Ccr4 antagonist and medical use thereof

• US 20060004010A1
• Filed: 07/08/2003
• Published: 01/05/2006
• Est. Priority Date: 07/10/2002
• Status: Abandoned Application

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Shibayama, Shiro, Habashita, Hiromu, Tada, Hideaki, Kokubo, Masaya, Sagawa, Kenji
• Application Number:
  US10/520,660
• Publication Number:
  US 20060004010A1
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 241/22 : Benzenesulfonamido pyrazines
• CPC Class Codes: C07D 241/26 : with nitrogen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/44 : 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 hetero ring
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

A compound of formula (I) or a salt thereof, and medical use thereof (the symbols in the formula are as described in the specification). The compound of formula (I) has CCR4 antagonistic activity, and therefore is useful as a preventive and/or therapeutic agent for diseases associated with CCR4, i.e., CCR4-mediated diseases such as inflammatory and/or allergic diseases [e.g., systemic inflammatory response syndrome (SIRS), anaphylaxis or anaphylaxis-like reaction, allergic vasculitis, reject reaction for graft organ, hepatitis, nephritis, nephrosis, pancreatitis, rhinitis, arthritis, inflammatory ocular diseases, inflammatory bowel diseases, diseases in cerebro and/or circulatory system, respiratory diseases, dermatic diseases, autoimmune diseases, etc.], and the like.

Claims

1. A compound of formula (I):

2. The compound according to claim 1, wherein

3. The compound according to claim 2, wherein ring D is a carbocyclic ring which may be substituted.

4. The compound according to claim 2, wherein ring D is a heterocyclic ring which may be substituted.

5. The compound according to claim 4, wherein the heterocyclic ring is a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s).

6. The compound according to claim 2, wherein

7. The compound according to claim 6, wherein

8. The compound according to claim 1, wherein ring A is a carbocyclic ring which may be substituted.

9. The compound according to claim 1, wherein ring A is a heterocyclic ring which may be substituted.

10. The compound according to claim 8, wherein the carbocyclic ring is a C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring.

11. The compound according to claim 9, wherein the heterocyclic ring is a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s).

12. The compound according to claim 10, wherein the carbocyclic ring is a benzene ring or a naphthalene ring.

13. The compound according to claim 11 wherein the heterocyclic ring is a pyridine ring, a pyrazole ring, a dioxaindane ring or a benzodioxane ring.

14. The compound according to claim 1, wherein ring B is a carbocyclic ring which may be substituted.

15. The compound according to claim 1, wherein ring B is a heterocyclic ring which may be substituted.

16. The compound according to claim 14, wherein the carbocyclic ring is a C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring.

17. The compound according to claim 15;

wherein the heterocyclic ring is a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s).

18. The compound according to claim 16, wherein the carbocyclic ring is a C3-8 monocyclic carbocyclic ring.

19. The compound according to claim 17, wherein the heterocyclic ring is a 3- to 8-membered monocyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s).

20. The compound according to claim 18, wherein the carbocyclic ring is a benzene ring.

21. The compound according to claim 19, wherein the heterocyclic ring is a pyridine ring or a thiophene ring.

22. The compound according to claim 1, wherein J is a spacer having 1 to 8 atoms in its main chain and containing at least one oxygen atom.

23. The compound according to claim 22, wherein the oxygen atom binds to ring D.

24. The compound according to claim 22, wherein J is

25. The compound according to claim 24, wherein R³ and R⁴ each independently represents hydrogen or methyl.

26. The compound according to claim 24, wherein E is a bond,

27. The compound according to claim 24, wherein E is a spacer having 1 to 6 atoms in its main chain.

28. The compound according to claim 27, wherein E is C1-4 alkylene or C1-3 alkyleneoxy.

29. The compound according to claim 28, wherein E is methylene or methylenoxy.

30. The compound according to claim 1, wherein G is a spacer having 1 to 4 atoms in its main chain and containing at least one nitrogen atom.

31. The compound according to claim 30, wherein G is —

NR^T1—

, —

NR^T1—

SO₂—

, —

NR^T1—

CO—

, —

NR^T1—

CO—

NR^T2—

, —

NR^T1—

SO₂—

NR^T2—

, —

NR^T1—

COO—

, —

NR^T1—

O—

, —

NR^T1—

NR^T2—

, —

NR^T1—

W—

, —

SO₂—

NR^T1—

, —

CO—

NR^T1—

, —

OCO—

NR^T1—

, —

O—

NR^T1—

or W—

NR^T1—

, wherein W represents a bivalent C1-3 aliphatic hydrocarbon group which may be substituted;

R^T1 and R^T2 each independently represents hydrogen, C1-8 alkyl which may be substituted, C2-8 alkenyl which may be substituted, C2-8 alkynyl which may be substituted or a 3- to 8-membered cyclic group which may be substituted.

32. The compound according to claim 31, wherein G is —

NH—

SO₂—

.

33. The compound according to claim 1, wherein the compounds is a compound of formula (A):

34. A prodrug for the compound according to claim 1.

44. A method for preventing and/or treating CCR4-mediated diseases in a mammal, which comprises administering to a mammal an effective amount of the compound according to claim 1 or a salt thereof.

45. Use of the compound according to claim 1 or a salt thereof for the manufacture of a preventive and/or therapeutic agent for CCR4-mediated diseases.

46. A pharmaceutical composition which comprises:

a preventive and/or therapeutic agent for CCR4-mediated diseases, which comprises the compound according to claim 1 or a salt thereof as an active ingredient; and

one or at least two medicaments selected from a bronchodilator drug, a steroid drug, a non-steroidal antiinflammatory drug, a leukotriene receptor antagonist, a phosphodiesterase inhibitor, an immunosuppressant, an anti-allergic drug, a mediator-release inhibitor, an antihistamine drug, a metabolism promoter and/or a chemokine inhibitor.

35. A pharmaceutical composition which comprises the compound of formula (I):

36. The pharmaceutical composition according to claim 35, which is a chemokine receptor antagonist.

37. The pharmaceutical composition according to claim 36, wherein the chemokine receptor is CCR4.

38. The pharmaceutical composition according to claim 37, which is a preventive and/or therapeutic agent for CCR4-mediated diseases.

39. The pharmaceutical composition according to claim 38, wherein the CCR4-mediated diseases are inflammatory and/or allergic diseases, metabolism and/or endocrine system diseases, cancer diseases or infections.

40. The pharmaceutical composition according to claim 39, wherein the CCR4-mediated diseases are inflammatory and/or allergic diseases.

41. The pharmaceutical composition according to claim 40, wherein the inflammatory and/or allergic diseases are respiratory diseases or dermatosis.

42. The pharmaceutical composition according to claim 41, wherein the respiratory diseases are asthma.

43. The pharmaceutical composition according to claim 41, wherein the dermatosis is atopic dermatitis.

47. The pharmaceutical composition according to claim 35, which is an inhibitor of effector cell function.

48. The pharmaceutical composition according to claim 47, which is an inhibitor of cell migration function.

49. The pharmaceutical composition according to claim 35, which is a TNFα

regulator.