Pyrimidine A2b selective antagonist compounds, their synthesis and use

• US 20030162764A1
• Filed: 12/20/2002
• Published: 08/28/2003
• Est. Priority Date: 12/20/2001
• Status: Active Grant

• Current Assignee: Osi Pharmaceuticals Incorporated (Astellas Pharma Incorporated)
• Original Assignee: Osi Pharmaceuticals Incorporated (Astellas Pharma Incorporated)
• Inventors: McKibben, Bryan, Steinig, Arno, Castelhano, Arlindo, Collington, Eric
• Granted Patent: US 6,916,804 B2
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 35/00 Antineoplastic agents
• 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 9/00 Drugs for disorders of the cardiovascular 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 239/48 Two nitrogen 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

Abstract

The subject invention provides compounds having the structure:

wherein R₁ is substituted or unsubstituted phenyl or a 5-6 membered heterocyclic or heteroaromatic ring containing from 1 to 5 heteroatoms; R₂ is hydrogen, or a substituted or unsubstituted alkyl, —C(O)-alkyl, —C(O)—O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety; R₃ is hydrogen, or a substituted or unsubstituted alkyl, —C(O)-alkyl, —C(O)—O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety, or R₂ and R₃ are joined to form a heterocyclic ring; wherein the dashed line represents a second bond which may be present or absent, and when present R₃ is oxygen; R₄ and R₅ are each independently substituted or unsubstituted alkyl, —C(O)-alkyl, —C(O)—O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety, or R₄NR₅ together form a substituted or unsubstituted monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms; R₁₂ is hydrogen, alkyl, halogen or cyano; and n is 0, 1, 2, 3 or 4, or an enantiomer, or a specific tautomer, or a pharmaceutically acceptable salt thereof and a method for treating a disease associated with the A_2b adenosine receptor by administering a therapeutically effective amount of the compounds of the invention.

Claims

1. A compound having the structure:

2. The compound of claim 1, wherein R₃ is hydrogen, or a substituted or unsubstituted alkyl or aryl.

3. The compound of claim 2, wherein any heterocyclic or heteroaryl ring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.

4. The compound of claim 1, having the structure:

5. The compound of claim 4, wherein,

R₇ is hydrogen, OH, or CN.

6. The compound of claim 4, wherein the compound is selected from the group consisting of:

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin<sup>−

4</sup>-yl]-2-[4-(3-chlorophenoxy)-piperidin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorophenoxy)-piperidin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperidin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin<sup>−

4</sup>-yl]-2-[4-(4-fluorobenzyl)-piperidin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperidin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperidin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperidin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzylpiperazin-1-yl)-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin<sup>−

4</sup>-yl]-2-[4-(4-methoxybenzyl)-piperazin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-methoxybenzyl)-piperazin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-methoxybenzyl)-piperazin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperazin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperazin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperazin-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-piperazine-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2.-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-piperazine-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-piperazine-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-cyclohexylmethylpiperazin-1-yl)-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethylpiperazin-1-yl)-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethyl-[1,4] diazepan-1-yl)-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzyl-[1,4]diazepan-1-yl)-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-trifluoromethylbenzyl)-[1,4] diazapan-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-[1,4]diazepan-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide;

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-pyridin-3-ylmethyl-[1,4]diazapan-1-yl)-acetamide;

N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(3-chlorobenzyl)-[1,4]diazepan-1-yl]-acetamide;

N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-(4-pyridin-2-ylmethyl-[1,4]diazepan-1-yl)-acetamide;

N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(6-methylpyridin-2-ylmethyl)-[1,4]diazepan-1-yl]-acetamide;

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl} acetamide;

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4-tert-butylbenzyl)piperazin-1-yl]acetamide;

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide, and

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide.

7. The compound of claim 4, wherein the compound is N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-acetamide.

8. The compound of claim 1, having the structure:

9. The compound of claim 8, wherein

R₄ and R₅ are each independently substituted or unsubstituted alkyl, —

C(O)-alkyl, —

C(O)—

O-alkyl, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety, or

R₄NR₅ together form a substituted or unsubstituted, monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms.

10. The compound of claim 9, wherein R₄ and R₅ are each independently substituted or unsubstituted alkyl, —

C(O)-alkyl, —

C(O)—

O-alkyl, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety.

11. The compound of claim 9, wherein R₄ and R₅ are each independently substituted or unsubstituted alkyl, —

C(O)-alkyl, —

C(O)—

O-alkyl, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety.

12. The compound of claim 9, wherein any heterocyclic or heteroaryl ring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.

41. The compound of claim 1, wherein,

R₁ is unsubstituted phenyl or phenyl substituted with Cl;

R₂ is hydrogen;

R₃ is hydrogen or oxygen;

R₄, N, R₅ together form a piperidine ring substituted with —

O(C₆H₅), —

O(C₆H₄Cl), —

O(C₆H₄[OCH₃]), —

(C₆H₅), —

CH₂(C₆H₄[OCH₃]), —

CH₂(C₆H₄F), —

CH₂(C₆H₄Cl), —

(OH)(CH₂)(C₆H₅), —

(CN)(C₆H₅), —

(CN)(C₆H₄Cl);

a 3,5-dimethyl piperazine ring substituted with —

CH₂(C₆H₅);

a piperazine ring substituted with —

CH₂(C₆H₅), —

(C₆H₅), —

CH₂(C₆H[OCH₃]), —

CH₂(C₆H₄Cl), —

CH₂(C₆H₄F), —

CH₂(C₆H₄[CF₃]), —

CH₂(C₅H₄N), —

CH₂(C₆H₁₁), —

(CH₂)₂(C₆H₅);

or a [1,4]diazepan ring substituted with —

(C₆H₅), —

(CH₂)₂(C₆H₅), —

CH₂(C₆H₅), —

CH₂(C₆H₄F), —

CH₂(C₆H₄[CF₃]), —

CH₂(C₅H₄N), —

CH₂(C₆H₄Cl), or —

CH₂(C₅H₃N[CH₃]); and

R₁₂ is hydrogen.

42. A method for treating a disease associated with the A_2b adenosine receptor in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of the compound of claim 1 so as to thereby treat the disease associated with the A_2b adenosine receptor in the subject, wherein the disease associated with the A_2b adenosine receptor is asthma, urticaria, scleroderm arthritis, myocardial infarction, myocardial reperfusion after ischemia, diabetic retinopathy, retinopathy of prematurity, diabetes, diarrhea, inflammatory bowel disease, proliferating tumor or is associated with mast cell degranulation, vasodilation, hypertension, hypersensitivity or the release of allergic mediators.

43. The method of claim 42, wherein the disease associated with the A_2b adenosine receptor is diabetes.

44. The method of claim 42, wherein the disease associated with the A_2b adenosine receptor is asthma.

45. The method of claim 42, wherein the disease associated with the A_2b adenosine receptor is associated with mast cell degranulation.

46. The method of claim 42, wherein the disease associated with the A_2b adenosine receptor is a proliferating tumor.

47. A pharmaceutical composition comprising the compound of claim 1, 8, 13 or 18 and a pharmaceutically acceptable carrier.

48. The pharmaceutical composition of claim 47, formulated for oral, topical, parenteral or nasal administration.

49. A process for the manufacture of a pharmaceutical composition comprising admixing the compound of claim 1, 8, 13 or 18 with a pharmaceutically acceptable carrier.

50. An article of manufacture comprising packaging material;

the pharmaceutical composition of claim 46;

and

instructions for use of the pharmaceutical composition in the treatment of a disease associated with the A_2b adenosine receptor.

51. The pharmaceutically acceptable salt of claim 1, wherein the salt is a hydrochloride salt.

57. A process for manufacturing the compound of claim 4, comprising reacting a compound having the structure:

60. A compound produced by the process of claim 57.

61. Use of the compound of any one of claims 1-5 or 41 for manufacturing a medicament useful for treating a disease associated with the A_2b adenosine receptor in a subject, wherein the disease associated with the A_2b adenosine receptor is asthma, urticaria, scleroderm arthritis, myocardial infarction, myocardial reperfusion after ischemia, diabetic retinopathy, retinopathy of prematurity, diabetes, diarrhea, inflammatory bowel disease, proliferating tumor or is associated with mast cell degranulation, vasodilation, hypertension, hypersensitivity or the release of allergic mediators.

62. The use of claim 61, wherein the disease associated with the A_2b adenosine receptor is diabetes.

63. The use of claim 61, wherein the disease associated with the A_2b adenosine receptor is asthma.

64. The use of claim 61, wherein the disease associated with the A_2b adenosine receptor is associated with mast cell degranulation.

65. The use of claim 61, wherein the disease associated with the A_2b adenosine receptor is a proliferating tumor.

66. The compound of any one of claims 1-5,8-26 or 58, wherein any alkyl is a straight chain (C₁-C₃₀)alkyl or a branched chain (C₃-C₃₀)alkyl, any cycloalkyl is (C₃-C₁₀)cycloalkyl, and any substituent, if present, is selected from halogen, hydroxyl, straight chain (C₁-C₃₀)alkyl, branched chain (C₃-C₃₀)alkyl, (C₃-C₁₀)cycloalkyl, straight chain(C₁-C₃₀)alkylcarbonyloxy, branched chain (C₃-C₃₀)alkylcarbonyloxy, arylcarbonyloxy, straight chain(C₁-C₃₀)alkoxycarbonyloxy, branched chain(C₃-C₃₀)alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, straight chain(C₁-C₃₀)alkylcarbonyl, branched chain (C₃-C₃₀)alkylcarbonyl, straight chain (C₁-C₃₀)alkoxycarbonyl, branched chain (C₃-C₃₀)alkoxycarbonyl, aminocarbonyl, straight chain (C₁-C₃₀)alkylthiocarbonyl, branched chain (C₃-C₃₀)alkylthiocarbonyl, straight chain (C₁-C₃₀)alkoxyl, branched chain (C₁-C₃₀)alkoxyl, phosphate, phosphonato, cyano, amino, straight chain (C₁-C₃₀)alkylamino, branched chain (C₃-C₃₀)alkylamino, straight chain (C₁-C₃₀)dialkylamino, branched chain (C₃-C₃₀)dialkylamino, arylamino, diarylamino, straight chain (C₁-C₃₀)alkylarylamino, branched chain (C₃-C₃₀)alkylarylamino, acylamino, straight chain (C₁-C₃₀)alkylcarbonylamino, branched chain (C₃-C₃₀)alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, straight chain (C₁-C₃₀)alkylthio, branched chain (C₃-C₃₀)alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, 4-10 membered heterocyclyl, straight chain (C₁-C₃₀)alkylaryl, branched chain (C₃-C₃₀)alkylaryl, or an aromatic or 5-6 membered heteroaromatic moiety, which substituent may be further substituted by any of the above.

13. A compound having the structure:

14. The compound of claim 13, wherein

R₁₀ is a substituted or unsubstituted alkyl, —

C(O)-alkyl, —

C(O)—

O-alkyl, cycloalkyl, alkenyl, or a substituted or unsubstituted, monocyclic or bicyclic aryl, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms.

15. The compound of claim 14, wherein R₁₁ is hydrogen.

16. The compound of claim 14, wherein R₁₁ is a halogen atom.

17. The compound of claim 13, wherein any heterocyclic or heteroaryl ring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.

18. A compound having the structure:

19. The compound of claim 18, wherein,

R₁₀ is substituted or unsubstituted alkyl, —

C(O)-alkyl, —

C(O)—

O-alkyl, cycloalkyl, alkenyl, or a substituted or unsubstituted monocyclic or bicyclic aryl, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms; and

R₁₂ is hydrogen or methyl.

20. The compound of claim 19, wherein R₁₁ is hydrogen.

21. The compound of claim 20, wherein R₁₂ is hydrogen.

22. The compound of claim 20, wherein R₁₂ is methyl.

23. The compound of claim 19, wherein R₁₁ is a halogen atom.

24. The compound of claim 23, wherein R₁₂ is hydrogen.

25. The compound of claim 23, wherein R₁₂ is methyl.

26. The compound of claim 18, wherein any heterocyclic or heteroaryl ring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.

27. A compound having the structure:

28. The compound of claim 27, wherein R_a is Cl.

29. The compound of claim 27, wherein R_a is Br.

52. A process of manufacturing the compound of claim 28 or 29 comprising the steps of:

(a) reacting

with a 2-substituted diethyl malonate in the presence of a base in a solvent under suitable conditions to provide;

(b) reacting the product of step (a) with a chlorinating agent to provide;

(c) reacting the product of step (b) with an aminating agent in the presence of solvent to provide;

(d) reacting the product of step (c) with N-acetylethylenediamine to provide;

(e) reacting the product with

in the presence of base in solvent to provide;

wherein

R_a is Cl or Br; and

R₁₂ is hydrogen, alkyl, halogen or cyano.

53. The process of claim 52, wherein the solvent in step (a) is DMF and the base is DBU.

54. The process of claim 53, wherein the chlorinating agent in step (b) is POCl₃.

55. The process of claim 54, wherein the aminating agent of step (c) is ammonia and the solvent is DMSO.

56. The process of claim 55, wherein the base is 2,6-lutidine and the solvent is CH₂Cl₂/DMF.

59. A compound produced by the process of claim 52.

30. A compound having the structure:

31. The compound of claim 30, wherein R_b is hydrogen.

32. The compound of claim 30, wherein R_b is methyl.

33. A compound having the structure:

34. The compound of claim 33, wherein R_c is Cl.

35. The compound of claim 34, wherein R₁₁ is hydrogen.

36. The compound of claim 35, wherein R₁₂ is hydrogen.

37. The compound of claim 35, wherein R₁₂ is methyl.

38. The compound of claim 34, wherein R₁₁ is Cl.

39. The compound of claim 38, wherein R₁₂ is hydrogen.

40. The compound of claim 38, wherein R₁₂ is methyl.

58. A compound having the structure: