Plasminogen activator inhibitor-1 inhibitor

1. A compound represented by Formula (I) or a salt thereof:

wherein R 1 represents halogen, R 2 represents hydrogen, halogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X represents —CH═CH—;

A represents a group represented by the following Formula (II):

wherein R 3 and R 4 are the same or different, and each represents hydrogen, substituted or unsubstituted C 1-6 -alkyl, or CF 3 ;

T represents a single bond;

D represents substituted or unsubstituted aryl, heteroaryl except pyrazolyl, or

benzo-condensed heteroaryl; substituted or unsubstituted C 4-8 -cycloalkyl;

substituted or unsubstituted C 3-8 -cycloalkenyl or heterocycloalkenyl; or adamantyl;

q is 1 ;

L represents a single bond;

B is located at ortho position on the benzene ring to which imino is bound, and is COOR 9

wherein R 9 represents hydrogen; or a group converted to hydrogen in vivo, which is selected from the group consisting of C 1-6 -alkyl, aryl, aralkyl, —CH(R 10 )—O—CO—R 11 , —CH(R 10 )—O—CO—OR 11 , and a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group represented by the following formula:

wherein R 10 is hydrogen or C 1-6 -alkyl, R 11 is C 1-6 -alkyl or C 3-8 -cycloalkyl, and R 12 is C 1-6 alkyl; or

a heterocyclic group represented by any of the following Formulae (XI)-(XIII):

wherein Z represents oxygen or sulfur,

provided that the following compounds and salts thereof are excluded:

2-[(biphenyl-4-ylcarbonyl)amino]-5-chlorobenzoic acid, and 5-chloro-2-({[4-(1H-pyrrol-1-yl)phenyl]carbonyl}amino)benzoic acid.

2. A pharmaceutical composition comprising an effective amount of the compound or a salt thereof according to claim 1 , or a solvate thereof; and a pharmacologically acceptable carrier or additive.

3. A method for producing a compound represented by Formula (I-2), comprising steps (a) and (b) below:

(a) a step of condensing a compound (1) and a compound (2), which are represented by the following formulae, to form an ester compound (I-1); and

(b) a step of removing R 9a in the compound (I-1) formed in step (a) above to form a carboxylic acid (I-2):

wherein R 1 , R 2 , X, L, and A are as defined claim 1 ; and R 9a represents alkyl, aryl, or aralkyl.

4. A method for producing a compound represented by Formula (I-3), comprising steps (a″) and (d) below:

(a″) a step of condensing a compound (1″) and a compound (2), which are represented by the following formulae, to form a nitrile compound (4); and

(d) a step of reacting the nitrile compound (4) formed in step (a″) above with an azide (5) to form a tetrazole compound (I-3):

wherein R 1 , R 2 , X, A, and L are as defined claim 1 .

5. A method for producing a compound represented by Formula (I-1) or a compound (5), comprising steps (j) and (k) below:

(j) a step of condensing a compound (1) and a compound (12), which are represented by the following formulae, to form a compound (13); and

(k) a step of reacting the compound (13) formed in step (j) above with a compound (14) to form a compound (I-1):

wherein R 1 , R 2 , D, L, R 9a , and X are as defined claims 1 and 3 , provided that Aa represents a group in which W in a group represented by Formula (XIV) below is replaced by D-Ta—;

Ba represents ester (—COOR 9a );

A′ represents a group represented by Formula (XIV) below having halogen or trifluoromethanesulfonyloxy represented by W;

Ta represents a single bond;

M represents —B(OR 13 )OR 13 (R 13 represents hydrogen or alkyl: in the case of alkyl, R 13 substituents may bind to each other to form a ring);

or —ZnV (Zn represents zinc, and V represents halogen):

wherein R 3 and R 4 are the same or different, and each represents hydrogen, substituted or unsubstituted C 1-6 -alkyl, or CF 3 ; and W represents halogen or trifluoromethanesulfonyloxy.

6. The compound or a salt thereof according to claim 1 , wherein the compound represented by Formula (I) above is a compound wherein R 1 is halogen except bromine when D is unsubstituted aryl.

7. The compound or a salt thereof according to claim 1 , wherein the compound represented by Formula (I) above is a compound wherein D represents substituted or unsubstituted heteroaryl, aryl or C 4-8 -cycloalkyl.

8. The compound or a salt thereof according to claim 6 , wherein the compound represented by Formula (I) above is a compound wherein D represents substituted or unsubstituted heteroaryl, aryl or C 4-8 -cycloalkyl.

9. The compound or a salt thereof according to claim 1 , wherein the compound represented by Formula (I) above is a compound wherein B is COOH, or a heterocyclic group represented by the following Formula (XI):

10. The compound or a salt thereof according to claim 6 , wherein the compound represented by Formula (I) above is a compound wherein B is COOH, or a heterocyclic group represented by the following Formula (XI):

11. The compound or a salt thereof according to claim 1 , wherein the compound represented by Formula (I) above is a compound selected from the following compounds:

5-chloro-2-({[3-(furan-3-yl)phenyl]carbonyl }amino)benzoic acid,

5-chloro-2-({[4-(thiophen-2-yl)phenyl]carbonyl }amino)benzoic acid,

5-chloro-2-({[3-(pyridin-4-yl)phenyl]carbonyl }amino)benzoic acid,

5-chloro-2-{[(4′-methylbiphenyl-3-yl)carbonyl]amino }benzoic acid,

5-chloro-2-{[(2′-methoxybiphenyl-3-yl)carbonyl]amino }benzoic acid,

5-chloro-2-({[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]carbonyl}amino)benzoic acid,

2-({[4-(adamantan-1-yl)phenyl]carbonyl }amino)-5-chlorobenzoic acid,

5-chloro-2-({[3-(naphthalen-1-yl)phenyl]carbonyl }amino)benzoic acid,

2-({[3-(adamantan-1-yl)phenyl]carbonyl}amino)-5-chlorobenzoic acid,

5-chloro-2-({[3-(quinolin-3-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(isoquinolin-4-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(quinolin-6-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(isoquinolin-5-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[4-(quinolin-8-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(quinolin-8-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2- {[(4-cyclohexylphenyl)carbonyl]amino }benzoic acid,

5-chloro-2-({[3-(cyclohex-1-en-1-yl)phenyl]carbonyl }amino) benzoic acid,

5-chloro-2-{[(3-cyclohexylphenyl)carbonyl]amino }benzoic acid,

5-chloro-2-({[4-(1-methylcyclohexyl)phenyl]carbonyl }amino) benzoic acid, and

N-[4-chloro-2-(1H-tetrazol-5-yl)phenyl]-3- (quinolin-8-yl)benzamide.

12. The pharmaceutical composition according to claim 2 , wherein the compound is a compound selected from the following compounds:

5-chloro-2-({[3-(furan-3-yl)phenyl]carbonyl}amino)benzoic acid,

2-[(biphenyl-3-ylcarbonyl)amino]-5-chlorobenzoic acid,

2-[(biphenyl-2-ylcarbonyl)amino]-5-chlorobenzoic acid,

5-chloro-2-({[4-(thiophen-2-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(pyridin-4-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-{[(4′-methylbiphenyl-3-yl)carbonyl]amino }benzoic acid,

5-chloro-2-{[(2′-methoxybiphenyl-3-yl)carbonyl]amino }benzoic acid,

5-chloro-2-({[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]carbonyl}amino)benzoic acid,

2-({[4-(adamantan-1-yl)phenyl]carbonyl}amino)-5-chlorobenzoic acid,

5-chloro-2-({[3-(naphthalen-1-yl)phenyl]carbonyl }amino)benzoic acid,

2-({[3-(adamantan-1-yl)phenyl]carbonyl}amino)-5-chlorobenzoic acid,

5-chloro-2-({[3-(quinolin-3-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(isoquinolin-4-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(quinolin-6-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[3-(isoquinolin-5-yl)phenyl]carbonyl}amino)benzoic acid,

5-chloro-2-({[4-(quinolin-8-yl)phenyl]carbonyl }amino)benzoic acid,

5-chloro-2-({[3-(quinolin-8-yl)phenyl]carbonyl }amino)benzoic acid,

5-chloro-2-{[(4-cyclohexylphenyl)carbonyl]amino }benzoic acid,

5-chloro-2-({[3-(cyclohex-1-en-1-yl)phenyl]carbonyl }amino) benzoic acid,

5-chloro-2-({[(3-cyclohexylphenyl)carbonyl]amino }benzoic acid,

5-chloro-2-({[4-(1-methylcyclohexyl)phenyl]carbonyl}amino) benzoic acid, and

N-[4-chloro-2-(1H-tetrazol-5-yl)phenyl]-3-(quinolin-8-yl)benzamide.

13. The pharmaceutical composition according to claim 12 , the composition comprising the compound in the range of from 0.001% to 50% by weight.

14. The pharmaceutical composition according to claim 12 , the composition being orally administered.