, J=8.8 Hz), 6.32 (d, 1H, J=8.8 Hz), 5.23 (s, 1H), 4.25 (t, 2H, J=5.2Hz), 4.07 (s, 2H), 3.74 (s, 3H), 3.58 (s, 3H), 2.25∼1.26 (m, 21H), 0.90 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 3350, 2850, 1725, 1225 Elemental analysis for: C₂₃H₃₈N₂O₄Calculated (%): C 67.94; H 9.42; N 6.89; O 15.74 Found (%): C 67.99; H 9.34; N 6.78; O 15.89
[0098] In accordance with EXAMPLE 1, ethyl 4-nitro-N-(2-propenyl)-anthranilate andmethoxyacetic acid were used instead of ethyl 4-nitroanthranilate and octyloxyacetic acid, thetitle compound (11) was obtained. ¹H-NMR (CDCl₃, δ-TMS) 9.68 (s, 1H), 8.21(d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 5.95 (m, 1H), 5.20∼5.02 (m, 2H),4.23(t, 2H, J=7.2 Hz), 4.13 (s, 2H), 3.78 (s, 3H), 3.45 (d, 2H, J=7.2 Hz), 1.15 (t, 3H, J=6.8Hz) IR (KBr, cm^-1) : 2850, 1740, 1550, 1345 Elemental analysis for: C₁₅H₁₈N₂O₆Calculated (%): C 57.48; H 5.43; N 8.38; O 28.72 Found (%): C 57.55; H 5.45; N 8.22; O 28.78
[0099] In accordance with EXAMPLE 3, ethyl 2-[N-geranyl-N-(ethoxyacetyl)amino]-4-nitrobenzoatewas used instead of Ethyl 2-(octyloxyacetyl)amino-4-nitrobenzoate, the titlecompound (12) was obtained. ¹H-NMR (CDCl₃, δ-TMS) 8.13 (s, 1H), 7.88 (d, 1H, J=8.8 Hz), 6.32 (d, 1H, J=8.8 Hz), 5.40 (m, 1H), 5.10 (m, 1H), 4.35(t, 2H, J=5.2 Hz), 4.22 (bs, 2H), 4.07 (s, 2H), 3.74 (t, 2H, J=5.2 Hz), 3.45 (m, 2H), 2.25∼1.55(m, 13H), 1.18 (m, 6H) IR (KBr, cm^-1) : 3350, 2850, 1725, 1225 Elemental analysis for: C₂₃H₃₄N₂O₄Calculated (%): C 68.63; H 8.51; N 6.96; O 15.90 Found (%): C 68.55; H 8.57; N 6.86; O 16.02
[0100] In accordance with EXAMPLE 1, ethyl 4-acetylamino -N-methyl-anthranilate andgeranyloxyacetic acid were used instead of ethyl 4-nitroanthranilate and octyloxyacetic acid,the title compound (13) was obtained. ¹H-NMR (CDCl₃, δ-TMS) 10.89 (s, 1H), 8.13 (S, 1H), 7.88 (d, 1H, J=8.8 Hz), 6.32 (d, 1H, J=8.8 Hz), 5.40 (m, 1H),5.10 (m, 1H), 4.13 (t, 2H, J=5.2 Hz), 4.07 (s, 2H), 3.74 (t, 2H, J=5.2 Hz),3.55 (s, 3H), 2.25∼1.55 (m, 13H), 2.23 (s, 3H), 1.18 (m, 3H) IR (KBr, cm^-1) : 3350, 2850, 1725, 1225 Elemental analysis for: C₂₄H₃₄N₂O₅Calculated (%): C 66.95; H 7.96; N 6.51; O 18.58 Found (%): C 66.89; H 7.97; N 6.45; O 18.69
[0101] In accordance with EXAMPLE 1, ethyl 4-(N,N-dimethyl)amino-N-methylanthranilatewas used instead of ethyl 4-nitroanthranilate, the title compound (14) wasobtained. ¹H-NMR (CDCl₃, δ-TMS) 7.94 (d, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 6.32 (d, 1H, 7=1.6 Hz), 4.27 (m, 2H), 4.06 (s,2H), 3.78 (m, 2H), 3.18 (s, 3H), 2.56 (s, 6H), 1.80∼1.20 (m, 15H), 0.87 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 2850, 1725, 1225 Elemental analysis for: C₂₂H₃₆N₂O₄Calculated (%): C 67.31; H 9.24; N 7.14; O 16.30 Found (%): C 67.34; H 9.14; N 7.13; O 16.39
[0102] In accordance with EXAMPLE 1, ethyl 4-vinylamino -N-methyl-anthranilate andmethoxyacetic acid were used instead ofethyl 4-nitroanthranilate and octyloxyacetic acid, thetitle compound (15) was obtained. ¹H-NMR (CDCl₃, δ -TMS) 7.88 (d, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 6.32 (d, 1H, J=1.6 Hz), 6.23 (m, 1H),5.26 (s, 1H), 4.90 (m, 1H), 4.56 (m, 1H), 4.25 (t, 2H, J=5.2 Hz), 4.07 (s, 2H), 3.74 (s, 3H),3.58 (s, 3H), 1.22 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 2850, 1725, 1225 Elemental analysis for: C₁₅H₂₀N₂O₄Calculated (%): C 61.63; H 6.90; N 9.58; O 21.89 Found(%): C 61.55; H 6.84; N 9.43; O 22.18
[0103] In accordance with EXAMPLE 1, ethyl 4-geranylamino -N-methylanthranilate andmethoxyacetic acid were used instead of ethyl 4-nitroanthranilate and octyloxyacetic acid, thetitle compound (16) was obtained. ¹H-NMR (CDCl₃, δ -TMS) 7.88 (d, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 6.32 (d, 1H, J=1.6 Hz), 6.23 (m, 1H), 5.45 (m,1H), 5.26 (s, 1H), 5.08 (m, 1H), 4.25 (t, 2H, J=5.2 Hz), 4.10 (d, 2H, J=7.5 Hz),4.07 (s, 2H), 3.58 (s, 3H), 2.25∼1.55 (m, 13H), 1.22 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 2850, 1725, 1225 Elemental analysis for: C₂₃H₃₄N₂O₄Calculated (%): C 68.63; H 8.51; N 6.96; O 15.90 Found (%): C 68.55; H 8.64; N 6.93; O 15.88
[0104] In accordance with EXAMPLE 5, 3, 4, 5-trimethoxycinnamic acid was used insteadof 3, 5-dimethoxy-4-hydroxycinnamic acid, the title compound (17) was obtained. ¹H-NMR (d₆-DMSO, δ -TMS) 10.52 (s, 1H), 7.96 (d, 1H, J=8.8 Hz), 7.83 (d, 1H, J=2.0 Hz), 7.76 (d, 1H, J=8.8 Hz),7.57 (d, 1H, 15.6 Hz), 6.93 (s, 2H), 6.68 (d, 1H, J=15.6 Hz), 4.24 (q, 2H), 3.78 (s, 9H), 3.78(s, 3H), 3.68 (m, 2H), 3.38 (s, 3H), 3.27 (m, 2H), 1.40∼1.10 (m, 12H), 0.83 (m, 3H) IR (KBr, cm^-1) : 3350, 1745, 1680, 1225 Elemental analysis for: C₃₃H₄₄N₂O₈Calculated (%): C 65.73; H 7.59; N 4.79; O 21.89 Found (%): C 65.67; H 7.55; N 4.86; O 21.92
[0105] To a solution 16.25 g of potassium tert-butoxide (114.9 mmol) in 97 ml oftetrahydrofuran was stirred at room temperature. After the solution was cooled at 0°C, asolution of 18.77 g of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate(32.9 mmol) in 56 ml of tetahydrofuran was added at 0 to 10°C. After the mixture was stirred at 0 to 10°C for 30 minutes, 85 g of 2 mol / l ofaqueous hydrogen chloride solution was added, and extracted with 38 ml of ethyl acetate.The organic layer was washed with 60 g of 1%-NaCl solution in water, and concentratedunder reduced pressure to give a crude product. The resulting crude product was crystallizedfrom 2-propanol to give 15.87 g of title compound (18). (yield = 92.0%) ¹H-NMR (d₆-DMSO, δ -TMS) 10.39 (s, 1H), 10.29 (s, 1H), 8.92 (s, 1H), 7.99 (s, 1H), 7.85 (d, 1H, J=8.8 Hz),7.53 (d, 1H, J=15.6 Hz), 7.49 (s, 1H), 6.93 (s, 2H), 6.75 (d, 1H, J=15.6 Hz), 3.92 (t, 2H,J=6.8 Hz), 3.82 (s, 6H), 3.54 (s, 3H), 1.68 (m, 2H), 1.25 (m, 10H), 0.86 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1) : 3550, 2940, 1600, 1515, 1250 Elemental analysis for: C₂₉H₃₆N₂O₇Calculated (%): C 66.39; H 6.92; N 5.34; O 21.35 Found (%): C 66.45; H 7.08; N 4.96; O 21.51
[0106] To a mixture of 5.80 g of sodium hydride (purity 60%, 114.9 mmol) in 90 ml oftetrahydrofuran was added a solution of 18.77 g of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate(32.9mmol) in 56 ml of tetrahydrofuran at 0 to 10°C. After the mixture was stirred at 0 to 10°C for30 minutes, 85 g of 2 mol / l of aqueous hydrogen chloride solution was added, and extractedwith 38 ml of ethyl acetate. The organic layer was washed with 60 g of 1%-NaCl solution inwater, and concentrated under reduced pressure to give a crude product. The resulting crudeproduct was crystallized from 2-propanol to give 15.70 g of title compound (18). (yield =92.0%) EXAMPLE 217-[(3,5-dimethoxy-4-hydroxy-cinnamoyl)amino]-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone(compound 18)
[0107] To a solution of 144.9 mmol of LHDS in 150 ml of tetrahydrofuran was added asolution of 18.77 g of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate(32.9 mmol) in 56 ml of tetrahydrofuran at -40°C. After the mixture was stirred at -40°C for 30 minutes, 85 g of 2 mol / l of aqueous hydrogenchloride solution was added, and extracted with 38 ml of ethyl acetate. The organic layer waswashed with 60 g of 1%-NaCl solution in water, and concentrated under reduced pressure togive a crude product. The resulting crude product was crystallized from 2-propanol to give16.05 g of title compound (18). (yield = 93.0%) EXAMPLE 227-[(3,5-dimethoxy-4-hydroxy-cinnamoyl)amino]-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone(compound 18)
[0108] To a solution of 144.9 mmol of LDA in 150 ml of tetrahydrofuran was added asolution of 18.77 g of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4hydroxycinnamoyl)amino]-benzoate (32.9 mmol) in 56 ml of tetrahydrofuran at -40°C.After the mixture was stirred at -40°C for 30 minutes, 85 g of 2 mol / l of aqueous hydrogenchloride solution was added, and extracted with 38 ml of ethyl acetate. The organic layer waswashed with 60 g of 1%-NaCl solution in water, and concentrated under reduced pressure togive a crude product. The resulting crude product was crystallized from 2-propanol to give15.18 g of title compound (18). (yield = 88.0%) EXAMPLE 237-acetylamino-3-octyloxy-4-hydroxy-1-methyI-2(1H)-quinolinone (compound 19)
[0109] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-acetylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (19) was obtained. ¹H-NMR (d₆-DMSO, δ -TMS) 10.28 (s, 1H), 10.23 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H, J=8.8 Hz), 7.42 (d, 1H J=8.8 Hz),3.94 (t, 2H, J=6.8 Hz), 3.52 (s, 3H), 2.10 (s, 3H), 1.69 (m, 2H), 1.25 (m, 10H),0.86 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250 Elemental analysis for; C₂₀H₂₈N₂O₄Calculated (%); C 66.64; H 7.83; N 7.77; O 17.76 Found (%): C 66.55; H 7.78; N 7.86; O 17.81
[0110] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-benzoylaminobenzoatewas used instead ofethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (20) wasobtained. ¹H-NMR (d₆-DMSO, δ -TMS) 10.28 (s, 1H), 10.23 (s, 1H), 8.10 (m, 2H), 7.85 (s,1H), 7.80 (d, 1H, J=8.8 Hz), 7.60∼7.45 (m,3H), 7.42 (d, 1H, J=8.8 Hz), 3.94 (t, 2H, J=6.8 Hz), 3.52 (s, 3H), 1.69 (m, 2H), 1.25 (m, 10H),0.86 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250 Elemental analysis for: C₂₅H₃₀N₂O₄Calculated (%): C 71.06; H 7.16; N 6.63; O 15.15 Found (%): C 71.00; H 7.28; N 6.56; O 15.16
[0111] In accordance with EXAMPLE 20, ethyl 2-[N-ethyl-N-(methoxyacetyl)amino]-4-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (21) was obtained. ¹H-NMR (d₆-DMSO, δ -TMS) 11.05 (s, 1H), 8.05 (m, 3H), 3.75 (s, 3H), 3.68 (d, 2H, J=6.8 Hz), 1.23 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₂H₁₂N₂O₅Calculated (%): C 54.54; H 4.58; N 10.60; O 30.28 Found (%): C 54.44; H 4.65; N 10.56; O 30.35
[0112] In accordance with EXAMPLE 21, ethyl 2-[N-octyl-N-(methoxyacetyl)amino]-5-nitrobenzoatewas used instead of ethyl 2[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (22) was obtained. ¹H-NMR (d₆-DMSO, δ -TMS) 11.05 (s, 1H), 8.05 (m, 3H), 3.75 (s, 3H), 3.68 (d, 2H, J=6.8 Hz), 1.87∼1.23 (m, 12H), 0.90 (t,3H, J=6.9 Hz) IR (KBr, cm^-1): 3500, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₈H₂₄N₂O₅Calculated (%): C 62.05; H 6.94; N 8.04; O 22.96 Found (%): C 62.00; H 7.08; N 8.02; O 22.90
[0113] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(ethoxyacetyl)amino]-6-aminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (23) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.88∼7.50 (m, 3H), 5.90 (bs, 2H), 4.23 (q, 2H, J=6.8 Hz), 3.65 (s, 3H), 1.23 (t,3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₁₂H₁₄N₂O₃Calculated (%): C 61.52; H 6.02; N 11.96; O 20.49 Found (%): C 61.55; H 6.07; N 11.78; O 20.60
[0114] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(phenoxyacetyl)amino]-5-aminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (24) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.90∼7.23 (m, 8H), 5.65 (bs, 2H), 3.65 (s, 3H), IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₆H₁₄N₂O₃Calculated (%): C 68.07; H 5.00; N 9.92; O 17.00 Found (%): C 68.00; H 5.18; N 9.89; O 16.93
[0115] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(ethoxyacetyl)amino]-6-acetylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (25) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.07 (s, 1H), 10.85 (s, 1H), 7.90∼7.23 (m, 3H), 4.22 (m, 2H), 3.65 (s, 3H), 2.35 (s, 3H), 1.23(t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₄H₁₆N₂O₄Calculated (%): C 60.86; H 5.84; N 10.14; O 23.16 Found (%): C 60.99; H 5.78; N 10.09; O 23.14
[0116] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(phenoxyacetyl)amino]-5-acetylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (26) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.07 (s, 1H< 10.85 (s, 1H9, 7.90∼7.23 (m, 8H), 3.65 (s, 3H), 2.35 (s, 3H), IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₈H₁₆N₂O₄Calculated (%): C 66.66; H 4.97; N 8.64; O 19.73 Found (%): C 66.54; H 4.90; N 8.66; O 19.90
[0117] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(ethoxyacetyl)amino]-6-propenylaminobenzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (27) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H, 7.90∼7.23 (m, 3H), 5.96 (m, 1H), 5.26 (m, 3H), 4.22 (m, 2H), 3.88 (m, 2H),3.65 (s, 3H), 1.23 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₅H₁₈N₂O₃Calculated (%): C 65.67; H 6.61; N 10.21; O 17.50 Found (%): C 65.55; H 6.64; N 10.34; O 17.47
[0118] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(phenoxyacetyl)amino]-5-benzylaminobenzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (28) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.90∼7.15 (m, 13H), 5.26 (s, 1H), 3.65 (s, 3H), 3.45 (m, 2H) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₂₃H₃₃N₂O₃Calculated (%): C 74.17; H 5.41; N 7.52; O 12.89 Found (%): C 74.00; H 5.48; N 7.56; O 12.96
[0119] In accordance with EXAMPLE 19, ethyl 2-[N-ethyl-N-(ethoxyacetyl)amino]-6-hydroxybenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (29) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.07 (s, 1H), 10.75 (s, 1H), 7.65∼7.13 (m, 3H), 4.22 (m, 2H), 3.65 (t, 2H), 1.23 (m, 6H) IR(KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₃H₁₅N₁O₄Calculated (%): C 62.64; H 6.07; N 5.62; O 25.68 Found (%): C 62.68; H 6.05; N 5.56; O 25.71
[0120] In accordance with EXAMPLE 20, ethyl 2[N-methyl-N-(octyloxyacetyl)amino]-4-hydroxybenzoatewas used instead of ethyl 2[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (30) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.23 (s, 1H), 9.98 (s, 1H), 7.85 (s, 1H), 7.76 (d, 1H, J=7.2 Hz), 7.50 (d, 1H, J=7.2 Hz), 4.23(d, 2H, J=7.6 Hz), 3.54 (s, 3H), 1.86∼1.45 (m, 12H), 0.97 (t, 3H, J=7.5 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₈H₂₅N₁O₄Calculated (%): C 67.69; H 7.89; N 4.39; O 20.04 Found (%): C 67.78; H 7.78; N 4.44; O 20.00
[0121] In accordance with EXAMPLE 20, ethyl 2-[N-ethyl-N-(ethoxyacetyl)amino]-6-phenoxybenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (31) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.75 (s, 1H), 7.65∼7.13 (m, 8H), 4.22 (m, 2H), 3.65 (t, 2H), 1.23 (m, 6H) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₉H₁₉N₂O₄Calculated (%): C 70.14; H 5.89; N 4.31; O 19.67 Found (%): C 70.08; H 5.78; N 4.46; O 19.68
[0122] In accordance with EXAMPLE 21, ethyl 2[N-methyl-N-(octyloxyacetyl)amino]-4-methoxybenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (32) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.23 (s, 1H), 7.85 (s, 1H), 7.76 (d, 1H, J=7.2 Hz), 7.50 (d, 1H, J=7.2 Hz), 4.23 (d, 2H, J=7.6Hz), 3.78 (s, 3H), 3.54 (s, 3H), 1.86∼1.45 (m, 12H), 0.97 (t, 3H, J=7.5 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₉H₂₇N₁O₄Calculated (%): C 68.44; H 8.16; N 4.20; O 19.20 Found (%): C 68.24; H 8.28, N 4.21; O 19.27
[0123] In accordance with EXAMPLE 21, ethyl 2-[N-propenyl-N-(octyloxyacetyl)amino]-4-butoxybenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (33) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.02 (s, 1H), 7.85 (s, 1H), 7.76 (d, 1H J=7.2 Hz), 7.50 (d, 1H, J=7.2 Hz), 5.95 (m, 1H), 5.10(m, 2H), 4.23 (m, 4H), 3.30 (d, 2H, J=7.2 Hz), 1.86∼1.45 (m, 16H9, 0.97 (m, 6H) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₂₄H₃₅N₁O₄Calculated (%): C 71.79; H 8.79; N 3.49; O 15.94 Found (%): C 71.67; H 8.66; N 3.48; O 16.19
[0124] In accordance with EXAMPLE 22, ethyl 2-[N-octyl-N-(phenoxyacetyl)amino]-5phenylbenzoate was used instead of ethyl 2[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (34) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.90∼7.15 (m, 13H), 3.65 (d, 2H, J=6.8 Hz), 1.84∼1.23 (m, 12H), 0.90 (t, 3H,J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₂₉H₃₁N₁O₄Calculated (%): C 76.12; H 6.83; N 3.06; O 13.99 Found (%): C 76.01; H 6.87; N 3.05; O 14.07
[0125] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-methylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (35) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.23 (s, 1H), 7.85 (s, 1H), 7.76 (d, 1H, J=7.2 Hz), 7.50 (d, 1H, J=7.2 Hz), 4.23 (d, 2h, J=7.6Hz), 3.54 (s, 3H), 2.25 (s, 3H), 1.86∼1.45 (m, 12H), 0.97 (t, 3H, J=7.5Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₉H₂₇N₁O₃Calculated (%): C 71.89; H 8.57; N 4.41; O 15.12 Found (%): C 71.77; H 8.43; N 4.45; O 15.35
[0126] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4,6-dihydroxy-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (36) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.23 (s, 1H), 10.87 (s, 1H), 10.23 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 3.89 (s, 3H), 3.64 (s,3H) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₁₁H₁₁N₁O₅Calculated (%): C 71.06; H 7.16; N 6.63; O 15.15 Found (%): C 71.00; H 7.28; N 6.56; O 15.16
[0127] In accordance with EXAMPLE 19, ethyl 2[N-benzyl-N-(geranyloxyacetyl)amino]-4,6-dibenzyloxy-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amlno]-benzoate, the title compound (37) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.87 (s, 1H), 7.65∼7.13 (m, 23H), 5.40 (m, 1H), 4.12 (m, 2H), 2.15∼1.60 (m, 13H) IR (KBr, cm^-1): 3550, 2940, 1610, 1250, 1100 Elemental analysis for: C₄₀H₄₁N₁O₅Calculated (%): C 78.02; H 6.71; N 2.27; O 12.99 Found (%): C 78.00; H 6.78; N 2.34; O 12.88
[0128] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-6-ethoxycarbonylbenzoatewas used instead ofethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (38) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.68 (s, 1H), 7.88∼7.55 (m, 3H), 4.22 (t, 2h, J=6.9 Hz), 3.84 (t, 2H, J=6.8 Hz), 3.62 (s, 3H),1.78∼1.34 (m, 4H), 1.22 (t, 3H, J=6.8 Hz), 0.96 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1715, 1610, 1250, 1100 Elemental analysis for: C₄₀H₄₁N₁O₅Calculated (%): C 63.93; H 6.63; N 4.39; O 25.05 Found (%): C 63.99; H 6.56; N 4.23; O 25.22
[0129] In accordance with EXAMPLE 21, ethyl 2-[N-(2-hydroxyethyl)-N-(methoxyacetyl)amino]-4-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (39) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.05 (s, 1H), 8.05 (m, 3H), 3.75 (s, 3H), 3.68 (s, 3H), 2.88 (m, 2H) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1400, 1250 Elemental analysis for: C₁₂H₁₂N₂O₆Calculated (%): C 51.43; H 4.32; N 9.99; O 34.26 Found (%): C 51.33; H 4.35; N 10.01; O 34.31
[0130] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-acetylaminobenzoateand magnesium ethoxide were used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate andpotassium tert-butoxide, the title compound (19) was obtained. EXAMPLE 457-acetylamino-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone (compound 19)
[0131] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-acetylaminobenzoateand calcium hydridewere used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate andsodium hydride, the title compound (19) was obtained. EXAMPLE 465-nitro-3-methoxy-4-hydroxy-1-ethyl-2(1H)-quinolinone (compound 40)
[0132] In accordance with EXAMPLE 25, ethyl 2-[N-ethyl-N-(methoxyacetyl)amino]-6-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (40) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.05 (s, 1H), 8.09 (m, 3H), 3.75 (s, 3H), 3.68 (d, 2H, J=6.8 Hz), 1.23 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₂H₁₂N₂O₅Calculated (%): C 54.54; H 4.58; N 10.60; O 30.28 Found (%): C 54.43; H 4.58; N 10.67; O 30.45
[0133] In accordance with EXAMPLE 19, ethyl 2-[N-decyl-N-(butoxyacetyl)amino]-5-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (41) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.05 (s, 1H), 8.09 (m, 3H), 4.12 (d, 2H, J=6.8 Hz), 3.75 (d, 2H, J=6.9 Hz), 2.23∼1.23 (m,20H), 0.90 (m, 6H) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₂₃H₃₄N₂O₅Calculated (%): C 66.00; H 8.19; N 6.69; O 19.12 Found (%): C 66.09; H 8.09; N 6.67; O 19.15
[0134] In accordance with EXAMPLE 19, ethyl 2-[N-benzyl-N-(methoxyacetyl)amino]-3-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]benzoate,the title compound (42) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.05 (s, 1H), 8.09 (m, 3H), 7.25 (m, 5H), 5.23 (s, 2H), 3.89 (s, 3H) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₇H₁₄N₂O₅Calculated (%): C 62.57; H 4.32; N 8.59; O 24.52 Found (%): C 62.45; H 4.45; N 8.67; O 24.43
[0135] In accordance with EXAMPLE 19, ethyl 2-[N-(6-hydroxyhexyl)-N-(butoxyacetyl)amino]-5-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (43) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.05 (s, 1H), 8.05 (m, 3H), 4.12 (d, 2H, j=6.8 Hz), 3.87 (m, 3H), 3.75 (d, 2H, J=6.9 Hz),2.23∼1.23 (m, 12H), 0.90 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₉H₂₅N₂O₆Calculated (%): C 60.30; H 6.93; N 7.40; O 25.38 Found (%): C 60.24; H 7.09; N 7.28; O 25.39
[0136] In accordance with EXAMPLE 20, ethyl 2-[N-geranyl-N-(ethoxyacetyl)amino]-6-aminobenzoatewas used instead ofethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (44) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.87 (s, 1H), 7.65∼7.06 (m, 3H), 5.40 (m, 1H), 5.25 (m, 2H), 5.10 (m, 1H), 4.12 (m, 2H),3.34 (m, 2H), 2.15∼1.60 (m, 13H), 1.23 (t, 3H, J=7.2 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₂₁H₂₈N₂O₃Calculated (%): C 70.76; H 7.92; N 7.86; O 13.47 Found (%): C 70.74; H 7.89; N 7.78; O 25.39
[0137] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-3-aminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (45) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.87 (s, 1H), 7.65∼7.06 (m, 3H), 5.40 (m, 1H), 5.25 (m, 2H), 5.10 (m, 1H), 4.23 (m, 2H),3.67 (s, 3H), 2.15∼1.60 (m, 13H) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₂₀H₃₅N₂O₃Calculated (%): C 70.15; H 7.65; N 8.18; O 14.02 Found (%): C 70.18; H 7.79; N 7.98; O 14.05
[0138] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,4,5-trimethoxycinnamoyl)amino]-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (46) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.39 (s, 1H), 8.92 (s, 1H), 7.99 (s, 1H), 7.85 (d, 1H, J=8.8 Hz), 7.53 (d, 1H, J=15.6 Hz),7.49 (s, 1H), 6.93 (s, 2H), 6.75 (d, 1H, J=15.6 Hz), 3.92 (t, 2H, J=6.8 Hz), 3.78 (s, 9H), 3.54(s, 3H), 1.68 (m, 2H), 1.25 (m, 10H), 0.86 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1600, 1515, 1250, 1100 Elemental analysis for: C₃₀H₃₈N₂O₇Calculated (%): C 66.89; H 7.12; N 5.20; O 20.79 Found (%): C 66.78; H 7.08; N 5.23; O 20.91
[0139] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(benzyloxyacetyl)amino]-6-methylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]benzoate, the title compound (47) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.88∼7.20 (m, 8H), 5.70 (bs, 1H), 5.15 (s, 2H), 3.65 (s, 3H), 2.78 )s, 3H) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1100 Elemental analysis for: C₁₈H₁₈N₂O₃Calculated (%): C 69.66; H 5.85; N 9.03; O 15.47 Found (%): C 69.78; H 5.78; N 9.00; O 15.44
[0140] In accordance with EXAMPLE 21, ethyl 2-[N-ethyl-N-(3, 5-dimethylbenzyloxyacetyl)amino]-6-hexylaminobenzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (48) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.88∼7.20 (m, 6H), 5.65 (bs, 1H), 5.13 (s, 2H), 3.65 (d, 2H, J=7.2 Hz), 2.89 (t,2H, J=6.9 Hz), 1.86∼1.23 (m, 8H), 2.18 (s, 6H), 1.15 (t, 3H, J=7.2 Hz), 0.90 (t, 3H, J=6.9 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₆H₃₄N₂O₃Calculated (%): C 73.90; H 8.11; N 6.63; O 11.36 Found (%): C 73.88; H 8.05; N 6.69; O 11.38
[0141] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-5-decylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (49) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.88∼7.40 (m, 3H), 5.65 (bs, 1H), 3.79 (s, 3H), 3.65 (s, 3H), 2.78 (t, 2H, J=6.9Hz), 1.89∼1.18 (m, 16H), 0.90 (t, 3H, J=6.9 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₁H₃₂N₂O₃Calculated (%): C 69.97; H 8.95; N 7.77; O 13.32 Found (%): C 69.98; H 8.95; N 7.58; O 13.49
[0142] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-5-vinylaminobenzoatewas used instead of ethyl 2-[N-methyI-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (50) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.88∼7.40 (m, 3H), 6.23 (m, 1H), 5.26 (s, 1H), 4.90 (m, 1H), 4.56 (m, 1H),3.87 (s, 3H), 3.65 (s, 3H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₁₃H₁₄N₂O₃Calculated (%): C 63.40; H 5.73; N 11.38; O 19.49 Found (%): C 63.39; H 5.78; N 11.45; O 19.38
[0143] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-5-(3,5-dimethylbenzylamino)-benzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (51) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.88∼7.20 (m, 6H), 5.65 (bs, 1H), 3.78 (s, 3H), 3.56 (s, 3H), 3.06 (s, 2H), 2.18(s, 6H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₀H₂₂N₂O₃Calculated (%): C 70.98; H 6.55; N 8.28; O 14.18 Found (%): C 71.01; H 6.45; N 8.33; O 14.21
[0144] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-5-geranylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (52) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.68∼7.20 (m, 3H), 5.65 (bs, 1H), 5.45 (m, 1H), 5.08 (m, 1H), 3.78 (s, 3H),3.56 (s, 3H), 3.34 (d, 2H, J=7.5 Hz), 2.25∼1.55 (m, 13H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₁H₂₈N₂O₃Calculated (%): C 70.76; H 7.92; N 7.86; O 13.47 Found (%): C 70.67; H 7.96; N 7.87; O 13.50
[0145] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(geranyloxyacetyl)amino]-3-butylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (53) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.68∼7.20 (m, 3H), 5.58 (bs, 1H), 5.45 (m, 1H), 5.08 (m, 1H), 4.12 (d, 2H,J=7.5 Hz), 3.56 (s, 3H), 2.89 (d, 2H, J=7.2 Hz), 2.25∼1.55 (m, 17H), 0.90 (t, 3H, J=6.9 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₄H₃₄N₂O₃Calculated (%): C 72.33; H 8.60; N 7.03; O 12.04 Found (%): C 72.18; H 8.59; N 7.07; O 12.16
[0146] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-5-decyloxybensoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (54) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.68∼7.20 (m, 3H), 4.18 (d, 2H, J=7.2 Hz), 3.80 (d, 2H), 3.56 (s, 3H),1.86∼1.18 (m, 16H), 0.90 (t, 3H, J=6.9 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₁H₃₁N₁O₄Calculated (%): C 69.77; H 8.65; N 3.88; O 17.71 Found (%): C 69.68; H 8.59; N 3.90; O 17.83
[0147] In accordance with EXAMPLE 20, ethyl 2-[N-octyl-N-(phenoxyacetyl)amino]-5-(2-propenyloxy)-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (55) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20 (m, 8H), 5.80 (m, 1H), 5.25 (m, 2H), 4.45 (m, 2H), 3.67 (t, 2H,J=7.4 Hz), 1.86∼1.18 (m, 12H), 0.90 (t, 3H, J=6.9 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₆H₃₁N₁O₄Calculated (%): C 74.08; H 7.41; N 3.32; O 15.18 Found (%): C 74.10; H 7.43; N 3.40; O 15.07
[0148] In accordance with EXAMPLE 21, ethyl 2-[N-benzyl-N-(geranyloxyacetyl)amino]-3-benzylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (56) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20 (m, 13H), 5.40 m, 1H), 5.10 (m, 1H), 5.20(s, 2H), 4.24 (t, 2H, J=7.4Hz), 3.67 (s, 2H), 2.15∼1.45 (m, 13H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₃₃H₃₅N₁O₄Calculated (%): C 77.77; H 6.92; N 2.75; O 12.56 Found (%): C 77.88; H 6.89; N 2.76; O 12.47
[0149] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-methylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (57) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20 (m, 3H), 3.78 (s, 3H), 3.65 (s, 3H), 2.15 (s, 3H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₁₂H₁₃N₁O₃Calculated (%): C 65.74; H 5.98; N 6.93; O 21.89 Found (%): C 65.77; H 5.89; N 6.55; O 21.79
[0150] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-hexylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (58) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20 (m, 3H), 3.74 (s, 3H), 3.65 (s, 3H), 2.22 (d, 2H, J=7.0 Hz),1.78∼1.23 (m, 8H), 0.89 (t, 3H, J=7.0 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₁₇H₂₃N₁O₃Calculated (%): C 70.56; H 8.01; N 4.84; O 16.59 Found (%): C 70.55; H 7.97; N 4.87; O 16.61
[0151] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-4-decylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (59) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20 (m, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 2.14 (d, 2H, J=7.0 Hz),1.78∼1.23 (m, 16H), 0.89 (t, 3H, J=7.0 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₁H₃₁N₁O₃Calculated (%): C 73.00; H 9.05; N 4.05; O 13.89 Found (%): C 72.89; H 8.97; N 4.03; O 14.11
[0152] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-5-(2-propenyl)-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (60) wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20 (m, 3H), 6.06 (m, 1H), 5.33 (m, 1H), 5.15 (m, 1H), 3.74 (s, 3H),3.69 (s, 3H), 3.23 (m, 2H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₁₄H₁₅N₁O₃Calculated (%): C 68.55; H 6.16; N 5.71; O 19.57 Found (%): C 68.45; H 6.23; N 5.69; O 19.63
[0153] In accordance with EXAMPLE 22, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-5-geranylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (61) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.15 (m, 3H), 5.42 (m, 1H), 5.10 (m, 1H), 3.74 (s, 3H), 3.69 (s, 3H),2.23∼1.55 (m, 15H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₁H₂₇N₁O₃Calculated (%): C 73.87; H 7.97; N 4.10; O 14.06 Found (%): C 73.78; H 7.87; N 4.09; O 14.26
[0154] In accordance with EXAMPLE 19, ethyl 2-[N-ethyl-N-(ethoxyacetyl)amino]-6-butylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (62) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.78 (s, 1H), 7.75∼7.15 (m, 3H), 4.23 (d, 2H, J=7.3 Hz), 3.68 (d, 2H, J=6.8 Hz), 2.34 (d, 2H,J=7.1 Hz), 1.85∼1.23 (m, 10H), 0.90 (t, 3H, J=6.9 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₁₇H₂₃N₁O₃Calculated (%): C 70.56; H 8.01; N 4.84; O 16.59 Found (%): C 70.45; H 7.99; N 4.89; O 16.67
[0155] In accordance with EXAMPLE 20, ethyl 2-[N-benzyl-N-(geranyloxyacetyl)amino]-3-methylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (63) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.78 (s, 1H), 7.79∼7.15 (m, 8H), 4.33 (s, H), 4.24 (d, 2H, J=7.3 Hz), 2.34 (d, 2H, J=7.1 Hz),2.25 (s, 3H), 2.34∼1.56 (m, 13H) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₇H₃₁N₁O₃Calculated (%): C 77.66; H 7.48; N 3.35; O 11.50 Found (%): C 77.65; H 7.39; N 3.32; O 11.64
[0156] In accordance with EXAMPLE 21, ethyl 2-[N-(2-propenyl)-N-(octyloxyacetyl)amino]-4-butylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (64) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.78 (s, 1H), 7.80∼7.15 (m, 3H), 5.95 (m, 1H), 5.20∼5.00 (m, 2H), 4.24 (d, 2H, J=7.3 Hz),3.89 (m, 2H), 2.25 (t, 2H, J=7.2 Hz), 1.80∼1.25 (m, 16H), 0.89 (m, 6H) IR (KBr, cm^-1): 3550, 2940, 1610, 1105 Elemental analysis for: C₂₄H₃₅N₁O₃Calculated (%): C 74.76; H 9.15; N 3.63; O 12.45 Found (%): C 74.75; H 9.09; N 3.52; O 12.64
[0157] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(2-pyridyloxyacetyl)amino]-4-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (65) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.78 (s, 1H), 8.56 (m, 1H), 8.15∼7.23 (m, 6H), 3.58 (s, 3H) IR (KBr, cm^-1): 3550, 2940, 1550, 1255 Elemental analysis for: C₁₅H₁₁N₃O₅Calculated (%): C 57.51; H 3.54; N 13.42; O 25.54 Found (%): C 57.65; H 3.49; N 13.35; O 25.51
[0158] In accordance with EXAMPLE 21, ethyl 2-[N-(2-franyl)-N-(methoxyacetyl)amino]-4-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (66) was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.78 (s, 1H), 8.15∼7.69 (m,3H), 7.28 (m, 1H), 6.25 (m, 1H), 5.85 (m, 1H), 3.78 (s, 3H), 2.56(s, 2H) IR (KBr, cm^-1): 3550, 2920, 1550, 1255 Elemental analysis for: C₁₅H₁₂N₂O₆Calculated (%): C 56.96; H 3.82; N 8.86; O 30.35 Found (%): C 56.85; H 3.89; N 8.89; O 30.37
[0159] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-6-phenoxycarbonylbenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (67)wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.68 (s, 1H), 7.88∼7.35 (m, 8H), 3.84 (t, 2H, J=6.8 Hz), 3.62 (s, 3H), 1.78∼1.34 (m, 4H),0.96 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2920, 1715, 1610, 1250, 1100 Elemental analysis for: C₂₀H₂₁N₁O₅Calculated (%): C 67.59; H 5.69; N 3.94; O 22.51 Found (%): C 67.45; H 5.99; N 3.97; O 22.59
[0160] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-6-decyloxycarbonyl-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (68)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.68 (s, 1H), 7.88∼7.45 (m, 3H), 4.23 (t, 2H, J=6.8 Hz), 3.84 (t, 2H, J=6.8 Hz), 3.62 (s, 3H),1.78∼1.34 (m, 20H), 0.96 (m, 6H) IR (KBr, cm^-1): 3550, 2940, 1715, 1610, 1250, 1100 Elemental analysis for: C₂₄H₃₇N₁O₅Calculated (%): C 68.70; H 8.89; N 3.34; O 19.07 Found (%): C 68.64; H 8.79; N 3.23; O 19.34
[0161] In accordance with EXAMPLE 21, ethyl 2-[N-(3, 5-dimethylbenzyl)-N-(ethoxyacetyl)amino]-6-hexylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (69)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.78 (s, 1H), 7.79∼7.20 (m, 6H), 5.65 (bs, 1H), 3.65 (d, 2H, J=7.2 Hz), 3.33 (s, 2H), 2.89 (t,2H, J=6.9 Hz), 1.86∼1.23 (m, 8H), 2.25 (s, 6H), 1.15 (t, 3H, J-7.2 Hz), 0.90 (t, 3H, J-6.9 Hz) IR (KBr, cm^-1): 3550, 2940, 1715, 1610, 1100 Elemental analysis for: C₂₆H₃₄N₂O₃Calculated (%): C 73.90; H 8.11; N 6.63; O 11.36 Found (%): C 73.89; H 8.10; N 6.58; O 11.43
[0162] In accordance with EXAMPLE 1, ethyl 2-benzylamino-4-nitrobenzoate andmethoxyacetic acid were used instead of ethyl 4-nitrobenzoate and octyloxyacetic acid, thetitle compound (70) was obtained. ¹H-NMR (CDCl₃, δ -TMS) 9.55 (s, 1H), 8.21 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 7.25 (m, 5H), 4.23 (t, 2H, J=7.2Hz), 4.13 (s, 2H), 3.78 (s, 3H), 3.33 (s, 2H), 1.15 (t 3H, J=6.8 Hz) IR (KBr, cm^-1): 2850, 1740, 1550, 1345, 1225 Elemental analysis for: C₁₉H₂₀N₂O₆Calculated (%): C 61.28; H 5.41; N 7.52; O 25.78 Found (%): C 61.24; H 5.35; N 7.45; O 25.96
[0163] In accordance with EXAMPLE 1, ethyl 2-methylamino-4-nitrobenzoate andphenoxyacetic acid were used instead of ethyl 4-nitrobenzoate and octyloxyacetic acid, thetitle compound (71) was obtained. ¹H-NMR (CDCl₃, δ -TMS) 9.55 (s,1H), 8.18 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 7.35 (m, 5H), 4.23 (t, 2H, J=7.2Hz), 4.13 (s, 2H), 3.56 (s, 3H), 1.15 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 2850, 1740, 1550, 1345, 1225 Elemental analysis for: C₁₈N₁₈N₂O₆Calculated (%): C 60.33; H 5.06; N 7.82; O 26.79 Found (%): C 60.24; H 5.15; N 7.75; O 26.86
[0164] In accordance with EXAMPLE 1, ethyl 2-methylamino-4-nitrobenzoate andbenzyloxyacetic acid were used instead of ethyl 4-nitrobenzoate and octyloxyacetic acid, thetitle compound (72) was obtained. ¹H-NMR (CDCl₃, δ-TMS) 9.55 (s, 1H), 8.18 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 7.35 (m, 5H), 5.25 (s, 2H), 4.23(t, 2H, J=7.2 Hz), 4.13 (s, 2H), 3.56 (s, 3H), 1.15 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 2850, 1740, 1550, 1345, 1225 Elemental analysis for: C₁₉H₂₀N₂O₆Calculated (%): C 61.28; H 5.41; N 7.52; O 25.78 Found (%): C 61.22; H 5.45; N 7.55; O 25.78
[0165] In accordance with EXAMPLE 1, ethyl 2-(6-hydroxyhexyl)amino-4-nitrobenzoateand butoxyacetic acid were used instead of ethyl 4-nitrobenzoate and octyloxyacetic acid, thetitle compound (73) was obtained. ¹H-NMR (CDCl₃, δ -TMS) 9.55 (s, 1H), 8.18 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 5.25 (s, 2H), 4.23 (t, 2H, J=7.2Hz), 4.13 (s, 2H), 3.45 (m, 2H), 2.87 (m, 2H), 1.78∼1.25 (m, 12H), 1.15 (t, 3H, J=6.8 Hz),0.88 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 2850, 1740, 1550, 1345, 1225 Elemental analysis for: C₂₁H₃₂N₂O₇Calculated (%): C 59.42; H 7.60; N 6.60; O 26.39 Found (%): C 59.28; H 7.45; N 6.65; O 26.62
[0166] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-6-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (74)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.05 (s, 1H), 8.09 (m, 3H), 3.64 (s, 3H), 3.68 (d, 2H, J=6.8 Hz), 1.87∼1.23 (m, 12H), 0.90 (t,3H, J=6.9 Hz) IR (KBr, cm^-1): 3500, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₈H₂₄N₂O₅Calculated (%): C 62.05; H 6.94; N 8.04; O 22.96 Found (%): C 62.02; H 7.04; N 8.00; O 22.64
[0167] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-3-nitrobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (75)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.05 (s, 1H), 8.05 (m, 3H), 3.66 (s, 3H), 3.64 (d, 2H, J=6.8 Hz), 1.87∼1.23 (m, 12H), 0.89 (t,3H, J=6.9 Hz) IR (KBr, cm^-1): 3500, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₈H₂₄N₂O₅Calculated (%): C 62.05; H 6.94; N 8.04; O 22.96 Found (%): C 62.00; H 7.03; N 8.05; O 22.98
[0168] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-acetylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (76)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.28 (s, 1H), 10.23 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H, J=8.8 Hz), 7.42 (d, 1H, j=8.8 Hz), 3.94(t, 1H, J=6.8 Hz), 3.52 (s, 3H), 2.10 (s, 3H), 1.69 (m, 2H), 1.25(m, 10H), 0.86 (t, 3H, J=6.8Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1515, 1250, 1100 Elemental analysis for: C₁₈H₂₆N₂O₃Calculated (%): C 67.90; H 8.23; N 8.80; O 15.07 Found (%): C 67.95; H 8.21; N 8.81; O 15.03
[0169] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-6-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (77)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.39 (s, 1H), 10.29 (s, 1H), 8.90 (s, 1H), 7.96 (s, 1H), 7.85 (d, 1H, J=8.8 Hz), 7.52 (d, 1H,J=15.6 Hz), 7.49 (s, 1H), 6.93 (s, 2H), 6.75 (d, 1H, J=15.6 Hz), 3.92 (t, 2H, J=6.8 Hz), 3.82 (s,6H), 3.54 (s, 3H), 1.68 (m, 2H), 1.25 (m, 10H), 0.87 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1600, 1515, 1250, 1100 Elemental analysis for: C₂₉H₃₆N₂O₇Calculated (%): C 66.39; H 6.92; N 5.34; O 21.35 Found (%): C 66.44; H 7.00; N 5.30; O 21.26
[0170] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-5-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (78)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.31 (s, 1H), 10.23 (s, 1H), 8.90 (s, 1H), 7.96 (s, 1H), 7.85 (d, 1H, J=8.8 Hz), 7.54 (d, 1H,J=15.6 Hz), 7.49 (s, 1H), 6.93 (s, 2H), 6.75 (d, 1H, J=15.6 Hz), 3.92 (t, 2H, J=6.8 Hz), 3.81 (s,6H), 3.54 (s, 3H), 1.68 (m, 2H), 1.25 (m, 10H), 0.85 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2950, 1600, 1515, 1240, 1100 Elemental analysis for: C₂₉H₃₆N₂O₇Calculated (%): C 66.39; H 6.92; N 5.34; O 21.35 Found (%): C 66.32; H 6.98; N 5.41; O 21.29
[0171] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-3-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (79)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.35 (s, 1H), 10.23 (s, 1H), 8.90 (s, 1H), 7.94 (s, 1H), 7.85 (d, 1H, J=8.8 Hz), 7.54 (d, 1H,J=15.6 Hz), 7.50 (s, 1H), 6.93 (s, 2H), 6.74 (d, 1H, J=15.6 Hz), 3.92 (t, 2H, J=6.8 Hz), 3.81 (s,6H), 3.54 (t, 2H, J=6.8 Hz), 1.68 (m, 2H), 1.25 (m, 10H), 0.87 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1550, 1515, 1240, 1100 Elemental analysis for: C₂₉H₃₆N₂O₇Calculated (%): C 66.39; H 6.92; N 5.34; O 21.35 Found (%): C 66.33; H 6.90, N 5.36; O 21.41
[0172] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-5-ethoxycarbonyl-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (80)wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.68 (s, 1H), 7.88∼7.55 (m, 3H), 4.22 (t, 2H, J=6.9 Hz), 3.84 (t, 2H, J=6.8 Hz), 3.62 (s, 3H),1.78∼1.34 (m, 4H), 1.22 (t, 3H, J=6.8 Hz), 0.96 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1715, 1610, 1250, 1100 Elemental analysis for: C₁₇H₂₁N₁O₅Calculated (%): C 63.93; H 6.63; N 4.39; O 25.05 Found (%): C 63.70; H 6.58; N 4.45; O 25.27
[0173] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-5-phenoxycarbonyl-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (81)wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.68 (s, 1H), 7.88∼7.35 (m, 8H), 3.84 (t, 2H, J=6.8 Hz), 3.62 (s, 3H), 1.78∼1.34 (m, 4H),0.96 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1715, 1610, 1250, 1100 Elemental analysis for: C₂₀H₂₁N₁O₅Calculated (%): C 67.59; H 5.96; N 3.94; O 22.51 Found (%): C 67.57; H 6.04; N 3.90; O 22.49
[0174] In accordance with EXAMPLE 20, ethyl 2-[N-1-methyl-N-(butoxyacetyl)amino]-3-ethoxycarbonyl-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnammoyl)amino]-benzoate, the title compound (82)wasobtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.62 (s, 1H), 7.88∼7.55 (m, 3H), 4.20 (t, 2H, J=6.9 Hz), 3.85 (t, 2H, J=6.8 Hz), 3.62 (s, 3H),1.78∼1.34 (m, 4H), 1.22 (t, 3H, J=6.8 Hz), 0.95 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1715, 1610, 1250, 1100 Elemental analysis for: C₁₇H₂₁N₁O₅Calculated (%): C 63.93; H 6.63; N 4.39; O 25.05 Found (%): C 63.88; H 6.59; N 4.35; O 25.18
[0175] In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-3-phenoxycarbonyl-benzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the titlecompound (83)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.58 (s, 1H), 7.88∼7.35 (m, 8H), 3.82 (t, 2H, J=6.8 Hz), 3.64 (s, 3H), 1.78∼1.34 (m, 4H),0.99 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3550, 2940, 1715, 1610, 1250, 1100 Elemental analysis for: C₂₀H₂₁N₁O₅Calculated (%): C 67.59; H 5.96; N 3.94; O 22.51 Found (%): C 67.48; H 5.95; N 3.99; O 22.58
[0176] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(methoxyacetyl)amino]-6-octyloxybenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (84)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20 (m, 3H), 3.74 (s, 3H), 3.65 (s, 3H), 2.22 (d, 2H, J=7.0 Hz),1.78∼1.23 (m, 12H), 0.89 (t, 3H, J=7.0 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₁₉H₂₇N₁O₄Calculated (%): C 68.44; H 8.16; N 4.20; O 19.20 Found (%): C 68.46; H 8.19; N 4.27; O 19.08
[0177] In accordance with EXAMPLE 21, ethyl 2-[N-methyl-N-(hexyloxyacetyl)amino]-3-hexyloxybenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3, 5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (85)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.85 (s, 1H), 7.75∼7.20)m, 3H), 3.65 (s, 3H), 2.22 (d, 2H, J=7.0 Hz), 2.00 (d, 2H, J=7.0 Hz),1.78∼1.23 (m, 16H), 0.89 (t, 3H, J=7.0 Hz), 0.83 (t, 3H, J=7.0 Hz) IR (KBr, cm^-1): 3550, 2940, 1610, 1100 Elemental analysis for: C₂₂H₃₃N₁O₄Calculated (%): C 70.37; H 8.86; N 3.73; O 17.04 Found (%): C 70.39; H 8.92; N 3.71; O 16.98
[0178] In accordance with EXAMPLE 19, ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-3-methylaminobenzoatewas used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (86)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 11.23 (s, 1H), 7.85 (s, 1H), 7.76 (d, 1H, J=7.2 Hz), 7.50 (d, 1H, J=7.2 Hz), 4.23 (d, 2H, J=7.6Hz), 3.54 (s, 3H), 3.34 (s, 3H), 1.86∼1.45 (m, 12H), 0.97 (t, 3H, J=7.5 Hz) IR (KBr, cm^-1): 3550, 2940, 1550, 1515, 1240, 1100 Elemental analysis for: C₁₉H₂₈N₂O₃Calculated (%): C 68.64; H 8.49; N 8.43; O 14.44 Found (%): C 68.61; H 8.50; N 8.49; O 14.40
[0179] In accordance with EXAMPLE 4, Methyl 2-[(octyloxyacetyl)amino]-4-aminobenzoatewas used instead of ethyl 2-[(octyloxyacetyl)amino-4-aminobenzoate, thetitle compound (87)was obtained. ¹H-NMR (CDCl₃, δ-TMS) 7.94 (d, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 6.32 (d, 1H, J=1.6 Hz), 4.40 (s, 2H), 4.27(m,2H), 3.82 (s, 3H), 3.40 (m, 2H), 3.18 (s, 3H), 1.80∼1.20 (m, 12H), 0.87 (t, 3H, J=6.8 Hz) IR (KBr, cm^-1): 3350, 2850, 1725 Elemental analysis for: C₁₉H₃₀N₂O₄Calculated (%): C 65.11; H 8.63; N 7.99; O 18.26 Found (%): C 65.08; H 8.59; N 8.02; O 18.31
[0180] In accordance with EXAMPLE 4, butyl 2-[(octyloxyacetyl)amino]-4-aminobenzoatewas used instead of ethyl 2-[(octyloxyacetyl)amino]-4-aminobenzoate, the title compound(88)was obtained. ¹H-NMR (CDCl₃, δ-TMS) 7.94 (d, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 6.32 (d, 1H, J=1.6 Hz), 4.40 (s, 2H), 4.27 (m,2H), 3.82 (s, 3H), 3.40 (m, 2H), 3.18 (s, 3H), 2.30∼1.20 (m, 14H), 0.87 (m, 6H) IR (KBr, cm^-1): 3350, 2850, 1725 Elemental analysis for: C₂₂H₃₆N₂O₄Calculated (%): C 67.31; H 9.24; N 7.14; O 16.30 Found (%): C 67.28; H 9.27; N 7.21; O 16.24
[0181] In accordance with EXAMPLE 5, Methyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-aminobenzoatewas used instead of Ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-aminobenzoate,the title compound (89)was obtained. ¹H-NMR (d₆-DMSO, δ-TMS) 10.52 (s, 1H), 8.94 (s, 1H), 7.96 (d, 1H, J=8.8 Hz), 7.83 (d. 1H, J=2.0 Hz), 7.76 (d, 1H, J=8.8Hz), 7.57 (d, 1H, J=15.6 Hz), 6.93 (s, 2H), 6.68 (d, 1H, J=15.6 Hz), 3.85 (s, 6H), 3.81 (s, 3H),3.78 (s, 3H), 3.68 (m, 2H), 3.27 (m, 2H), 1.40∼1.10 (m, 12H), 0.83 (m, 3H) IR (KBr, cm^-1): 3350, 1745, 1680, 1225 Elemental analysis for: C₃₀H₄₀N₂O₈Calculated (%): C 64.73; H 7.24; N 5.03; O 23.00 Found (%): C 64.77; H 7.20; N 4.95; O 23.07
[0182] In accordance with EXAMPLE 19, methyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (18)was obtained. EXAMPLE 977-[(3, 5-dimethoxy-4-hydroxy-cinnamoyl)amino]-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone(compound 18)
[0183] In accordance with EXAMPLE 19, butyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate was used instead of ethyl 2-[N-methyl-N-(octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate,the title compound (18)was obtained. REFERENCE EXAMPLE 1Cyclisation of ethyl 2-[(methoxyacetyl)amino]-7-nitro-benzoate
[0184] To a mixture of 0.58 g of sodium hydride (purity 60%, 14.49 mmol) in 9 ml oftetrahydrofuran was added a solution of 1.02 g of ethyl 2-[(methoxyacetyl)amino]-7-nitrobenzoate(3.62 mmol) in 6 ml of tetrthydrofuran at 0 to 10°C. After the mixture was stirred at0 to 10°C for 5 hours. No proceeding of cyclization was observed. TEST EXAMPLE 1Acute toxicity test in mice
[0185] We performed this test in order to confirm the low toxicity of the compounds of thepresent invention, quinolinone derivatives. In the following, the method of the acute toxicitytest will be explained.
[0186] Method:Each of quinolinone derivatives (compound No. 18 to 69, 74 to 86) wereforcibly admimstered orally at the doses of 1000 and 2000 mg/kg to male ICR mice (bodyweight is 20 to 25 g, 5 mice per one(1) group), using an esophageal sound. After theadministration, the animals were kept in cages for 7 days, to observed general symptoms andto count dead animals. Lethal dose (LD₅₀:mg/kg) was extrapolated from the mortality at 7thday after administration.
[0187] In result, the LD₅₀ of all compounds were over 1000 mg/kg, and therefore it wasclearly shown that the compounds of the present invention, quinolinone derivatives, haveextremely low toxicity. TEST EXAMPLE 2Effect on homologous passive cutaneous anaphylaxis (PCA) reaction in rats
[0188] We performed this pharmacological test by PCA reaction, which was well knownscreening test for anti-allergic agents in order to demonstrate that the compounds of thepresent invention, quiuolinone derivatives, possess anti-allergic activity. This experimentalanimal model is caused by immediate type allergic reaction, namely, antigen-antibodyreaction. In the following, the method of this pharmacological test will be explained.
[0189] Method:Male wistar rats (9 weeks old) were intradermally administered 0.05 ml ofanti-serum against dinitrophenylated ascaris (DNP-As) into two sites on the shaved dorsalskin. 48 hours later, quinolinone derivatives (test compounds) suspended in 0.5 %methylcellulose (MC) were given orally at a dose of 100 mg/kg to the animals. 1 hour afteradministration of Test compounds, the animals were induced anaphylaxis by injection ofsaline (1 ml) dissolving 1 mg of trinitrophenylated ascaris (TNP-As) and 5 mg of Evans Blueinto the tail vein of the animals. 30 minutes after induction of anaphylaxis, animals wereanesthetised by ether and killed by bleeding, and were flayed dorsal skin. The leakage of dyewas assessed by measuring the diameter (mean of shortest and longest diameter) of the blue spot on the inside surface of dorsal skin. As vehicle control group, only 0.5 % MC solutionwas administered orally, and as positive control group, Tranilast suspended in 0.5 % MCwere administered orally at a dose of 200 mg/kg to the animals with the same method as thetest compounds groups. The inhibition (%) of PCA reaction was calculated according toequation 1 and the result was shown in table 1. Each experimental group consisted of 5 rats.In the conditions ofthis experiment, it was considered that the compound, which inhibitedPCA reaction by over forty (40) percent agalnst that in vehicle control group, was evidentlyeffective for immediate type allergy.Inhibition (%) = (A - B)/A x 100
[0190] In equation 1: A: leakage of dye in vehicle control group B : leakage of dye in test compound group or positive control group Compound No. Inhibition(%) Compound No. Inhibition(%) 23 40 61 42 24 42 68 49 26 39 76 51 34 37 77 55 36 45 78 50 38 45 79 49 44 42 80 41 45 46 83 42 49 50 84 49 52 49 85 50 53 45 86 53 54 50 Tranilast 52FORMULATION EXAMPLE 1
[0191] (5 % powders)the compound of the present invention50 mglactos950 mg 1000 mg
[0192] In the following, the procedure for powders of compound 22, 24 and 45 will beshown. Crystals of the compound of the present invention were pulverised in amortar andthoroughly mixed with lactose. Secondly the mixture was pulverised with a pestle and 5%powders of compound 22, 24 and 45 were obtained. FORMULATION EXAMPLE 2
[0193] (10% powders)the compound of the present invention100 mglactos900 mg 1000 mg
[0194] In the following, the procedure for powders of compound 34, 52, 53 and 61 will beshown. The procedure of FORMULATION EXAMPLE 1 was repeated to obtain 10%powders of compound 34, 52, 53 and 61. FORMULATION EXAMPLE 3
[0195] (10% granules)the compound of the present invention300 mglactose2000 mgstarch670 mggelatin30 mg 3000 mg
[0196] In the following, the procedure for granules of compound 38, 44, 49 and 68 will beshown. The compound of the present invention was mixed with the equivalent amount ofstarch and pulverised in a mortar. This was further mixed with lactose and the remainingportion of starch. Separately from this, 30 mg of gelatin was mixed with 1 ml of purifiedwater, solubilised by heating, cooled and then, with stirring, mixed with 1 ml of ethanol toprepare a gelatin solution. Thereafter, the mixture prepared above was mixed with the gelatin solution, and the resulting mixture was kneaded, granulated and then dried to obtain granulesof compound 38, 44, 49 and 68. FORMULATION EXAMPLE 4
[0197] (5 mg tablets)the compound of the present invention5 mglactose62 mgstarch30 mgtalc2 mgmagnesium stearate1 mg 100 mg/tablet
[0198] In the following, the procedure for tablets of compound 76 to 80 will be shown. A 20times larger portion of the above composition was used to prepare tablets each of whichcontaming 5 mg of the active ingredient.. That is, 100 mg of the compound of the presentinvention in a crystal form was pulverised in a mortar and mixed with lactose and starch.The thus prepared formulation was mixed with 10% starch paste, and the mixture waskneaded and then subjected to granulation. After drying, the resulting granules were mixedwith talc and magnesium stearate and subjected to tablet making in usual way. With theabove procedure, tablets of compound 76 to 80 were prepared. FORMULATION EXAMPLE 5
[0199] (20 mg tablets)the compound of the present invention20 mg6% hydroxypropylcellulose/lactose75 mgstearate/talc2 mgpotato starch3 mg 100 mg/tablet
[0200] In the following, the procedure for tablets of compound 76 to 80 will be shown. A 10times larger portion of the above composition was used to prepare tablets each of whichcontalning 20 mg of the active ingredient. That is, 6 g of hydroxypropylcellulose wasdissolved in an appropriate volume of ethanol and mixed with 94 g of lactose, followed by kneading. After drying to a degree, the mixture was passed through a No. 60 mesh, and thethus graded granules were used as 6% hydroxypropylcellulose/lactose. Separately from this,magnesium stearate and talc were mixed at a ratio of 1:4 and used as stearate/talc. Thereafter,the compound of the present invention, 6% hydroxypropylcellulose/lactose, stearate/talc andpotato starch were thoroughly mixed and subjected to tablet making in usual way. With theabove procedure, tablets of compound 76 to 80 were prepared. FORMULATION EXAMPLE 6
[0201] (25 mg tablets)the compound of the present invention25 mglactose122 mgcarboxymethylstarch50 mgtalc2 mgmagnesium stearate1 mg 200 mg/tablet
[0202] In the following, the procedures for tablets of compound 44, 54, 76 to 80, 85 and 86will be shown. A 10 times larger portion of the above composition was used to preparetablets each of which containing 25 mg of the active ingredient. That is, 250 mg of thecompound of the present invention in a crystal form was pulverised in a mortar andthoroughly mixed with lactose. An appropriate volume of purified water was added tocarboxymethylstarch, which was subsequently added to the above mixture, and the resultingmixture was kneaded and then subjected to granulation. After drying, the thus preparedgranules were mixed with talc and magnesium stearate and subjected to tablet making inusual way. With the above procedure, tablets of compound 44, 54, 76 to 80, 85 and 86 wereprepared. FORMULATION EXAMPLE 7
[0203] (10 mg capsules)the compound of the present invention300 mglactose2000 mgstarch670 mggelatin30 mg 3000 mg
[0204] In the following, the procedures for tablets of compound 44, 54, 76 to 80, 85 and 86will be shown. Granules were prepared in accordance with the procedure described inFormulation EXAMPLE 3 and packed in capsules in 100 mg portions. With the aboveprocedure, capsules of compound 44, 54, 76 to 80, 85 and 86 were prepared. FORMULATION EXAMPLE 8
[0205] (0.5 % ointment)the compound of the present invention5 mgliquid paraffin80 mgpetrolatum album915 mg 1000 mg
[0206] In the following, the procedures for tablets of compound 44, 54, 76 to 80, 85 and 86will be shown. A 10 times larger portion of the above composition was used to prepareointment each of which containing 5 % of the active ingredient. This is, the compound of thepresent invention and a little liquid paraffin were sufficiently mixed and pulverised in amortar, and used as dispersive solution. Separately from this, petrolatum album was mixedwith liquid paraffin by heating to prepare bases. The above dispersive solution was bydegrees added to the bases, and thoroughly kneaded to homogenise. With the aboveprocedure, ointment of 44, 54, 76 to 80, 85 and 86 were prepared. Industrial manufacturing method of quinolinone derivative and a novel amide derivatives as aintermediate to use this method
[0207] Thus, it is apparent that there has been provided, in accordance with the presentinvention, a industrial manufacturing method of quinolinone derivative and a novel amidederivatives as a intermediate to use this method. Also provided quinolinone derivative and itsphysiologically acceptable salt are excellent antiallergic agents which have low toxicity andare useful for the treatment or prevention of immediate type and delayed type allergicdiseases, particularly an excellent antiallergic agent which is highly effective on delayed typeallergy that cannot be treated effectively with the prior art antiallergic agents.
[0208] While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in the art that various changesand modifications can be made therein without departing from the spirit and scope thereof.

权利要求:
Claims (19)
[1] A method for preparing a quinolinone derivative, expressed by the following generalformula (II), characterized in that an amide derivative expressed by the following generalformula (I) is reacted with a basic agent, followed by intramolecular ring formation.
[2] A method for preparing a quinolinone derivative according to Claim 1, wherein R₁, isselected from the group consisting of a hydrogen atom, a straight-chain or branched-chainalkyl group having 1 to 9 carbon atoms, a straight-chain or branched-chain alkyl groupcontaining a hydroxyl group and having 1 to 5 carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to 9 carbon atoms, and an aryl group having 5 to 8 carbonatoms; R₂ is selected from the group consisting of a straight-chain or branched-chain alkylgroup having 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group having2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkyl group having7 to 9 carbon atoms; R₄, R₅ and R₇ each represents a hydrogen atom; and R₆ represents aR₈R₉N group (wherein, R₈ and R₉ represent, respectively and independently, a hydrogenatom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbonatoms, an aralkyl group having 7 to 9 carbon atoms, or an acyl group having 2 to 12 carbonatoms).
[3] A method for preparing a quinolinone derivative according to Claim 1, wherein R₁represents a hydrogen atom; R₂ is selected from the group consisting of a straight-chain orbranched-chain alkyl group having 1 to 10 carbon atoms, a straight-chain or branched-chainalkenyl group having 2 to 10 carbon atoms, an aryl group havIng 5 to 8 carbon atoms, and anaralkyl group having 7 to 9 carbon atoms; R₄, R₅ and R₇ each represents a hydrogen atom;and R₆ represents a R₈R₉N group (wherein, R₈, and R₉ represent, respectively andindependently, a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenylgroup having 2 to 10 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, or an acylgroup havIng 2 to 12 carbon atoms).
[4] A method for preparing a quniolinone derivative according to Claim 1, wherein R₁ isselected from the group consisting of a hydrogen atom, a straight-chain or branched-chainalkyl group having 1 to 9 carbon atoms, a straight-chain or branched-chain alkyl groupcontaining a hydroxyl group and having 1 to 5 carbon atoms, a straight-chain or branched-chainalkenyl group having 2 to 9 carbon atoms, and an aryl group having 5 to 8 carbonatoms; R₂ is selected from the group consisting of a straight-chain or branched-chain alkylgroup having 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group having2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkyl group having7 to 9 carbon atoms; R₄, R₅ and R₇ each represents a hydrogen atom; and R₆ represents a nitrogroup.
[5] A method for preparing a quinolinone derivative according to Claim 1, wherein R₁represents a hydrogen atom; R₂ is selected from the group consisting ofa straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms, a straight-chain or branched-chainalkenyl group having 2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, and anaralkyl group having 7 to 9 carbon atoms; R₄, R₅ and R₇ each represents a hydrogen atom;and R₆ represents a nitro group.
[6] A method for preparing a quinolinone derivative according to Claim 1, wherein R₁ isselected from the group consisting of a hydrogen atom, a straight-chain or branched-chainalkyl group having 1 to 9 carbon atoms, a straight-chain or branched-chain alkyl groupcontaining a hydroxyl group and having 1 to 5 carbon atoms, a straight-chain or branched-chainalkenyl group having 2 to 9 carbon atoms, and an aryl group having 5 to 8 carbonatoms; R₂ is selected trom the group consisting of a straight-chain or branched-chain alkylgroup having 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group havIng2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkyl group having7 to 9 carbon atoms; R₄, R₅ and R₇ each represents a hydrogen atom; and R₆ is selected fromthe group consisting of a hydroxyl group, a straight-chain or branched-chain alkyloxy grouphaving 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyloxy group having 2 to10 carbon atoms, and an aralkyloxy group having 7 to 9 carbon atoms.
[7] A method for preparing a quinolinone derivative according to one of Claims 1 to 6,characterised in that said basic agent is an alkali metal alkoxide.
[8] A method for preparing a quinolinone derivative according to one of Claims 1 to 6,characterised in that said basic agent is an alkali metal amide.
[9] An amide derivative expressed by the following general formula (I).
[10] An amide derivative according to Claim 9, wherein R₁ is selected from the groupconsisting of a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 9carbon atoms, a straight-chain or branched-chain alkyl group containing a hydroxyl groupand having 1 to 5 carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to9 carbon atoms, and an aryl group having 5 to 8 carbon atoms; R₂ is selected from the groupconsisting of a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms, astraight-chain or branched-chain alkenyl group having 2 to 10 carbon atoms, an aryl grouphaving 5 to 8 carbon atoms, and an aralkyl group having 7 to 9 carbon atoms; and R₈ and R₉represent, respectively and independently, a hydroxyl group, an alkyl group having 1 to 10carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 9carbon atoms, or an acyl group having 2 to 12 carbon atoms.
[11] An amide derivative according to Claim 10, wherein R₁ represents a hydrogen atom;R₂ is selected from the group consisting of a straight-chain or branched-chain alkyl grouphaving 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to 10carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkyl group having 7 to 9carbon atoms; and R₈ and R₉ represent, respectively and independently, a hydroxyl group, analkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, anaralkyl group having 7 to 9 carbon atoms, or an acyl group having 2 to 12 carbon atoms.
[12] An amide derivative according to Claim 10, wherein R₁ is selected from the groupconsisting of a hydrogen atom and a straight-chain or branched-chain alkyl group having 1 to9 carbon atoms; and R₂ is selected from the group consisting of a straight-chain or branched-chainalkyl group having 1 to 10 carbon atoms, a straight-chain or branched-chain alkenylgroup having 2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkylgroup having 7 to 9 carbon atoms.
[13] A quinolinone derivative and physiological salt of the same, expressed by thefollowing general formula (II).
[14] A quinolinone derivative and physiological salt of the same according to Claim 13,wherein R₁ is selected from the group consisting of a hydrogen atom, a straight-chain orbranched-chain alkyl group having 1 to 9 carbon atoms, a straight-chain or branched-chainalkyl group containing a hydroxyl group and having 1 to 5 carbon atoms, a straight-chain orbranched-chain alkenyl group having 2 to 9 carbon atoms, and an aryl group having 5 to 8carbon atoms; R₂ is selected from the group consisting of a straight-chain or branched-chainalkyl group having 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl grouphaving 2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkyl grouphaving 7 to 9 carbon atoms; R₄ to R₇ represent, respectively and independently, a hydrogen atom, a hydroxyl group, a straight-chain or branched-chain alkyl group having 1 to 10 carbonatoms, a stralght-chain or branched-chain alkoxy group having 1 to 10 carbon atoms, astraight-chain or branched-chain alkenyl group having 2 to 10 carbon atoms, a straight-chainor branched-chain alkenyloxy group having 2 to 10 carbon atoms, an aryl group having 5 to 8carbon atoms, an aryloxy group having 5 to 8 carbon atoms, and an aralkyloxy group having7 to 9 carbon atoms; R₈ and R₉ represent, respectively and independently, a hydrogen atom,an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms,an arakyl group having 7 to 9 carbon atoms, or an acyl group having 2 to 12 carbon atoms;and R₁₀ is selected from the group consisting of a straight-chain or branched-chain alkylgroup having 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group having2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkyl group having7 to 9 carbon atoms.
[15] A quinolinone derivative and physiological salt of the same according to Claim 13,wherein R₁ represents a hydrogen atom; R₂ represents a straight-chain or branched-chainalkyl group having 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl grouphaving 2 to 10 carbon atoms, an aryl group having 5 to 8 carbon atoms, or an aralkyl grouphaving 7 to 9 carbon atoms; R₄ to R₇ represent, respectively and independently, a hydrogenatom, a hydroxyl group, a straight-chain or branched-chain alkyl group having 1 to 10 carbonatoms, a straight-chain or branched-chain alkoxy group having 1 to 10 carbon atoms, astraight-chain or branched-chain alkenyl group having 2 to 10 carbon atoms, a straight-chainor branched-chain alkenyloxy group having 2 to 10 carbon atoms, an aryl group having 5 to 8carbon atoms, an aryloxy group having 5 to 8 carbon atoms, or an aralkyloxy group having 7to 9 carbon atoms; R₈ and R₉ represent, respectively and independently, a hydrogen atom, analkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, anaralkyl group having 7 to 9 carbon atoms, or an acyl group having 2 to 12 carbon atoms; andR₁₀ is selected from the group consisting of a straight-chain or branched-chain alkyl grouphaving 1 to 10 carbon atoms, a straight-chain or branched-chain alkenyl group having 2 to 10carbon atoms, an aryl group having 5 to 8 carbon atoms, and an aralkyl group having 7 to 9carbon atoms.
[16] A quinolinone derivative and physiological salt of the same according to Claim 13,wherein R₁ is selected from the group consisting of a hydrogen atom and a straight-chain or branched-chain alkyl group having 1 to 9 carbon atoms; and R₂ is selected from the groupconsisting of a straight-chaln or branched-chain alkyl group having 1 to 10 carbon atoms, astraight-chain or branched-chain alkenyl group having 2 to 10 carbon atoms, an aryl grouphaving 5 to 8 carbon atoms, and an aralkyl group having 7 to 9 carbon atoms.
[17] A medicament containing, as the active ingredients, a quinolinone derivative and/orphysiological salt of the same according to one of Claims 13 to 16.
[18] An anti-allergic agent containing, as the active ingredients, a quinolinone derivativeand/or physiological salt of the same according to one of Claims 13 to 16.
[19] Use of quinolinone derivatives or physiologically acceptable salts thereof as definedin one of Clalms 13 to 16 for manufacture of anti-allergic agents.

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同族专利:

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公开号 | 公开日

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US6136822A|2000-10-24|

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CA2255333C|2004-07-13|

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TW430656B|2001-04-21|

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AU737388B2|2001-08-16|

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AT260257T|2004-03-15|

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CN1221738A|1999-07-07|

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CN1161337C|2004-08-11|

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JP3900720B2|2007-04-04|

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DE69821898T2|2004-08-19|

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KR19990062717A|1999-07-26|

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CA2255333A1|1999-06-03|

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DE69821898D1|2004-04-01|

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EP0927718B1|2004-02-25|

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AU9515198A|1999-06-24|

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KR100511626B1|2005-12-20|

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US6271416B1|2001-08-07|

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JPH11236374A|1999-08-31|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

US4124587A|1976-03-01|1978-11-07|Sandoz, Inc.|4-Hydroxy-3-sulfinyl-quinolin-2-ones|

---

US4127574A|1976-03-01|1978-11-28|Sandoz, Inc.|4-Hydroxy-3-sulfonyl-quinolin-2-ones|

---

JPH09100267A|1995-07-31|1997-04-15|Dainippon Ink & Chem Inc|Quinoline derivative and antiallergic agent containing the same as active ingredient|

---

EP0785190A2|1996-01-17|1997-07-23|Dainippon Ink And Chemicals, Inc.|Quinolinone derivative and antiallergic agent with said quinolinone derivative as the active ingredient|EP1129712A1|1999-09-10|2001-09-05|Dainippon Ink And Chemicals, Inc.|Quinolinone derivative preparations and process for producing the same|

---

EP1270006A2|2001-06-20|2003-01-02|Dainippon Ink And Chemicals, Inc.|Quinolone derivative pharmaceutical composition and production method therefor|

---

US6706733B2|2001-05-08|2004-03-16|Dainippon Ink And Chemicals, Inc.|Quinolinone derivative formulation and its production method|

---

US8420650B2|2008-08-06|2013-04-16|Biomarin Pharmaceutical Inc.|Dihydropyridophthalazinone inhibitors of polypolymerase |

---

US8541403B2|2010-02-03|2013-09-24|Biomarin Pharmaceutical Inc.|Dihydropyridophthalazinone inhibitors of polypolymerasefor use in treatment of diseases associated with a PTEN deficiency|

---

US8735392B2|2010-10-21|2014-05-27|Biomarin Pharmaceutical Inc.|Crystalline -5-fluoro-8--9--8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3-one tosylate salt|

---

US8765945B2|2010-02-08|2014-07-01|Biomarin Pharmaceutical Inc.|Processes of synthesizing dihydropyridophthalazinone derivatives|US5179107A|1990-09-07|1993-01-12|Schering Corporation|Antiviral quinolinone compounds|

---

US5190956A|1990-09-07|1993-03-02|Schering Corporation|Certain N-substituted 3-oximino-2,4-dioxoquinolin-2,4-diones useful for treating viral infections|

---

TW430656B|1997-12-03|2001-04-21|Dainippon Ink & Chemicals|Quinolinone derivative, method for preparing the same, and anti-allergic agent|TW430656B|1997-12-03|2001-04-21|Dainippon Ink & Chemicals|Quinolinone derivative, method for preparing the same, and anti-allergic agent|

---

US6858540B2|2000-05-11|2005-02-22|Applied Materials, Inc.|Selective removal of tantalum-containing barrier layer during metal CMP|

---

US6524167B1|2000-10-27|2003-02-25|Applied Materials, Inc.|Method and composition for the selective removal of residual materials and barrier materials during substrate planarization|

---

US6709316B1|2000-10-27|2004-03-23|Applied Materials, Inc.|Method and apparatus for two-step barrier layer polishing|

---

US7012025B2|2001-01-05|2006-03-14|Applied Materials Inc.|Tantalum removal during chemical mechanical polishing|

---

US7008554B2|2001-07-13|2006-03-07|Applied Materials, Inc.|Dual reduced agents for barrier removal in chemical mechanical polishing|

---

US7104869B2|2001-07-13|2006-09-12|Applied Materials, Inc.|Barrier removal at low polish pressure|

---

US6821881B2|2001-07-25|2004-11-23|Applied Materials, Inc.|Method for chemical mechanical polishing of semiconductor substrates|

---

US7037174B2|2002-10-03|2006-05-02|Applied Materials, Inc.|Methods for reducing delamination during chemical mechanical polishing|

---

WO2005012251A1|2003-07-30|2005-02-10|Dainippon Ink And Chemicals, Inc.|Therapeutic agent for chronic obstructive pulmonary disease and method of treatment for chronic obstructive pulmonary disease with the same|

---

USPP17182P3|2003-10-02|2006-11-07|Plantas De Navarra S.A.|Peach tree plant named ‘Plawhite 5’|

---

JP2009088486A|2007-08-29|2009-04-23|Applied Materials Inc|High throughput low topography copper cmp process|

---

FR2951447B1|2009-10-19|2012-10-19|Rhodia Operations|ETHER AMIDE COMPOUNDS AND USES THEREOF |

---

FR2970964B1|2011-01-28|2013-12-13|Univ Claude Bernard Lyon|NOVEL AZACOUMARIN DERIVATIVES WITH INHIBITOR ACTIVITY OF MDR PUMPS|

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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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JP33289497||1997-12-03||

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JP33289497||1997-12-03||

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