Piperidine/piperazine-type inhibitors of p38 kinase

• US 6,696,443 B2
• Filed: 11/20/2001
• Issued: 02/24/2004
• Est. Priority Date: 11/20/2000
• Status: Expired due to Fees

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Tan, Xuefei, Dugar, Sundeep, Luedtke, Gregory, McEnroe, Glenn, Mavunkel, Babu
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Habte, Kahsay
• Application Number:
  US09/990,184
• Publication Number:
  US 20020198214A1
• Time in Patent Office: 826 Days
• Field of Search: 544/180, 544/182, 544/236, 544/238, 544/257, 544/279, 544/333, 544/350, 514/333, 514/350, 514/242, 514/241, 514/248, 514/252.03, 514/255.05, 514/259.3, 514/259.2, 514/259.41, 514/256, 514/300-302, 514/314, 514/318-324, 514/326, 546/114, 546/115, 546/121, 546/122, 546/139, 546/194, 546/199, 546/208, 546/209, 546/202, 546/211, 546/212, 546/214
• US Class Current: 514/241
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• 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 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C07D 207/416 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 other ring carbon atoms
• CPC Class Codes: C07D 211/18 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Certain compounds which contain a piperidine moiety flanked by aryl groups are inhibitors of p38-α kinase and thus useful in the treatment of a variety of conditions characterized by inappropriate p38-α kinase activity.

Claims

1. A compound of the formula:

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein;

Ar¹ is an aryl group substituted with 0-5 non-interfering substituents, wherein two adjacent noninterfering substituents can form a fused aromatic or nonaromatic ring;

L¹ and L² are linkers;

each R¹ is independently a noninterfering substituent;

R² is hydrogen or a noninterfering substituent;

m is 0-4;

Ar² is a substantially planar, monocyclic or polycyclic aromatic moiety having one or more optional ring heteroatoms, said moiety being optionally substituted with one or more non-interfering substituents, two or more of which may form a fused ring;

Z is —

W_i—

COX_jY wherein Y is COR³ or an isostere thereof;

R³ is a noninterfering substituent, each of W and X is a spacer of 2-6 Å

, and each of i and j is independently 0 or 1;

wherein the distance in space between the atom of Ar¹ bonded to L² and the atom of Ar² bonded to L¹ is no more than 24 angstroms;

with the proviso that the portion of the compound represented by Ar²—

Z is not

 

wherein represents a single or double bond;

one Z² is CA or CRA and the other is CR, CR₂, NR or N;

A is —

W_i—

COX_jY wherein Y is COR or an isostere thereof, each of W and X is a spacer of 2-6 Å

, and each of i and j is independently 0 or 1;

Z³ is NR or O; and

each R is independently hydrogen or a noninterfering substituent.

2. The compound of claim 1 wherein Z is COX_jCOR³, and

wherein R³ is H, or is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, heteroalkyl, SR, SOR, SO₂R, SO₂NR₂, OR, NR₂, OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, CN, COOR, CONR₂, COR, or R₃Si wherein each R is independently H, alkyl, alkenyl or aryl or the heteroatom-containing forms thereof, or

wherein R³ is OR, NR₂, SR, NRCONR₂, OCONR₂, or NRSO₂NR₂, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroatom-containing forms thereof, and wherein two R attached to the same atom may form a 3-8 member carbocyclic or heterocyclic ring and wherein said ring may further be substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with halo, SR, OR, NR₂, OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, or R₃Si wherein each R is independently H, alkyl, alkenyl or aryl or the heteroatom-containing forms thereof wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined; and

X, if present, is CR₂ where R is as defined above.

3. The compound of claim 1 wherein Y is an isostere of COR³.

4. The compound of claim 3 wherein Y is tetrazole;

1,2,3-triazole;

1,2,4-triazole;

or imidazole.

5. The compound of claim 1 wherein each of i and j is 0.

6. The compound of claim 2 wherein j is 0.

7. The compound of claim 1 wherein —

Ar²—

comprises an optionally substituted monocyclic or polycyclic aromatic nucleus, wherein said aromatic nucleus consists of carbocyclic or heterocyclic ring selected from (i) a five-membered heterocyclic or carbocyclic ring (ii) a six-membered carbocyclic or heterocyclic ring;

(iii) a five-membered carbocyclic or heterocyclic ring fused to another five-membered carbocyclic or heterocyclic ring;

(iv) a six-membered carbocyclic or heterocyclic ring fused to another six-membered carbocyclic or heterocyclic ring; and

(v) a five-membered heterocyclic or carbocyclic ring fused to a six-membered carbocyclic or heterocyclic ring.

8. The compound of claim 7 wherein Ar² is selected from:

wherein G is CR₂, NR, O or S; and

H is N or CR

wherein R is hydrogen or a noninterfering substituent.

9. The compound of claim 7 wherein the portion of said compound represented by L¹—

Ar—

Z is selected from the following;

wherein n is 0, 1 or 2;

X¹ is NR, CR₂, O or S; and

each R is independently H or a noninterfering substituent; and

two or more R groups may form a fused ring;

wherein n is 0-4;

R is H or a noninterfering substituent where two or more R groups may form a fused ring; and

one or more ring carbons may be optionally replaced with nitrogen;

wherein each n is independently 0 to 3;

R is H or a noninterfering substituent, where two or more R groups may form a fused ring; and

one or more ring carbons may be optionally replaced with nitrogen;

wherein, subject to the proviso of claim 1, one B is L¹ and the other is Z;

wherein a is 0 to 4 such that the positions on the six membered rings (1) and (3) to which (R)_a is bonded can include X² when X² is C;

b is 0-3 such that the positions on the five-membered rings (2) and (4) to which (R)_b is bonded can include X² and X¹, when X² is C and X¹ N or C;

each X² is independently N or CR;

X¹ NR, CR₂, O or S;

each R is H or a noninterfering substituent where two or more R groups may form a fused ring;

wherein one or more of the ring carbons that are at positions other than X² or X¹ and that are also not bound to B can be optionally replaced with N;

wherein one B is L¹ and the other is Z;

a is 0-4 such that the positions on the rings (1) and (3) to which (R)_a can be bonded include X² and X¹ where X² is C and X¹ is C or N;

b is 0 or 3 such that the positions on the rings (2) and (4) to which (R)_b can be bonded include X¹, X² and X³ when X¹ is C or N and X² and/or X³ are C;

each X¹ is independently NR, C(R)₂, O or S;

X² and X³ are independently N or CR;

each R is independently H or a noninterfering substituent where two or more R groups can optionally form a fused ring;

wherein one or more of the ring carbons that are at positions other than X¹, X² or X³, and that are also not bound to B, can be optionally replaced with N.

10. The compound of claim 9 wherein L¹—

Ar²—

Z is structure (I).

11. The compound of claim 10 wherein X¹ in structure (I) is NR.

12. The compound of claim 11 wherein X¹ in structure (I) is NH.

13. The compound of claim 12 wherein R is methyl.

14. The compound of claim 13 wherein n is 2.

15. The compound of claim 14 wherein structure (I) is:

16. The compound of claim 9 wherein L¹—

Ar²—

Z is structure (II).

17. The compound of claim 16 wherein the R in structure (II) is methoxy.

18. The compound of claim 17 wherein n in structure (II) is 1.

19. The compound of claim 18 wherein structure (II) is

20. The compound of claim 19 wherein the compound is:

21. The compound of claim 9 wherein L¹—

Ar²—

Z is structure (III).

22. The compound of claim 9 wherein L¹—

Ar²—

Z is structure (IV-a) or (IV-b).

23. The compound of claim 22 wherein L¹—

Ar²—

Z is (IV-a) and both X² in structure (IV-a) are nitrogen.

24. The compound of claim 23 wherein structure (IV) is:

25. The compound of claim 24 wherein the compound is:

26. The compound of claim 7 wherein L¹—

Ar²—

Z is structure (V-a) or (V-b).

27. The compound of claim 26 wherein L¹—

Ar²—

Z is structure (V-a) and X² and X³ in structure (V-a) are N.

28. The compound of claim 27 wherein at least one R in structure (V) is methyl.

29. The compound of claim 27 wherein X¹ in structure (V) is S.

30. The compound of claim 29 where in structure (V) is:

31. The compound of claim 30 wherein the compound is:

32. The compound of claim 1 wherein L¹ is CO, CHOH or CH₂.

33. The compound of claim 32 wherein L¹ is CO.

34. The compound of claim 1 wherein R² is H, OR, NR₂, SR or halo, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroatom-containing forms thereof.

35. The compound of claim 1 wherein L² is alkylene (1-4C) or alkenylene (1-4C) optionally substituted with a moiety selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof, and wherein two substituents on L² can be joined to form a non-aromatic saturated or unsaturated ring that includes 0-3 heteroatoms which are O, S and/or N and which contains 3 to 8 members or said two substituents can be joined to form a carbonyl moiety or an oxime, oximeether, oximeester or ketal of said carbonyl moiety.

36. The compound of claim 35 wherein L² is unsubstituted alkylene.

37. The compound of claim 35 wherein L² is unsubstituted methylene, methylene substituted with alkyl, or —

CH═

.

38. The compound of claim 1 wherein Ar¹ is optionally substituted with 0-5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof, and wherein two of said optional substituents on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members.

39. The compound of claim 38 wherein Ar¹ is optionally substituted phenyl.

40. The compound of claim 39 wherein said optional substitution is by halo, OR, or alkyl.

41. The compound of claim 40 wherein said phenyl is unsubstituted or has a single substituent.

42. The compound of claim 1 wherein R¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof and two of R⁴ on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or R⁴ is ═

O or an oxime, oximeether, oximeester or ketal thereof.

43. The compound of claim 42 wherein each R¹ is halo, OR, or alkyl.

44. The compound of claim 43 wherein m is 0, 1, or 2.

45. The compound of claim 44 wherein m is 2 and both R¹ are alkyl.

46. The compound of claim 9 wherein each of the non-interfering groups R, when bonded to a ring carbon atom, are selected from the group consisting of:

(a) hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl and halo;

or

(b) or from OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R in the preceding (b) selections is independently H, alkyl, alkenyl or aryl or heteroforms thereof;

and wherein two of the non-interfering groups R can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members.

47. The compound of claim 46 wherein the non-interfering groups R are independently selected from the group consisting of H, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, halo, OR, NR₂, SR, NRCOR, alkyl-OOR, RCO, COOR, and CN, wherein each R is independently H, alkyl, or aryl or heteroforms thereof.

48. The compound of claim 9 wherein the noninterfering groups R, when bonded to a nitrogen ring atom, are selected from the group consisting of:

(a) H, or alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl; and

(b) SOR, SO₂R, RCO, COOR, alkyl-COR, SO₃R, CONR₂, SO₂NR₂, CN, CF₃, or R₃Si wherein each R in the preceding (b) selections is independently H, alkyl, alkenyl or aryl or heteroforms thereof.

49. A pharmaceutical composition for treating conditions characterized by enhanced p38-α

activity which composition comprises

a therapeutically effective amount of a compound of claim 1

or the pharmaceutically acceptable salts thereof, along with a physiologically acceptable excipient.

50. The composition of claim 49 which further contains an additional therapeutic agent.

51. The composition of claim 50 wherein said additional therapeutic agent is a corticosteroid, a monoclonal antibody, or an inhibitor of cell division.

52. A method to treat a condition mediated by p38-α

kinase comprising administering to a subject in need of such treatment a compound of claim 1

or the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

53. The method of claim 52 wherein said condition is a proinflammation response.

54. The method of claim 53 wherein said proinflammation response is multiple sclerosis, TBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, other arthritic conditions, sepsis, endotoxic shock, asthma, adult respiratory distress syndrome, reperfusion injury, psoriasis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, a bone resorption disease, graft-versus-host reaction, Crohn'"'"'s Disease, ulcerative colitis, or pyresis.