Five-membered-ring compound
View Patent ↗A 5-membered cyclic compound of the formula: wherein X is oxygen or sulfur, R 1 is hydrogen, substituted or unsubstituted alkyl, etc., R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, etc., Y 1 is a direct bond, substituted or unsubstituted alkylene, —CO(CH 2 ) n —, etc., the wavy line means (E)-configuration or (Z)-configuration, R 3 is substituted or unsubstituted aryl, etc., Y 2 is substituted or unsubstituted alkylene, etc., R 4 is hydrogen, substituted or unsubstituted alkanoyl, substituted or unsubstituted alkyl, etc., R 5 is hydrogen, etc., or a salt thereof, these compound being able to inhibit infiltration of leukocytes such as eosinophils and lymphocytes, by which being useful for the treatment of various kinds of inflammation.
1. A compound of the formula:
wherein X is a sulfur atom,
R 1 is a hydrogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl,
R 2 an aryl, or an aryl being substituted by one or more groups selected from the group consisting of a halogen atom, a C 1 -C 4 alkoxy, trifluoromethoxy, morpholino, or methylenedioxy,
Y 1 is a direct bond, a substituted or unsubstituted alkylene, —CO(CH 2 ) n —, —SO 2 (CH 2 ) n —, —CONH(CH 2 ) n —, —CSNH(CH 2 ) n —, or —COO(CH 2 ) n —,
n is an integer of from 0 to 5,
the wavy line means (E)-configuration or (Z)-configuration,
R 3 is a hydrogen atom, a substituted or unsubstituted aryl, or a substituted or unsubstituted cycloalkyl,
Y 2 is a substituted or unsubstituted alkylene, or an alkenylene,
R 4 is a substitiuted or unsubstituted alkanoyl, —COOR 8 , —SO 2 R 9 , —COR 10 , —CON(R 11 )R 12 , —CSN(R 13 )R 14 , or —C(═NH) N (R 15 )R 16 ,
R 5 is a hydrogen atom, or a substituted or unsubstituted alkyl,
R 8 is a substituted or unsubstituted alkyl, a cycloalkyl, or a substituted or unsubstituted aryl,
R 9 is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl,
R 10 is a cycloalkyl, or a substituted or unsubstituted aryl,
R 11 is a hydrogen atom or an alkyl,
R 12 is a hydrogen atom, a substituted or unsubstituted alkyl, a cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted arylcarbonyl,
R 13 is a hydrogen atom or an alkyl,
R 14 is a hydrogen atom, a substituted or unsubstituted alkyl, a cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted arylcarbonyl,
R 15 is a hydrogen atom or an alkyl,
R 16 is a hydrogen atom or a substituted or unsubstituted alkyl,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
2. The compound according to claim 1 , provided that when Y 1 is a direct bond, then —N(R 4 )R 5 is not an acetylamino, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
3. The compound according to claim 1 , which is a compound of the formula:
wherein X is a sulfur atom,
R 1 is a hydrogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl,
R 2 is an aryl, or an aryl being substituted by one or more groups selected from the group consisting of a halogen atom, a C 1 -C 4 alkoxy, trifluoromethoxy, morpholino, or methylenedioxy,
Y 1 is a direct bond, a substituted or unsubstituted alkylene, —CO(CH 2 ) n —, or —SO 2 (CH 2 ) n — (n is an integer of from 0 to 5),
the wavy line means (E)-configuration or (Z)-configuration,
R 3 is a substituted or unsubstituted aryl,
Y 2 is a substituted or unsubstituted alkylene, or an alkenylene,
R 4 is an alkanoyl, an aroyl, an alkylcarbamoyl, an alkoxycarbonyl, an alkylaminothiocarbonyl, an alkylsulfonyl, or a substituted or unsubstituted arylsulfonyl,
R 5 is a hydrogen atom, or a substituted or unsubstituted alkyl,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
4. The compound according to claim 1 , which is a compound of the formula:
wherein X is a sulfur atom,
R 1 is a hydrogen atom; an alkyl; an alkyl being substituted by a hydroxy group or a halogen atom; an aryl; an aryl which is substituted by one or more groups selected from the group consisting of an alkoxy, a halogen-substituted alkoxy, a hydroxy, a halogen atom, a cyano, an amino, a mono- or di-(alkyl)amino, a 5- or 6-membered cyclic imino group having optionally an oxygen atom or a nitrogen atom as a heteroatom for ring formation, a nitro, an alkyl, an alkyl being substituted by a halogen atom or a hydroxy, a cycloalkyl, a cycloalkyl-substituted alkyl, a methylenedioxy, an ethylenedioxy, a carboxy, an alkoxycarbonyl, a carbamoyl, an alkylcarbamoyl, a di(alkyl)carbamoyl, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, a sulfamoyl, an alkylsulfamoyl, a di(alkyl)sulfamoyl, an aryl, and an aryl being substituted by an alkyl, an alkoxy, a halogen atom or a hydroxy;
R 2 is an aryl, or an aryl being substituted by one or more groups selected from the group consisting of a halogen atom, a C 1 -C 4 alkoxy, trifluoromethoxy, morpholino, or methylenedioxy,
Y 1 is a direct bond; a straight chain or branched chain C 1 -C 5 alkylene; a straight chain or branched chain C 1 -C 5 alkylene being substituted by a hydroxy, a halogen atom or an amino; —CO(CH 2 ) n —; —SO 2 (CH 2 ) n — (n is an integer of from 0 to 5),
R 3 is an aryl; an aryl being substituted by one or more groups selected from the group consisting of an alkoxy, a halogen-substituted alkoxy, a hydroxy, a halogen atom, a cyano, an amino, a mono- or di-(alkyl)amino, a nitro, an alkyl, an alkyl being substituted by a halogen atom or a hydroxy, a cycloalkyl, a cycloalkyl-substituted alkyl, methylenedioxy, ethylenedioxy, a carboxy, an alkoxycarbonyl, a carbamoyl, an alkylcarbamoyl, a di-(alkyl)carbamoyl, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, a sulfamoyl, an alkylsulfamoyl, a di-(alkyl)sulfamoyl, an aryl, and an aryl being substituted by an alkyl, an alkoxy, a halogen atom or a hydroxy;
Y 2 is a straight chain or branched chain C 2 -C 5 alkylene; a straight chain or branched chain C 2 -C 5 alkylene being substituted by a hydroxy, an alkoxy, a halogen atom, an amino or an alkanoylamino; or a straight chain or branched chain C 3 -C 5 alkenylene,
R 4 is an alkanoyl; an aroyl; an alkylcarbamoyl; an alkoxycarbonyl; an alkylaminothiocarbonyl; an alkylsulfonyl; an arylsufonyl; or an alkyl-substituted arylsulfonyl,
R 5 is a hydrogen; an alkyl; or an alkyl being substituted by a hydroxy, a halogen atom or an amino,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
5. The compound according to claim 1 , wherein R 1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
6. The compound according to claim 1 , wherein Y 1 is a substituted or unsubstituted alkylene, —CO(CH 2 ) n —, —SO 2 (CH 2 ) n —, —CONH(CH 2 ) n —, —CSNH(CH 2 ) n —, or —COO(CH 2 ) n —, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
7. The compound according to claim 1 , wherein Y 1 is a direct bond, —CO—, —SO 2 —, —CONH—, or —COO—, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
8. The compound according to claim 1 , wherein Y 1 is a direct bond or a —CO—, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
9. The compound according to claim 1 , wherein R 3 is a substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
10. The compound according to claim 1 , wherein the wavy line means (Z)-configuration, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
11. The compound according to claim 1 , wherein Y 2 is ethylene or trimethylene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
12. The compound according to claim 1 , wherein R 4 is a substituted or unsubstituted alkanoyl, a substituted or unsubstituted alkylcarbamoyl, a substituted or unsubstituted alkylamtnothiocarbonyl, or a substituted or unsubstituted alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
13. The compound according claim 1 , wherein R 4 is a substituted or unsubstituted alkanoyl, or a substituted or unsubstituted alkylcarbamoyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
14. The compound according to claim 1 , wherein R 5 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
15. The compound according to claim 1 , which is a compound of the formula:
wherein Ring A is a benzene ring,
m is 2 or 3,
Y 3 is a direct bond or a carbonyl,
the number of R 17 is 1 or 2, and R 17 s are independently selected from a halogen atom, a C 1 -C 4 alkoxy, a trifluoromethoxy, a morpholino and a methylenedioxy,
the number of R 18 is 1 or 2, and R 18 s are independently selected from a halogen atom, a C 1 -C 4 alkoxy, a trifluoromethoxy and a hydroxy,
R 19 is a C 1 -C 4 alkyl; a C 1 -C 4 alkyl being substituted by a hydroxy, a C 1 -C 4 alkoxy, a mono- or di-(C 1 -C 4 alkyl)amino, a morpholino or a carboxy; a C 1 -C 4 alkylamino; or a C 1 -C 4 alkylamino being substituted by a hydroxy, a C 1 -C 4 alkoxy, a mono- or di- (C 1 -C 4 alkyl)amino, or a carboxy,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
16. The compound according to claim 15 , provided that when Y 3 is a direct bond, then R 19 is not a methyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
17. The compound according to claim 18 , wherein Ring A is a benzene ring, (i) Y 3 is a direct bond and R 19 is a C 1 -C 4 alkylamino, or (ii) Y 3 is a carbonyl and R 19 is a C 1 -C 4 alkyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
18. The compound according to claim 4 , wherein R 1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
19. The compound according to claim 4 , wherein Y 1 is a straight chain or branched chain C 1 -C 5 alkylene, —CO(CH 2 ) n —, or —SO 2 (CH 2 ) n —, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
20. The compound according to claim 4 , wherein Y 1 is a direct bond, —CO—, or —SO 2 —, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
21. The compound according to claim 4 , wherein Y 1 is a direct bond or a —CO—, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
22. The compound according to claim 4 , wherein the wavy line means (Z)-configuration, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
23. The compound according to claim 4 , wherein Y 2 is ethylene or trimethylene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
24. The compound according to claim 4 , wherein R 4 is an alkanoyl, an alkylcarbamoyl, an alkylaminothiocarbonyl, or an alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
25. The compound according to claim 4 , wherein R 4 is an alkanoyl, or an alkylcarbamoyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
26. The compound according to claim 4 , wherein R 5 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
27. A medicament, which comprises the compound as set forth in any one of claims 1 - 4 , 5 , 6 - 17 and 18 to 26 , or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
28. A method for inhibiting leukocyte infiltration, which comprises administering an effective amount of the compound as set forth in any one of claims 1 - 4 , 5 , 6 - 17 and 18 , 26 , or a pharmaceutically acceptable salt thereof, or a prodrug thereof to a patient in need.
29. A method for treatment of inflammation, which comprises administering an effective amount of the compound as set forth in any one of claims 1 - 4 , 5 , 6 - 17 and 18 to 26 , or a pharmaceutically acceptable salt thereof, or a prodrug thereof to a patient in need.
30. A method for treatment of autoimmune inflammation or allergic inflammation, which comprises administering an effective amount of the compound as set forth in any one of claims 1 - 4 , 5 , 6 - 17 and 18 to 26 , or a pharmaceutically acceptable salt thereof, or a prodrug thereof to a patient in need.