US2011039822A1PendingUtilityA1

Heterocyclic janus kinase 3 inhibitors

Assignee: ASTELLAS PHARMA INCPriority: Dec 28, 2005Filed: Oct 28, 2010Published: Feb 17, 2011

Est. expiryDec 28, 2025(expired)· nominal 20-yr term from priority

Inventors:Takayuki Inoue Akira Tanaka Kazuo Nakai Hiroshi Sasaki Fumie Takahashi Shohei Shirakami Keiko Hatanaka Yutaka Nakajima Koichiro Mukoyoshi Hisao Hamaguchi Shigeki Kunikawa Yasuyuki Higashi

A61P 35/00A61P 37/08A61P 37/00A61P 43/00A61P 35/02A61P 37/06A61P 25/28A61P 29/00A61P 25/00A61P 17/00A61P 11/06A61P 17/06A61P 19/02A61P 11/00C07D 471/14C07D 519/00A61K 31/437C07D 471/04C07D 451/04

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References

Claims

Abstract

The present invention provides a compound having an excellent JAK3 inhibition activity and being useful as an active ingredient of an agent for treating and/or preventing various immune diseases including autoimmune diseases, inflammatory diseases, and allergic diseases. As a result of studies on a novel condensed heterocyclic derivative, the inventors have found that a compound having a cross-linked structure has an excellent JAK3 inhibition activity, and have completed the present invention. In other words, it is verified that the compound according to the present invention has an inhibition activity against JAK3 and is thus useful as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission (e.g., rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, Alzheimer's disease, and atherosclerotic disease), or diseases caused by abnormal cytokine signal transmission (e.g., cancer and leukemia).

Claims

exact text as granted — not AI-modified

1 . A condensed pyridine compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

wherein
X is N or CR 3 ,
M is (CH 2 ) m ; m is 0 or 1,
R 1 is —H or lower alkyl which may be substituted,
R 2 is —H or lower alkyl which may be substituted,
R 3 is —H, halogen, or lower alkyl which may be substituted,
R 41 is —H or heteroaryl which may be substituted,
R 42 is polycyclic bridged cyclic hydrocarbon having three rings or aza-bridged cyclic hydrocarbon, each of which may be substituted,
R 5 is a group selected from the group consisting of cyano, acyl, acylamino, lower alkyl, lower alkenyl, —O-lower alkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, and 5-membered heteroaryl, each of which may be substituted,
provided that when R 5 is 5-membered heteroaryl, X is —CR 3 ,
or R 41 and R 5 may be linked via a specific functional group to form bivalent group selected from:

wherein R A is —H or acyl which may be substituted,
wherein “which may be substituted” in definitions of R 1 , R 2 , R 3 , R 41 , R 42 and R 5 , consisting of the groups described in items (a) to (g),
(a) halogen;
(b) —OH, —O—R Z , —O-phenyl, —OCO—R Z , —OCONH—R Z , oxo (═O);
(c) —SH, —S—R Z , —S-phenyl, —S-heteroaryl, —SO—R Z , —SO-phenyl, —SO-heteroaryl, —SO 3 H, —SO 2 —R Z , —SO 2 -phenyl, —SO 2 -heteroaryl, sulfamoyl which may be substituted with one or two R Z groups;
(d) amino which may be substituted with one or two R Z groups, —NHCO—R Z , —NHCO-phenyl, —NHCO 2 —R Z , —NHCONH 2 , —NHCONH—R Z , —NHSO 2 -phenyl, —NHSO 2 NH 2 , —NO 2 , ═N—O—R Z ;
(e) —CHO, —CO—R Z , —CO 2 H, —CO 2 —R Z , carbamoyl which may be substituted with one or two R Z groups, —CO-cyclic amino, —COCO—R Z , cyano;
(f) R Z ; and
(g) phenyl which may be substituted with one or more groups selected from the substituents described in the above items (a) to (f), 5- or 6-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; wherein R Z is cyano; —OH; and lower alkyl which may be substituted with one to three groups selected from the group consisting of —O-lower alkyl, —NH-lower alkyl, —CONH-lower alkyl, 5- or 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.

2 . The compound according to claim 1 , or a pharmaceutical acceptable salt thereof, wherein
R 1 is —H or lower alkyl which may be substituted with a group selected from the group consisting of mono- or di-lower alkylamino and —O-lower alkyl, R 2 is —H or lower alkyl, R 3 is —H or lower alkyl substituted with a group selected from the group consisting of halogen, mono- or di-lower alkylamino, and cyclic amino, R 41 is —H or heteroaryl which may be substituted with cyano, R 42 is polycyclic bridged cyclic hydrocarbon having three rings or aza-bridged cyclic hydrocarbon, each of which may be substituted, R 5 is a group selected from the group consisting of cyano, lower alkylcarbonyl, lower alkyloxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, —C (═O)-5- or -6-membered heterocycloalkyl, —C(═O)-5- or -6-membered heteroaryl, lower alkyl, lower alkenyl, —O-lower alkyl, 5- or 6-membered heterocycloalkyl, and 5-membered heteroaryl, each of which may be substituted, provided that when R 5 is 5-membered heteroaryl, X is —CR 3 .

3 . The compound according to claim 1 , or a pharmaceutical acceptable salt thereof, wherein R 42 is adamantyl or tropanyl, each of which may be substituted.

4 . The compound according to claim 1 , or a pharmaceutical acceptable salt thereof, wherein R 5 is carbamoyl, 5-membered heteroaryl, lower alkylcarbonyl, each of which may be substituted with NH 2 , hydroxymethyl or OH;
or R 41 and R 5 may be linked via a specific functional group to form (I-A); or R 41 and R 5 may be linked via a specific functional group to form (I-B); or R 41 and R 5 may be linked via a specific functional group to form (I-C), wherein R A is —C(═O)—C(═O)NH-lower alkyl which may be substituted with lower alkyloxy.

5 . The compound according to claim 1 , or a pharmaceutical acceptable salt thereof, wherein R 5 is oxadiazole or thiadiazole, each of which may be substituted.

6 . The compound according to claim 1 , or a pharmaceutical acceptable salt thereof, wherein R 42 is polycyclic bridged cyclic hydrocarbon having three rings and which may be substituted.

7 . The compound according to claim 6 , or a pharmaceutical acceptable salt thereof, wherein R 42 is adamantyl which may be substituted.

8 . The compound according to claim 1 , or a pharmaceutical acceptable salt thereof, wherein R 42 is aza-bridged cyclic hydrocarbon having three rings and which may be substituted.

9 . The compound according to claim 8 , or a pharmaceutical acceptable salt thereof, wherein R 42 is tropanyl which may be substituted.

10 . The compound according to claim 1 , or a pharmaceutical acceptable salt thereof, wherein X in the formula (I) is CH, R 1 is —H, R 2 is —H or CH 3 , R 41 is —H, R 42 is adamantyl or tropanyl and each of which may be substituted with OH, R 5 is carbamoyl which may be substituted or —C(═O)-lower alkyl which may be substituted by OH.

11 . The compound according to claim 10 , or a pharmaceutical acceptable salt thereof, wherein R 5 is —CONH 2 or hydroxyacetyl.

12 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

13 . A method of inhibiting janus kinase 3 activity in a patient with diseases or conditions caused by undesirable cytokine signal translations mediated by janus kinase 3, comprising administering to said patient a compound according to claim 1 , or a pharmaceutical acceptable salt thereof.

14 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering an effective amount of a compound according to claim 1 , or a pharmaceutical acceptable salt thereof, to said human being or animal in need thereof.

15 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administering an effective amount of a compound according to claim 1 , or a pharmaceutical acceptable salt thereof, to said human being or animal in need thereof.

16 . The method of claim 15 , wherein said autoimmune disease is rheumatoid arthritis.

17 . The method of claim 15 , wherein the autoimmune disease is psoriasis.

18 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, of a compound selected from the group consisting of:

19 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a compound selected from the group consisting of:

20 . The method of claim 19 , wherein said autoimmune disease is rheumatoid arthritis.

21 . The method of claim 19 , wherein the autoimmune disease is psoriasis.

22 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

23 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

24 . The method of claim 23 , wherein said autoimmune disease is rheumatoid arthritis.

25 . The method of claim 23 , wherein the autoimmune disease is psoriasis.

26 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

27 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

28 . The method of claim 27 , wherein said autoimmune disease is rheumatoid arthritis.

29 . The method of claim 27 , wherein the autoimmune disease is psoriasis.

30 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

31 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

32 . The method of claim 31 , wherein said autoimmune disease is rheumatoid arthritis.

33 . The method of claim 31 , wherein the autoimmune disease is psoriasis.

34 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

35 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

36 . The method of claim 35 , wherein said autoimmune disease is rheumatoid arthritis.

37 . The method of claim 35 , wherein the autoimmune disease is psoriasis.

38 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

39 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

40 . The method of claim 39 , wherein said autoimmune disease is rheumatoid arthritis.

41 . The method of claim 39 , wherein the autoimmune disease is psoriasis.

42 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

43 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

44 . The method of claim 43 , wherein said autoimmune disease is rheumatoid arthritis.

45 . The method of claim 43 , wherein the autoimmune disease is psoriasis.

46 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

47 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

48 . The method of claim 47 , wherein said autoimmune disease is rheumatoid arthritis.

49 . The method of claim 47 , wherein the autoimmune disease is psoriasis.

50 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

51 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

52 . The method of claim 51 , wherein said autoimmune disease is rheumatoid arthritis.

53 . The method of claim 51 , wherein the autoimmune disease is psoriasis.

54 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

55 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

56 . The method of claim 55 , wherein said autoimmune disease is rheumatoid arthritis.

57 . The method of claim 55 , wherein the autoimmune disease is psoriasis.

58 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

59 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

60 . The method of claim 59 , wherein said autoimmune disease is rheumatoid arthritis.

61 . The method of claim 59 , wherein the autoimmune disease is psoriasis.

62 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

63 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

64 . The method of claim 63 , wherein said autoimmune disease is rheumatoid arthritis.

65 . The method of claim 63 , wherein the autoimmune disease is psoriasis.

66 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

67 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

68 . The method of claim 67 , wherein said autoimmune disease is rheumatoid arthritis.

69 . The method of claim 67 , wherein the autoimmune disease is psoriasis.

70 . A method for treating a rejection during organ/tissue transplantation in a human being or animal in need thereof, wherein said method comprises administering to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

71 . A method for treating an autoimmune disease in a human being or animal in need thereof, wherein said method comprises administrating to said human being or animal in need thereof an effective amount of a pharmaceutically acceptable salt form of a compound having the formula:

72 . The method of claim 71 , wherein said autoimmune disease is rheumatoid arthritis.

73 . The method of claim 71 , wherein the autoimmune disease is psoriasis.

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