PAI-1 inhibitor

• US 8,633,245 B2
• Filed: 04/10/2009
• Issued: 01/21/2014
• Est. Priority Date: 04/11/2008
• Status: Active Grant

• Current Assignee: Institute of Medicinal Molecular Design, Inc.
• Original Assignee: Institute of Medicinal Molecular Design, Inc.
• Inventors: Yamaguchi, Youichi, Yanase, Takeshi, Muto, Susumu, Itai, Akiko
• Primary Examiner(s): ZAREK, PAUL E
• Application Number:
  US12/422,099
• Publication Number:
  US 20090312315A1
• Time in Patent Office: 1,747 Days
• Field of Search: 514/577, 562/406
• US Class Current: 514/557
• CPC Class Codes: C07C 205/06 having nitro groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 205/35 having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 205/37 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 205/38 the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
• CPC Class Codes: C07C 205/44 the carbon skeleton being further substituted by —CHO groups
• CPC Class Codes: C07C 205/56 having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 211/52 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 217/80 having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 217/86 to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
• CPC Class Codes: C07C 217/90 the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
• CPC Class Codes: C07C 229/18 the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 233/15 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 233/56 having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
• CPC Class Codes: C07C 233/60 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 237/40 having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 251/24 having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 255/13 containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 255/37 the carbon skeleton being further substituted by etherified hydroxy groups
• CPC Class Codes: C07C 255/54 containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 2603/74 : Adamantanes
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/29 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 323/20 : with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 323/41 : Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07C 39/27 : all halogen atoms being bound to ring carbon atoms
• CPC Class Codes: C07C 47/277 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 47/55 : containing halogen
• CPC Class Codes: C07C 47/565 : all hydroxy groups bound to the ring
• CPC Class Codes: C07C 47/575 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 49/84 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 59/90 : containing singly bound oxygen-containing groups
• CPC Class Codes: C07C 69/712 : the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 211/76 : attached in position 2 or 6
• CPC Class Codes: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/205 : Radicals derived from carbonic acid
• CPC Class Codes: C07D 317/18 : Radicals substituted by singly bound oxygen or sulfur atoms
• CPC Class Codes: C07D 317/28 : Radicals substituted by nitrogen atoms nitro radicals C07D317/16
• CPC Class Codes: C07F 7/1804 : Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The compound represented by the following formula (I) and the like have PAI-1 inhibition activity;

wherein: R¹ represents a C_6-10 aryl group which may be substituted or the like; T represents a single bond or the like; m represents 0 or 1; when m is 0, G represents —N—C(═O)—CO₂H or the like; when m is 1, G represents an oxygen atom or the like; R² represents a C_6-10 aryl group which may be substituted or the like; E represents the following formula (II) wherein one of R³¹, R³², R³³ and R³⁴ represents the formula R¹-T-, each of the other three independently represents a hydrogen atom or the like, and R³⁵ represents the formula —X—Y′, a hydrogen atom or the like; X represents —CH₂— or the like; Y′ represents a carboxy group or the like; M represents a single bond or the like.

Claims

1. A compound represented by the following formula (I) or a salt thereof:

2. A medicament comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof.

3. The compound or the salt thereof according to claim 1, wherein one of R³¹, R³², R³³ and R³⁴ is the formula R¹-T-, and each of the other three is a hydrogen atom.

4. The compound or the salt thereof according to claim 3, wherein R³² is the formula R¹-T-.

5. The compound or the salt thereof according to claim 1, wherein R¹ is a phenyl group substituted with one or two groups selected from the substituent group α

-1.

6. The compound or the salt thereof according to claim 1, wherein R¹ is a phenyl group substituted with a group selected from a C_1-6 alkyl group, a C_1-6 alkoxy group, and a halogenated C_1-6 alkoxy group.

7. The compound or the salt thereof according to claim 1, wherein R¹ is a phenyl group substituted with a halogenated C_1-6 alkoxy group.

8. The compound or the salt thereof according to claim 1, wherein R¹ is a group selected from the group consisting of:

9. The compound or the salt thereof according to claim 1, wherein T is a single bond.

10. The compound or the salt thereof according to claim 1, wherein R² is a phenyl group substituted with one or two groups selected from the substituent group β

-1.

11. The compound or the salt thereof according to claim 1, wherein R² is a phenyl group substituted with a group selected from a C_1-6 alkyl group, a halogenated C_1-6 alkyl group, a C_1-6 alkoxy group, and a halogenated C_1-6 alkoxy group.

12. The compound or the salt thereof according to claim 1, wherein R² is a group selected from the group consisting of:

13. The compound or the salt thereof according to claim 1, wherein X is —

CH₂CH₂—

.

14. The compound or the salt thereof according to claim 1, wherein M is a single bond.

15. The compound or the salt thereof according to claim 1, wherein the compound is selected from the group consisting of:

16. The compound or the salt thereof according to claim 15, wherein the compound is selected from the group consisting of:

17. The compound or salt thereof according to claim 15, wherein, the compound is selected from the group consisting of:

18. The compound or the salt thereof according to claim 15, wherein the compound is selected from the group consisting of:

19. The compound or salt thereof according to claim 15, wherein the compound is selected from the group consisting of:

20. The compound or the salt thereof according to claim 15, wherein, the compound is selected from the group consisting of: