RU2001122339A

RU2001122339A - Substituted 2-aryl-3- (heteroaryl) imidazo [1,2-a] pyrimidines, pharmaceutical compositions containing them and related processes

Info

Publication number: RU2001122339A
Application number: RU2001122339/04A
Authority: RU
Inventors: Джон Х. ДОДД; Джеймс Р. ГЕНРИ; Кеннет К. РУПЕРТ
Original assignee: Орто-Макнейл Фармасьютикал, Инк.
Priority date: 1999-11-10
Filing date: 2000-10-27
Publication date: 2003-06-27

Claims

1. The compound of formula I

or a pharmaceutically acceptable salt thereof,

where (a) R _{1 is} selected from the group consisting of NH ₂ , C _1-5 alkylamino, di-C _1-5 alkylamino, hydroxy, C _1-5 alkoxy, phenylmethylamino, heterocyclylmethyl, C _1-5 alkylcarbonylamino and substituted phenylcarbonylamino, wherein said phenylmethylamino and heterocyclylmethyl may be substituted in their phenyl group with one or more substituents selected from the group consisting of halogen, C _1-5 alkyl, C _1-5 alkoxy, aryl-C _1-3 alkylamino, R'R "NCH = N- and OR ″, wherein R ′, R ′ and R ″ ″ are independently selected from H, C _1-5 alkyl, phenylmethyl, substituted phenylmethyl, α-alkylphenylmethyl, substituted α-alkylphenylmethyl, heterocyclylmethyl and substituted heterocyclylmethyl;

(b) Y is selected from the group consisting of H, halogen, heterocycle, OR ₄ , SR ₄ , NR ₄ and NR ₄ R ₅ , where R ₄ and R ₅ are independently selected from H, heterocyclyl, C _3-5 carbocycle , phenyl, α-alkylphenyl-C _1-5 alkyl, straight or branched alkyl optionally substituted with R, NR, N (R) ₂ , C _3-5 carbocycle, phenyl or substituted phenyl, where (i) R is H, halogen C _1-5 alkyl, phenylmethyl, substituted phenylmethyl, SO ₂ Ph, pyridyl or pyridylmethyl, and (ii) said phenyl, heterocyclyl, and α-alkylphenyl-C _1-5 alkyl may be substituted with one or more substituents selected from the groups Consisting of halogen, C _1-5 alkyl, C _1-5 alkoxy, aryl-C _1-3 alkylamino, phenylmethyl, substituted phenylmethyl, R'R''NCH = N- and OR "', as indicated in (a) ;

(c) R ₂ represents one to five members independently selected from the group consisting of halogen, trifluoromethyl, —NCH ₂ PH, C _1-5 alkyl, and C _1-5 alkoxy;

(d) P ₃ represents H, or R ₃ taken together form an aromatic ring;

(e) X represents N or CH.

2. The compound according to claim 1, where X represents CH.

3. The compound according to claim 1, where R ₁ represents NH ₂ .

4. The compound according to claim 1, where Y is NR ₄ and R ₄ is phenylmethyl.

5. The compound according to claim 1, where R ₂ represents a substituent selected from the group consisting of halogen, trifluoromethyl, —NCH ₂ PH and C _1-5 alkoxy.

6. The compound according to claim 1, where Y is selected from the group consisting of

where Z is —CH ₂ -, —O ₂ S—, —O—, —N (R) - or S; R is H, halogen, C _1-5 alkyl, phenylmethyl, substituted phenylmethyl, SO ₂ Ph, pyridyl or pyridylmethyl;

n = 0-5.

7. The compound according to claim 1, where R ₄ selected from

where all R may be the same or different, and selected, independently, from H, halogen, C _1-5 alkyl, phenylmethyl, substituted phenylmethyl, SO ₂ Ph, pyridyl and pyridylmethyl;

n = 0-5.

8. The compound according to claim 1, which is 2- (3-chloro-4-fluorophenyl) -3- (4-pyridinyl) imidazo [1,2-a] pyrimidin-7-amine.

9. The compound according to claim 1, which is 2-phenyl-3- (4-pyridinyl) imidazo [1,2-a] pyrimidin-7-amine.

10. The compound according to claim 1, which is 2- (4-fluorophenyl) -3- [2 - [(phenylmethyl) amino] -4-pyridinyl] imidazo [1,2-a] pyrimidin-7-amine.

11. The compound according to claim 1, which is 3- (4-pyridinyl) -2- [3- (trifluoromethyl) phenyl] imidazo [1,2-a] pyrimidin-7-amine.

12. The compound according to claim 1, which is 3- [2 - [(phenylmethyl) amino] -4-pyridinyl] -2- [3- (trifluoromethyl) phenyl] imidazo [1,2-a] pyrimidin-7 -amine.

13. The compound according to claim 1, which is 2- (4-fluorophenyl) -3- (4-quinolinyl) imidazo [1,2-a] pyrimidin-7-amine.

14. The compound according to claim 1, which is 2- (3-chlorophenyl) -3- (4-pyridinyl) imidazo [1,2-a] pyrimidin-7-amine.

15. The compound according to claim 1, which is 2- (4-fluorophenyl) -3- [2- (methylthio) -4-pyrimidinyl] imidazo [1,2-a] pyrimidin-7-amine.

16. The compound according to claim 1, which is 3- [2- (methylthio) -4-pyrimidinyl] -2- [3- (trifluoromethyl) phenyl] imidazo [1,2-a] pyrimidine-7-amine.

17. The compound according to claim 1, which is 2- (3-fluorophenyl) -3- [2- (methylthio) -4-pyrimidinyl] imidazo [1,2-a] pyrimidin-7-amine.

18. The compound according to claim 1, which is 3- (4-pyrimidinyl) -2- [3- (trifluoromethyl) phenyl] imidazo [1,2-a] pyrimidin-7-amine.

19. The compound according to claim 1, which is 3- [2- (methylthio) -4-pyrimidinyl] -2-phenylimidazo [1,2-a] pyrimidin-7-amine.

20. The compound according to claim 1, which is 2-phenyl-3- (4-pyrimidinyl) imidazo [1,2-a] pyrimidin-7-amine.

21. The compound according to claim 1, which is 3- [2- (methylsulfonyl) -4-pyrimidinyl] -2-phenylimidazo [1,2-a] pyrimidin-7-amine.

22. The compound according to claim 1, which is 3- [2- (methylsulfonyl) -4-pyrimidinyl] -2- [3- (trifluoromethyl) phenyl] imidazo [1,2-a] pyrimidin-7-amine.

23. The compound according to claim 1, which is 2-phenyl-3- [2 - [[(1S) -1-phenylethyl] amino] -4-pyrimidinyl] imidazo [1,2-a] pyrimidin-7-amine.

24. The compound according to claim 1, representing 3 - [[[(4-methoxyphenyl) methyl] amino] -4-pyrimidinyl] -2-phenylimidazo [1,2-a] pyrimidin-7-amine.

25. The compound according to claim 1, which is 3- (2-methoxy-4-pyrimidinyl] -2-phenylimidazo [1,2-a] pyrimidin-7-amine.

26. The compound according to claim 1, which is 2- (4-fluorophenyl) -3- (4-pyrimidinyl) imidazo [1,2-a] pyrimidin-7-amine.

27. The compound according to claim 1, which is 2- (3-fluorophenyl) -3- (4-pyridinyl) imidazo [1,2-a] pyrimidin-7-amine.

28. The compound according to claim 1, which is 2- (4-fluorophenyl) -3- (4-pyridinyl) imidazo [1,2-a] pyrimidin-7-amine.

29. The compound according to claim 1, which represents 3- [2 - [[(1S) -1-phenylethyl] amino] -4-pyrimidinyl] -2- [3-trifluoromethyl) phenyl] imidazo [1,2-a] pyrimidine-7-amine.

30. The compound according to claim 1, which is 2-phenyl-3- [2- (1-piperidinyl) -4-pyrimidinyl] imidazo [1,2-a] pyrimidin-7-amine.

31. The compound according to claim 1, which represents 3- [2 - [[(1S) -1-cyclohexylethyl] amino] -4-pyrimidinyl] -2- (4-fluorophenyl) imidazo [1,2-] pyrimidin-7 -amine.

32. The compound according to claim 1, which is 2- (4-fluorophenyl) -3- [3 - [[(1S) -1-phenylethyl] amino] -4-pyrimidinyl] imidazo [1,2-a] pyrimidine- 7-amine.

33. The compound according to claim 1, which is 3- (2-bromo-4-pyridinyl) -2- (4-fluorophenyl) imidazo [1,2-a] pyrimidin-7-amine.

34. The compound according to claim 1, which is 3- (2-bromo-4-pyridinyl) -2- [3- (trifluoromethyl) phenyl] imidazo [1,2-a] pyrimidin-7-amine.

35. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

36. A method of treating a subject suffering from a condition, the relief of which is achieved by reducing cytokines of inflammation, the effect of which contributes to this condition, including the introduction to the subject of a therapeutically effective dose of the pharmaceutical composition according to clause 35.

37. A method of inhibiting the occurrence of a condition in a subject, the alleviation of which is achieved by reducing the cytokines of inflammation, the effect of which contributes to this condition, including administering to the subject a prophylactically effective dose of the pharmaceutical composition according to claim 35.

38. The method according to clause 36 or 37, where the condition is selected from the group comprising rheumatoid arthritis, inflammatory disease of the digestive tract, septic shock, osteoporosis, osteoarthritis, neuropathic pain, HIV replication, dementia caused by HIV, viral myocarditis, insulin-dependent diabetes, non-insulin-dependent diabetes, periodontal disease, restenosis, alopecia areata, drop in the number of T-lymphocytes with HIV infection or AIDS, psoriasis, acute pancreatitis, allograft rejection, allergic pneumonia, atherosclerosis, disseminated sclerosis, cachexia, Alzheimer's disease, stroke, Crohn's disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre Syndrome, and systemic lupus erythematosus.

39. The method of claim 38, wherein said condition is rheumatoid arthritis.

40. The method of obtaining the compound according to claim 1, where R ₁ represents NH ₂ , X represents CH, and R ₅ and Y represent H, including

a) the interaction of compound 1A or 1A 'with compound 1b in the presence of NaHMDS and THF to form compound 1c;

b) the conversion of compound 1c to compound 1d in the presence of 30% HBr / AcOH, Br ₂ and AcOH; and

c) reacting compound Id with compound 1e in the presence of EtOH to form compound 1f.

41. A method of obtaining a compound according to claim 1 of structure 2f

comprising a) the conversion of compound 2a in the presence of NaOH and CH ₃ I to compound 2b

b) reacting compound 2b with compound 2c in the presence of NaHMDS and THF to form compound 2d;

c) the conversion of compound 2d to compound 2e in the presence of HBr, Br ₂ and AcOH; and

d) reacting compound 2e with compound 1e in the presence of EtOH to form compound 2f.

42. The method according to paragraph 41, further comprising converting compound 2f to compound 2g in the presence of Raney Ni and EtOH

43. The method according to paragraph 41, further comprising

a) the conversion of compound 2f to compound 2h in the presence of oxone and MeOH, and

b) reacting a compound of formula 2h with compound X,

where Y is halogen, heterocycle, OR ₄ , SR ₄ , NR ₄ or NR ₄ R ₅ , with the formation of the compounds of formula 2i.

44. The method of obtaining the compound according to claim 1, where X represents CH, and Y represents halogen, heterocycle, OR ₄ , SR ₄ , NR ₄ or NR ₄ R ₅ , including

a) reacting a compound of formula 3a with a compound of formula 3b in the presence of NaHMDS and THF to form compound 3c

b) converting a compound of formula 3c into a compound of formula 3d in the presence of HBr, Br ₂ and AcOH;

c) reacting a compound of formula 3d with a compound of formula 1e in the presence of EtOH to form a compound of formula 3e, and

d) reacting a compound of formula 3e with Y to form a compound of formula 3f.

45. The method of obtaining the compound according to claim 1, where X represents CH, and Y represents NR ₄ , including

a) the conversion of a compound of formula 4a to a compound of formula 4b in the presence of (BOC) ₂ O and tert-BuOH;

b) reacting a compound of formula 4b with a compound of formula 4c in the presence of NaHMDS and HCl to form a compound of formula 4d;

c) converting a compound of formula 4a to a compound of formula 4e in the presence of 30% HBr / AcOH, Br ₂ and AcOH; and

d) reacting a compound of formula 4e with a compound of formula 1e in the presence of EtOH to form a compound of formula 4f.