Pyridone derivatives having affinity for cannabinoid 2-type receptor

• US 20040082619A1
• Filed: 06/30/2003
• Published: 04/29/2004
• Est. Priority Date: 12/28/2000
• Status: Active Grant

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Tada, Yukio, Iso, Yasuyoshi, Hanasaki, Kohji
• Granted Patent: US 6,977,266 B2
• Time in Patent Office: Days
• US Class Current: 514/340
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/69 Two or more oxygen atoms
• CPC Class Codes: C07D 213/70 Sulfur atoms
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/227 only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 217/22 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 217/26 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 221/10 Aza-phenanthrenes
• CPC Class Codes: C07D 221/16 containing carbocyclic rings other than six-membered
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 455/02 : containing not further condensed quinolizine ring systems
• CPC Class Codes: C07D 455/06 : containing benzo [a] quinolizine ring systems
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems

Abstract

It was found that the compound having a binding activity to the cannabinoid type 2 receptor represented by the formula (I):

wherein R¹ is a group represented by the formula: —Y¹—Y²—Y³—R^a wherein Y¹ is single bond or the like; Y² is —C(═O)—NH— or the like; Y³ is optionally substituted aryl or the like; R² is hydrogen or the like; R³ is alkyl or the like; R⁴ is alkyl or the like; R⁵ is optionally substituted alkyl or the like; or R³ and R⁴ taken together with the adjacent atom form cyclic group or the like.

Claims

1. A pharmaceutical composition having a binding activity to the cannabinoid type 2 receptor which contains as an active ingredient a compound of the formula (I):

2. The pharmaceutical composition according to claim 1 which has a binding activity to the cannabinoid type 2 receptor wherein R⁵ is optionally substituted C₂ or more alkyl which may have heteroatom and/or unsaturated bond or a group represented by the formula:

—

Y⁶—

R^e wherein Y⁶ and R^e are as defined in claim 1.

3. The pharmaceutical composition according to claim 2 which has a binding activity to the cannabinoid type 2 receptor wherein R⁵ is optionally substituted C₃ or more alkyl which may have heteroatom and/or unsaturated bond or a group represented by the formula:

—

Y⁶—

R^e wherein Y⁶ is optionally substituted alkylene;

R^e is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclic group.

4. The pharmaceutical composition according to any one of claims 1 to 3 which has a binding activity to the cannabinoid type 2 receptor wherein R¹ is a group represented by the formula:

—

Y¹—

Y²—

Y³—

R^a wherein Y¹, Y², Y³, R^a, and R^b are as defined in claim 1.

5. The pharmaceutical composition according to claim 4 which has a binding activity to the cannabinoid type 2 receptor wherein R¹ is a group represented by the formula:

—

Y¹—

Y²—

Y³—

R^a wherein Y¹, Y², Y³, and R^a are as defined in claim 1;

Y² is —

O—

, —

NR^b—

C(═

O)—

or —

C(═

O)—

NR^b—

;

R^b is hydrogen or optionally substituted alkyl.

6. The pharmaceutical composition according to any one of claims 1 to 5 which has a binding activity to the cannabinoid type 2 receptor wherein R³ and R⁴ are not taken together.

7. The pharmaceutical composition according to claim 6 which has a binding activity to the cannabinoid type 2 receptor wherein R³ is hydrogen, optionally substituted alkyl, halogen, or a group represented by the formula:

—

Y⁵—

R^d wherein Y⁵ is single bond, optionally substituted alkylene, alkenylene, alkynylene;

R^d is optionally substituted aryl or optionally substituted heteroaryl;

R⁴ is hydrogen or optionally substituted alkyl;

provided that the case wherein R³ and R⁴ are hydrogen at the same time is excluded.

8. The pharmaceutical composition according to any one of claims 1 to 5 which has a binding activity to the cannabinoid type 2 receptor wherein R³ and R⁴ taken together with the adjacent atom form optionally substituted cyclic group which may have heteroatom and/or unsaturated bond;

provided that the case wherein the optionally substituted cyclic group is optionally substituted benzene ring is excluded.

9. The pharmaceutical composition according to claim 1 which has a binding activity to the cannabinoid type 2 receptor wherein R¹ is hydrogen, cyano, formyl, carboxy, isothiocyanato, amino, hydroxy, carbamoyl, or a group represented by the formula:

—

Y¹—

Y²—

Y³—

R^a wherein Y¹ and Y³ each is independently single bond or optionally substituted alkylene (the substituent is halogen, alkenylene, hydroxy, azide, amino, acylamino, alkylsulfonylamino, alkenyloxycarbonylamino, alkoxycarbonylamino, alkenylamino, arylcarbonylamino, heteroarylcarbonylamino, cyano, alkoxy, alkylsulfonyloxy, trialkylsilyloxy, oxo, methylene, halogenated alkoxycarbonyloxy formyloxy and/or acylthio);

Y² is single bond, —

O—

, —

O—

C(═

O)—

, —

O—

C(═

O)—

O—

, —

O—

C(═

O)—

NH—

, —

NH—

, —

NR^b—

C(═

O)—

, —

NH—

C(═

O)—

O—

, —

NH—

C(═

O)—

NH—

, —

NH—

C(═

S)—

NH—

, —

S—

, —

SO₂—

O—

, —

SO₂—

NH—

, —

SO₂—

NH—

C(═

O)—

NH—

, —

C(═

O)—

O—

, —

C(═

O)—

NR^b—

, —

C(═

S)—

NH—

, —

C(═

O)—

NH—

C(═

O)—

, —

C(═

O)—

NH—

C(═

S)—

O—

, —

C(═

O)—

, —

C(═

O)—

NR^b—

C(═

NR^b)—

, or —

C(═

O)—

NH—

NR^b—

;

R^a is optionally substituted alkyl (the substituent is hydroxy and/or aralkyl), alkenyl, optionally substituted aryl (the substituent is carboxy, optionally substituted amino, alkoxy, alkylthio, alkylenedioxy, halogen, alkyl, hydroxy, halogenated alkyl and/or halogenated alkoxy), optionally substituted cycloalkyl (the substituent is aryl and/or hydroxy), optionally substituted cycloalkenyl (the substituent is alkenylene, hydroxy, alkylsulfonyloxy, azide, amino and/or acylamino), optionally substituted heteroaryl (the substituent is oxo, heteroaryl, halogen, aryl and/or alkyl), or optionally substituted heterocyclic group (the substituent is aryl optionally substituted halogen, aralkyl, acyl, arylcarbonyl, cycloalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkyl and/or halogenated alkylcarbonyl);

R^b is hydrogen, alkyl, acyl, hydroxy and/or alkoxy;

R² is hydrogen, alkyl, alkenyl, or a group represented by the formula;

—

Y⁴—

R^c wherein Y⁴ is —

O—

;

R^c is heteroaryl;

R³ is hydrogen, alkyl, halogen, or a group represented by the formula;

—

Y⁵—

R^d wherein Y⁵ is single bond, alkylene, —

C(═

O)—

NH-alkylene-;

R^d is optionally substituted aryl (the substituent is halogen, alkyl, alkoxy, alkylenedioxy and/or halogenated alkyl) or optionally substituted heteraryl (the substituent is halogen, alkyl, alkoxy, alkylenedioxy and/or halogenated alkyl);

R⁴ is hydrogen or alkyl;

R⁵ is hydrogen, optionally substituted C₃ or more alkyl which may have heteroatom and/or unsaturated bond (the substituent is halogen, hydroxy, azide, amino, alkoxy, alkenyloxy, alkylsulfonyloxy, acylthio, acylamino, arylcarbonylamino, cycloalkylcarbonylamino, halogenated alkylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, formyl, oxo and/or cyano) or a group represented by the formula;

—

Y⁶—

R^e wherein Y⁶ is alkylene;

R^e is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl or optionally substituted heterocyclic group;

or

R² and R³ taken together with the adjacent atom form optionally substituted cyclic group (the substituent is oxo and/or hydroxy), R³ and R⁴ taken together with the adjacent atom form optionally substituted cyclic group which may have heteroatom and/or unsaturated bond (the substituent is acyl, aralkyl, alkenylene and/or alkylene), or R⁴ and R⁵ taken together with the adjacent atom form optionally substituted carbocyclic group which may have unsaturated bond (the substituent is alkenylene).

10. The pharmaceutical composition according to any one of claims 1 to 9 which has a binding activity to the cannabinoid type 2 receptor as an anti-inflammatory agent.

11. The pharmaceutical composition according to any one of claims 1 to 9 which has a binding activity to the cannabinoid type 2 receptor as an immunosuppressive agent.

12. The pharmaceutical composition according to any one of claims 1 to 9 which has a binding activity to the cannabinoid type 2 receptor as a nephritis treating agent.

13. The pharmaceutical composition according to any one of claims 1 to 9 which has a binding activity to the cannabinoid type 2 receptor of any one of claims 1 to 9 as an analgesic agent.

14. A compound of the formula (I):

15. The compound according to claim 14 wherein R¹ is a group represented by the formula:

—

Y¹—

Y²—

Y³—

R^a wherein Y¹, Y³, R^a are as defined in claim 14;

Y² is —

O—

, —

NR^b—

C(═

O)—

or —

C(═

O)—

NR^b—

;

R^b is hydrogen or optionally substituted alkyl;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

16. The compound according to claim 14 or 15 wherein R³ and R⁴ are not taken together;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

17. The compound according to claim 14 or 15 wherein R³ and R⁴ taken together with the adjacent atoms form cyclic group which may have heteroatom and/or unsaturated bond;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

18. The compound according to claim 14 wherein R¹ is a group represented by the formula:

—

Y¹—

Y²—

Y³—

R^a wherein Y¹ is single bond;

Y³ is optionally substituted alkylene;

Y² is —

O—

, —

NH—

C(═

O)—

, or —

C(═

O)—

NH—

;

R^a is optionally substituted carbocyclic group or optionally substituted heterocyclic group;

R² is hydrogen;

R³ is alkyl, halogen or a group represented by the formula;

—

Y⁵—

R^d wherein Y⁵ is single bond;

R^d is optionally substituted carbocyclic group or optionally substituted heterocyclic group;

R⁴ is hydrogen or alkyl;

R⁵ is optionally substituted C₃ or more alkyl or a group represented by the formula;

—

Y⁶—

R^e wherein Y⁶ is optionally substituted alkylene;

R^e is optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heteroaryl;

or

R³ and R⁴ taken together with the adjacent atoms form cyclic group which may have heteroatom and/or unsaturated bond;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

29. A pharmaceutical composition which contains as an active ingredient a compound of claims 14 to 18, 20, 22, and 24 to 28.

30. The pharmaceutical composition according to claim 29 which has a binding activity to the cannabinoid type 2 receptor.

31. The pharmaceutical composition according to claim 29 which is useful as an anti-inflammatory agent.

32. The pharmaceutical composition according to claim 29 which is useful as an immunosuppressive agent.

33. The pharmaceutical composition according to claim 29 which is useful as a nephritis treating agent.

34. The pharmaceutical composition according to claim 29 which is useful as an analgesic agent.

35. A method for treating the diseases related to the cannabinoid type 2 receptor which comprises the administration of a compound of any one of claims 1 to 13.

36. Use of the compound according to claims 1 to 13 for the preparation of a treating agent against the diseases related to the cannabinoid type 2 receptor.

19. A library of compound of the formula (I):

20. The compound according to claim 19;

provided that the case wherein R³ and R⁴ taken together with adjacent atom form 6-membered carbocyclic group (provided that the bond between carbon atom substituted with R³ and carbon atom substituted R⁴ is the double bond, and the other bonds between carbon atoms are single bond), and R¹ is a group represented by the formula;

—

Y¹—

Y²—

Y³—

R^a wherein Y¹ and Y³ are single bond;

Y² is —

O—

;

R^a is phenyl is excluded;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

21. A library of compound of the formula (I):

22. The compound according to claim 21;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

23. A library of compound of the formula (I):

24. The compound according to claim 23;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

25. A compound of the formula:

26. The compound according to claim 25 wherein Y is —

(CH₂)₃—

;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

28. The compound according to any one of claims 25 to 27 wherein Y³ is optionally substituted alkylene;

a prodrug, a pharmaceutically acceptable salt or solvate thereof.

27. A compound of the formula: