Plasminogen activator inhibitor-1 inhibitor

1. A compound represented by formula (I), or a salt or solvate thereof

wherein

—R 1 and R 2 , the same or different, each represent a hydrogen atom, halogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, alkynyl, hydroxyl, alkoxy, cycloalkoxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyl, aralkyloxy, heterocyclic group, heterocyclic-alkyl, or heterocyclic-alkyloxy group; or substituted or unsubstituted aryl group; or amino, carbamoyl, cyano, carboxy or alkoxycarbonyl group that may be substituted or unsubstituted with 1 to 2 substituents; and may adjoin with each other to form a ring;

—R 3 is a hydrogen atom; or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group;

—X is a sulfur atom or —C(R 5 )═C(R 6 )—, wherein R 5 and R 6 each represent a hydrogen atom, halogen atom, or substituted or unsubstituted alkyl or alkoxy group;

—B is a carboxy, alkoxycarbonyl, 1H-tetrazol-5-yl, 4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl, 4,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl, or 4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl group;

-L is substituted or unsubstituted alkylene (some carbon atoms in the alkylene may form a cycloalkyl ring), alkenylene, alkynylene, cycloalkylene, alkyleneoxyalkylene, alkylenethioalkylene, alkylene-SO-alkylene or alkylene-SO 2 -alkylene, or alkylene-N(R 9 )-alkylene group, wherein R 9 is a hydrogen atom, or a substituted or unsubstituted alkyl group;

-n is an integer of 0 or 1;

-A is —COR 10

wherein

R 10 is N(R 14 )(R 15 ), wherein R 14 and R 15 , the same or different, each represent a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, cycloalkenyl, alkynyl, bicycloalkyl, bicycloalkenyl, adamanthyl, aryl, heterocyclic ring, aralkyl (including diphenylalkyl) or heterocyclic-alkyl group, or R 10 is a group represented by the following formula:

wherein m is an integer of 1 to 4, Y represents a nitrogen atom, CH, C(R 16 ′)—, C(OH)— or CH—O—; R 16 and R 16 ′, the same or different, each represent a hydrogen atom, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, bicycloalkyl, bicycloalkenyl, adamanthyl, aryl or aralkyl group (including diphenylalkyl); and R 21 and R 21 ′, the same or different, each represent a hydrogen atom, a substituted or unsubstituted alkyl, or phenyl group.

2. The compound according to claim 1 excluding thiophene compounds represented by formula (I′), or a salt thereof:

wherein R 1 ′ and R 1 ″, the same or different, each represent a hydrogen atom, substituted or unsubstituted phenyl or thienyl group, or C 1-6 straight- or branched-chain alkyl group; R 2 ′ and R 2 ″, the same or different, each represent a hydrogen atom, substituted or unsubstituted phenyl group, C 1-6 straight- or branched-chain alkyl group, or a halogen atom; R 1 ′ and R 2 ′, and R 1 ″ and R 2 ″, may join together to form a 5- or 6-membered ring; and L′ represents a C 1-7 straight- or branched-chain alkylene, alkenylene or alkynylene group, or C 3-8 cycloalkylene group.

3. The compound or salt or solvate thereof according to claim 1 , wherein the compound is a thiophen-3-carboxylic acid represented by formula (II), or a bioisoster thereof:

wherein R 1 , R 2 , R 3 , L, B, n and A are defined as in claim 1 .

4. The compound or salt or solvate thereof according to claim 1 , wherein the compound is a benzoic acid represented by formula (III), or a bioisoster thereof:

wherein R 1 , R 2 , R 3 , L, B, n and A are defined as in claim 1 .

5. A compound, or salt or solvate thereof, wherein the compound is selected from the group consisting of compounds (1) to (91):

(1) 2-(6-(3-(tert-butoxycarbonyl)-4-phenylthiophen-2-ylamino)-6-oxo-hexanamido)benzoic acid,

(2) 2-(6-(3-(tert-butoxycarbonyl)-4-phenylthiophen-2-ylamino)-6-oxo-hexanamido)-5-chlorobenzoic acid,

(3) 2-(6-oxo-6-(4-phenylthiophen-2-ylamino)hexanamido)benzoic acid,

(4) 2-(6-(2-carboxy-4-chlorophenylamine)-6-oxo-hexanamido)-4-phenylthiophen-3-carboxylic acid,

(5) 2-(6-oxo-6-(4-phenylpiperidin-1-yl)hexanamido)-4-phenylthiophen-3-carboxylic acid,

(6) 2-(6-(4-chlorophenylamino)-6-oxo-hexanamido)-4-phenylthiophen-3-carboxylic acid,

(7) 2,2′-(oxybis((1-oxo-2,1-ethanediyl)imino))bis(5-methyl-4-phenylthiophen-3-carboxylic acid),

(8) 2,2′-(oxybis((1-oxo-2,1-ethanediyl)imino))bis(5-phenylthiophen-3-carboxylic acid),

(9) 2,2′-(oxybis((1-oxo-2,1-ethanediyl)imino))bis(4-phenylthiophen-3-carboxylic acid),

(10) 2-(2-(2-(3-(tert-butoxycarbonyl)-5-methyl-4-phenylthiophen-2-ylamino)-2-oxoethoxy)acetamido)-5-methyl-4-phenylthiophen-3-carboxylic acid,

(11) 2-(6-(3-(tert-butoxycarbonyl)-4-isopropylthiophen-2-ylamino)-6-oxo-hexanamido)benzoic acid,

(12) 2-(6-(4-isopropylthiophen-2-ylamino)-6-oxo-hexanamido)benzoic acid,

(13) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-methyl-4-(pyridin-4-yl)thiophen-3-carboxylic acid,

(14) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-methyl-4-(pyridin-3-yl)thiophen-3-carboxylic acid,

(15) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-methyl-4-phenylthiophen-3-carboxylic acid,

(16) 2-(2-(benzyloxycarbonylamino)-5-(4-chlorophenylamino)-5-oxopentanamido)-5-chlorobenzoic acid,

(17) 2-(2-(benzyloxycarbonylamino)-5-((4-chlorophenyl)(methyl)amino)-5-oxopentanamido)-5-chlorobenzoic acid,

(18) 2-(2-(benzyloxycarbonylamino)-5-oxo-5-(4-phenylpiperazin-1-yl)pentanamido)-5-chlorobenzoic acid,

(19) 2-(5-(4-benzhydryl piperazin-1-yl)-2-(benzyloxycarbonylamino)-5-oxopentanamido)-5-chlorobenzoic acid,

(20) 2-(5-(4-benzhydryl piperazin-1-yl)-4-(benzyloxycarbonylamino)-5-oxopentanamido)-5-chlorobenzoic acid,

(21) 2-(5-(4-benzhydryl piperazin-1-yl)-2-(tert-butoxycarbonylamino)-5-oxopentanamido)-5-chlorobenzoic acid,

(22) 2-(2-amino-5-(4-benzhydryl piperazin-1-yl)-5-oxopentanamido)-5-chlorobenzoic acid,

(23) 5-chloro-2-(2-((2-(4-chlorophenylamino)-2-oxoethyl)(methyl)amino)acetamido)benzoic acid,

(24) 2-(2-((2-(4-benzhydryl piperazine-1-yl)-2-oxoethyl)(methyl)amino)acetamido)-5-chlorobenzoic acid,

(25) 5-chloro-2-(6-(4-chlorophenylamin)-6-oxo-hexanamido)benzoic acid,

(26) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-methoxybenzoic acid,

(27) 5-chloro-2-(2-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2-oxoethoxy)acetamido)benzoic acid,

(28) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(29) 2-(2-(2-(4-benzhydryloxy)piperidin-1-yl)-2-oxoethoxy)acetamido-5-chlorobenzoic acid,

(30) 5-chloro-2-(2-(2-(4,4-diphenylpiperidin-1-yl)-2-oxoethoxy)acetamido)benzoic acid,

(31) 2-(2-(2-(4-chloro-2-(methoxycarbonyl)phenylamino)-2-oxoethoxy)acetamido)-5-methyl-4-phenylthiophen-3-carboxylic acid,

(32) 2-(2-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(33) 2-(2-(2-(1-adamantylamino)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(34) 2-(2-(2-(4-(9H-fluoren-9-yl)piperazin-1-yl)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(35) 2-(2-(2-(benzhydrylamino)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(36) 2-(2-(2-(3-(tert-butoxycarbonyl)-5-methyl-4-phenylthiophen-2-ylamino)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(37) 5-chloro-2-(2-(2-(4-chlorophenylamino)-2-oxoethoxy)acetamido)benzoic acid,

(38) 2-(2-(2-(2-benzoyl-4-chlorophenylamino)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(39) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-fluorobenzoic acid,

(40) 3-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)benzoic acid,

(41) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-3-chlorobenzoic acid,

(42) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-4′-fluorobiphenyl-3-carboxylic acid,

(43) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-2′,4′-difluorobiphenyl-3-carboxylic acid,

(44) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-4′-cyano biphenyl-3-carboxylic acid,

(45) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-4′-(dimethylamino)biphenyl-3-carboxylic acid,

(46) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-4′-methoxybiphenyl-3-carboxylic acid,

(47) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-4′-morpholinobiphenyl-3-carboxylic acid,

(48) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-(pyridine-4-yl)benzoic acid,

(49) 2-(2(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-bromobenzoic acid,

(50) 2-(2-(2-benzhydrylamino)-2-oxoethoxy)acetamido-5-(pyridine-4-yl)benzoic acid,

(51) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-(pyridin-3-yl)benzoic acid,

(52) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-(pyridine-4-yl)benzoic acid,

(53) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid,

(54) 2-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)-5-benzylbenzoic acid,

(55) 4-(2-(2-(4-benzhydryl piperazin-1-yl)-2-oxoethoxy)acetamido)biphenyl-3-carboxylic acid,

(56) 4-(2-(2-(4-chlorophenylamino)-2-oxoethoxy)acetamido) biphenyl-3-carboxylic acid,

(57) 2,2′-(oxybis((1-oxo-2,1-ethanediyl)imino))bis(5-phenylbenzen-1-carboxylic acid),

(58) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-isobutyl benzoic acid,

(59) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-(1H-pirazol-4-yl)benzoic acid,

(60) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-(quinolin-3-yl)benzoic acid,

(61) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-(benzo[b]thiophen-2-yl)benzoic acid,

(62) 4-(2-(2-(benzhydrylamino)-2-oxoethoxy)acetamido)-4′-fluorobiphenyl-3-carboxylic acid,

(63) 5-chloro-2-(2-(2-(2,6-diisopropylphenylamino)-2-oxoethoxy)acetamido)benzoic acid,

(64) 5-chloro-2-(2-(2-(1-(naphthalen-1-yl)ethylamino)-2-oxoethoxy)acetamido)benzoic acid,

(65) 5-chloro-2-(2-(2-(5-isopropyl-2-methylphenylamino)-2-oxoethoxy)acetamido)benzoic acid,

(66) 5-chloro-2-(2-(2-oxo-2-(4-phenylbutylamino)ethoxy)acetamido)benzoic acid,

(67) 2-(2-(2-(bis(4-fluorophenyl)methyl)amino-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(68) 2-(2-(2-(bis(4-(trifluoromethyl)benzyl)amino)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(69) 2-(2-(2-(bis(4-fluorobenzyl)amino)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(70) 2-(2-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(71) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-4-chlorobenzoic acid,

(72) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-4-bromobenzoic acid,

(73) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-4-(pyridin-4-yl)benzoic acid,

(74) 3-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-4′-fluorobiphenyl-4-carboxylic acid,

(75) 2-(2-(benzhydrylamino)-2-oxoacetamido)-5-chlorobenzoic acid,

(76) 2-(5-(4-benzhydrylpiperazin-1-yl)-5-oxopentanamido)-5-chlorobenzoic acid,

(77) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-(2,4-dimethylthiazol-5-yl)benzoic acid,

(78) 2-(2-(2-(benzhydrylamino)-2-oxoethoxy)acetamido)-5-methyl-4-phenylthiophen-3-carboxylic acid,

(79) 5-chloro-2-(2-(2-(diphenylamino)-2-oxoethoxy)acetamido)benzoic acid,

(80) 5-chloro-2-(2-(2-(2,2-diphenylethylamino)-2-oxoethoxy)acetamido)benzoic acid,

(81) 2-(2-(2-((3S*,5R*)-4-benzhydryl-3,5-dimethylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-chlorobenzoic acid,

(82) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-(benzyloxy)benzoic acid,

(83) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)acetamido)-5-isobutoxybenzoic acid,

(84) 2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)-N-(4-chloro-2-(1H-tetrazol-5-yl)phenyl)acetamide,

(85) 2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)-N-(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)acetamide,

(86) 2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethoxy)-N-(5-methyl-4-phenyl-3-(1H-tetrazol-5-yl)thiophen-2-yl)acetamide,

(87) 2-(2-((2-(benzhydrylamino)-2-oxoethyl)(methyl)amino)acetamido)-5-chlorobenzoic acid,

(88) 2-(2-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethylthio)acetamido)-5-chlorobenzoic acid,

(89) 2-(2-(1-(2-(4-benzhydrylpiperazin-1-yl)-2-oxyethyl)cyclohexyl)acetamido)-5-chlorobenzoic acid,

(90) 2-((1S*,2S*)-2-(4-benzhydrylpiperazine-1-carbonyl)cyclohexanecarboxamido)-5-chlorobenzoic acid, and

(91) 2-((1S*,2R*)-2-(4-benzhydrylpiperazine-1-carbonyl)cyclohexanecarboxamido)-5-chlorobenzoic acid.

6. A method for producing an aromatic or heterocyclic carboxylic acid represented by formula (Ic), comprising the following steps (c), (d) and (x):

(c) a step of reacting the compound (1) and an intramolecular anhydride of dicarboxylic acid (5) to form an ester carboxylic acid compound (6a), represented by the formulae below,

(d) a step of reacting the ester carboxylic acid (6a) formed in the above step (c) and a compound (7) to form an ester compound (4c), and

(x) a step of removing the R 17 group from the ester compound (4c) formed in the above step (d) to produce an aromatic or heterocyclic carboxylic acid (Ic);

wherein R 1 , R 2 , R 3 , R 10 , L and X are defined as in claim 1 , and R 17 is alkyl, aryl or aralkyl.

7. A pharmaceutical composition comprising a compound, or a salt or solvate thereof, according to any one of claims 1 to 5 , and a pharmaceutically acceptable carrier or additive.

8. The pharmaceutical composition according to claim 7 , the composition being in a form for oral administration.