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−4-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−4-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−4-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.
- 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 Ra is Cl.
- 29. The compound of claim 27, wherein Ra is Br.
- 30. A compound having the structure:
- 31. The compound of claim 30, wherein Rb is hydrogen.
- 32. The compound of claim 30, wherein Rb is methyl.
- 33. A compound having the structure:
- 34. The compound of claim 33, wherein Rc 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.
- 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 A2b 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 A2b adenosine receptor in the subject, wherein the disease associated with the A2b 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 A2b adenosine receptor is diabetes.
- 44. The method of claim 42, wherein the disease associated with the A2b adenosine receptor is asthma.
- 45. The method of claim 42, wherein the disease associated with the A2b adenosine receptor is associated with mast cell degranulation.
- 46. The method of claim 42, wherein the disease associated with the A2b 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 A2b adenosine receptor.
- 51. The pharmaceutically acceptable salt of claim 1, wherein the salt is a hydrochloride salt.
- 52. A process of manufacturing the compound of claim 28 or 29 comprising the steps of:
(a) reacting 96with a 2-substituted diethyl malonate in the presence of a base in a solvent under suitable conditions to provide: 97(b) reacting the product of step (a) with a chlorinating agent to provide: 98(c) reacting the product of step (b) with an aminating agent in the presence of solvent to provide: 99(d) reacting the product of step (c) with N-acetylethylenediamine to provide: 100(e) reacting the product with 101in the presence of base in solvent to provide: 102wherein
Ra 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.
- 57. A process for manufacturing the compound of claim 4, comprising reacting a compound having the structure:
- 58. A compound having the structure:
- 59. A compound produced by the process of claim 52.
- 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 A2b adenosine receptor in a subject, wherein the disease associated with the A2b 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 A2b adenosine receptor is diabetes.
- 63. The use of claim 61, wherein the disease associated with the A2b adenosine receptor is asthma.
- 64. The use of claim 61, wherein the disease associated with the A2b adenosine receptor is associated with mast cell degranulation.
- 65. The use of claim 61, wherein the disease associated with the A2b 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.
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Application No. 60/342,595, filed Dec. 20, 2001, the contents of which are hereby incorporated by reference.
Provisional Applications (1)
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Number |
Date |
Country |
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60342595 |
Dec 2001 |
US |