Novel compounds
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Abstract
Novel substituted 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.
111 Citations
91 Claims
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1. A compound of the formula:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 84, 85, 86)
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2. The compound according to claim 1 which is Formula (I).
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3. The compound according to claim 1 which is Formula (Ia).
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4. The compound according to claim 1 wherein R1 is an optionally substituted phenyl or napthyl.
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5. The compound according to claim 4 wherein the phenyl is substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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6. The compound according to claim 5 wherein the substituents are independently fluorine, C1-4 alkyl, or CF3.
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7. The compound according to claim 5 wherein the phenyl ring is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position.
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14. The compound according to claim 1 wherein R2 is X1(CR10R20)qC(A1)(A2)(A3).
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15. The compound according to claim 14 wherein X1 is oxygen or N(R10).
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16. The compound according to claim 14 wherein at least one of A1, A2 or A3 is substituted by (CR10R20)nOR6.
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17. The compound according to claim 16 wherein q is 1 or 2.
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18. The compound according to claim 1 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
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19. The compound according to claim 18 wherein R3 is optionally substituted one or more times independently with C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-10alkyl, halogen, cyano, nitro, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nNR10S(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR4R14, (CR10R20)nNR10C(Z)R6, (CR10R20)nNR10C(═
- NR10)NR4R14, (CR10R20)nC(Z)NR4R14, (CR10R20)nNR10C(Z)NR4R14, or (CR10R20)nNR10C(Z)OR7.
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20. The compound according to claim 19 wherein the optional substitutent is halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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22. The compound according to claim 1 which is:
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2-(2-Diethylamino-ethylamino)-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
4-(2-Fluoro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
4-(2-Fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
4-(4-Fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclopropylmethyl-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-sec-Butyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
4,8-Bis-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one;
4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
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23. The compound according to claim 1 which is:
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8-(2,6-Dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido [2,3-d]pyrimidin-7-one;
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-ortho-tolyl-8H-pyrido [2,3-d]pyrimidin-7-one;
4-(4Fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[2-(tert-butoxycarbonylamino)ethoxy]-8H-pyrido[2,3-d]pyrimidin-7-one 2-(1-hydroxymethyl-1-methyl-2-hydroxyethylamino)-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(1-hydroxymethyl-1-methyl-2-hydroxyethylamino)-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-trihydroxy-methylaminomethyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Fluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-([2,2-dimethyl-2-hydroxy]ethylamino)]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[N-2,2-dimethylethanolamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[-N-dihydroxymethylmethylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-8-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one;
or a pharmaceutically acceptable salt thereof.
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24. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
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25. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound according to claim 1.
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26. The method according to claim 25 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerularnephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.
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27. A method of treating the common cold or respiratory viral infection caused by human rhinovirus (HRV), other enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, or adenovirus in a human in need thereof which method comprises administering to said human an effective amount of a compound according to claim 1.
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28. The method according to claim 27 wherein the respiratory viral infection exacerbates asthma, exacerbates chronic bronchitis, exacerbates chronic obstructive pulmonary disease, exacerbates otitis media, exacerbates sinusitis, or wherein the respiratory viral infection is associated with a secondary bacterial infection, otitis media, sinusitis, or pneumonia.
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31. The compound according to claim 25 wherein R1 is an optionally substituted aryl ring.
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32. The compound according to claim 31 wherein the aryl is a phenyl substituted one or more times independently with halogen, C1-4 alkyl, or halo-substituted-C1-4 alkyl.
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33. The compound according to claim 32 wherein the phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.
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34. The compound according to claim 31 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
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35. The compound according to claim 34 wherein the R3 moiety is optional substituted one or more times, independently by C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10 alkyl, halogen, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nNR10S(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR4R14, (CR10R20)nNR10C(Z)R6, (CR10R20)nNR10C(═
- NR10) NR4R14, (CR10R20)nOC(Z)NR4R14, (CR10R20)nNR10C(Z)NR4R14, or (CR10R20)nNR10C(Z)OR7.
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36. The compound according to claim 35 wherein the optional substituents are independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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84. The compound according to claim 1 wherein X1 is oxygen or N(R10).
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85. The compound according to claim 1 wherein at least one of A1, A2 or A3 is substituted by (CR10R20)nOR6.
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86. The compound according to claim 85 wherein q is 1 or 2.
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2. The compound according to claim 1 which is Formula (I).
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8-13. -13. (Cancelled)
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21. (cancelled)
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29. A compound of the formula
- View Dependent Claims (30, 37, 38)
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30. The compound according to claim 29 wherein R1 is an optionally substituted heteroaryl ring.
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37. The compound according to claim 29 which is:
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2-Methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde;
4-(2-Chlorophenyl)-6-(1-ethylpropylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2-Chlorophenyl)-6-(2-chlorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2-Fluorophenyl)-6-(2-chlorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
or4-(2-Fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
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38. The compound according to claim 29 which is
4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 4-Cyclopropylamino-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde; -
4-(Cyclopropylmethylamino)-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2,6-Difluorophenylamino)-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2-Fluorophenyl)-6-(2-fluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-sec-Butylamino-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(4-Fluoro-2-methylphenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(Cyclopropylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(Cyclopropylmethylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(4-Fluoro-2-methyl-phenyl)-6-(2-fluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-sec-Butylamino-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2,6-Difluorophenylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(1-Ethylpropylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylamino-pyrimidine-5-carbaldehyde;
or2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylamino-pyrimidine-5-carbaldehyde.
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30. The compound according to claim 29 wherein R1 is an optionally substituted heteroaryl ring.
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39. A compound of the formula
- View Dependent Claims (40, 41, 42, 43, 44, 45, 46, 47)
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40. The compound according to claim 39 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
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41. The compound according to claim 40 wherein the optional substituents are independently selected from C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10 alkyl, halogen, (CR10R20)nOR, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nNR10S(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR4R14, (CR10R20)nNR10C(Z)R6, (CR10R20)nNR10C(═
- NR10) NR4R14, (CR10R20)nOC(Z)NR4R14, (CR10R20)nNR10C(Z)NR4R14, or (CR10R20)nNR10C(Z)OR7.
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42. The compound according to claim 41 wherein the optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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43. The compound according to claim 40 wherein R1 is an optionally substituted aryl.
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44. The compound according to claim 43 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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45. The compound according to claim 44 wherein the phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.
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46. The compound according to claim 40 wherein R12 is a C1-10 alkyl.
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47. The compound according to claim 40 which is
(E)-3-[4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid ethyl ester.
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40. The compound according to claim 39 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
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48. A process for producing a compound according to Formula (Ia)
- View Dependent Claims (49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 74, 75)
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49. The process according to claim 48 wherein the base is pyridine, diisopropyl ethylamine, or pyrrolidine.
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50. The process according to claim 48 wherein the acetylating agent is acetic anhydride, acetyl chloride, or ketene.
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51. The process according to claim 48 wherein R3 is an optionally substituted aryl.
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52. The process according to claim 48 wherein R1 is a halogen or an optionally substituted aryl.
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53. The process according to claim 52 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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54. The compound according to claim 53 wherein the phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.
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55. The process according to claim 48 wherein X is (CH2)nNR4R14, or (CH2)nN(R2)2.
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56. The process according to claim 48 wherein R2 is the moiety X1(CR10R20)qC(A1)(A2)(A3), or C(A1)(A2)(A3).
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57. The process according to claim 56 wherein X1 is oxygen or N(R10).
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58. The process according to claim 57 wherein at least one of A1, A2 or A3 is substituted by (CR10R20)nOR6.
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74. The compound according to claim 56 wherein R1 is a phenyl ring substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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75. The compound according to claim 74 wherein the phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.
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49. The process according to claim 48 wherein the base is pyridine, diisopropyl ethylamine, or pyrrolidine.
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59. A process of making a compound of the Formula:
- View Dependent Claims (60, 61, 62, 63, 64, 65, 66, 67, 68, 69)
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60. The process according to claim 59 wherein the organic solvent is an organic hydrocarbon, cresol, dioxane, DMF, pyridine, or xylene.
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61. The process according to claim 59 wherein the base is diisopropyl ethylamine, pyridine, DBU, lithium bis(trimethylsilyl)amide, or LDA.
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62. The process according to claim 59 wherein R3 is an optionally substituted aryl.
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63. The process according to claim 59 wherein X is (CH2)nNR4R14, or (CH2)nN(R2)2.
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64. The process according to claim 59 wherein R2 is the moiety X1(CR10R20)qC(A1)(A2)(A3), or C(A1)(A2)(A3).
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65. The process according to claim 64 wherein X1 is oxygen or N(R10).
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66. The process according to claim 65 wherein at least one of A1, A2 or A3 is substituted by (CR10R20)nR6.
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67. The process according to claims 64 to wherein R1 is an optionally substituted aryl.
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68. The process according to claim 67 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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69. The compound according to claim 68 wherein the phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.
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60. The process according to claim 59 wherein the organic solvent is an organic hydrocarbon, cresol, dioxane, DMF, pyridine, or xylene.
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70. A compound of the formula
- View Dependent Claims (71, 72, 73)
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71. The compound according to claim 70 wherein the R3 optional substituents are independently selected from C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10 alkyl, halogen, (CR10R20)nOR, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nNR10S(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR4R14, (CR10R20)nNR10C(Z)R6, (CR10R20)nNR10C(═
- NR10)NR4R14, (CR10R20)nOC(Z)NR4R14, (CR10R20)nNR10C(Z)NR4R14, or (CR10R20)nNR10C(Z)OR7.
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72. The compound according to claim 71 wherein the optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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73. The compound according to claim 70 wherein R1 is an aryl which is optionally substituted one or more times, independently, by halogen, C1-4 alkyl, halo-substituted-C1-4 alkyl, cyano, nitro, (CR10R20)vNR4R14, (CR10R20)vC(Z)NR4R14, (CR10R20)vC(Z)OR8, (CR10R20)vCORa′
- , (CR10R20)vC(O)H, SR5, S(O)R5, S(O)2R5, (CR10R20)vOR8, ZC(Z)R11, NR10C(Z)R11, or NR10S(O)2R7.
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71. The compound according to claim 70 wherein the R3 optional substituents are independently selected from C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10 alkyl, halogen, (CR10R20)nOR, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nNR10S(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR4R14, (CR10R20)nNR10C(Z)R6, (CR10R20)nNR10C(═
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76. A compound of the formula
- View Dependent Claims (77, 78, 79, 80, 81, 82, 83)
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77. The compound according to claim 76 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
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78. The compound according to claim 77 wherein the optional substituents are independently selected from C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10 alkyl, halogen, (CR10R20)nOR6, (CR10R20)nSH, (CR10OR20)nS(O)mR7, (CR10R20)nNR10S(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR4R14, (CR10R20)nNR10C(Z)R6, (CR10R20)nNR10C(═
- NR10)NR4R14, (CR10R20)nOC(Z)NR4R14, (CR10R20)nNR10C(Z)NR4R14, or (CR10R20)nNR10C(Z)OR7.
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79. The compound according to claim 78 wherein the optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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80. The compound according to claim 76 wherein R1 is an optionally substituted aryl.
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81. The compound according to claim 80 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
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82. The compound according to claim 81 wherein the phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.
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83. The compound according to claim 76 wherein R12 is a C1-10 alkyl.
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77. The compound according to claim 76 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
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87. The compound 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one or a pharmaceutically acceptable salt thereof.
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88. A pharmaceutical composition comprising an effective amount of 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
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89. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.
- View Dependent Claims (90)
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90. The method according to claim 89 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerulamephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.
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90. The method according to claim 89 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerulamephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.
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91. A method of treating a inflammation in a mammal in need thereof, which method comprises administering to said mammal an effective amount of 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.
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Current AssigneeGlaxoSmithKline LLC (GlaxoSmithKline PLC)
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Original AssigneeSmithkline Beecham Corporation (Smithkline Beecham PLC)
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InventorsHall, Ralph, Jin, Qi, Kasparec, Jiri, Boehm, Jeffrey C., Silva, Domingos J., Adams, Jerry L., Taggart, John J.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/264.1
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CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 1/18 for pancreatic disorders, e...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/04 AntipruriticsA61P 17/06 AntipsoriaticsA61P 19/00 Drugs for skeletal disordersA61P 19/02 for joint disorders, e.g. a...A61P 19/06 Antigout agents, e.g. antih...A61P 19/08 for bone diseases, e.g. rac...A61P 19/10 for osteoporosisA61P 21/00 Drugs for disorders of the ...A61P 25/00 Drugs for disorders of the ...A61P 27/02 Ophthalmic agentsA61P 27/16 OtologicalsA61P 29/00 Non-central analgesic, anti...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/00 : Antiinfectives, i.e. antibi...A61P 31/04 : Antibacterial agentsA61P 31/12 : AntiviralsA61P 31/14 : for RNA virusesA61P 31/16 : for influenza or rhinovirusesA61P 35/00 : Antineoplastic agentsA61P 35/04 : specific for metastasisA61P 37/06 : Immunosuppressants, e.g. dr...A61P 43/00 : Drugs for specific purposes...A61P 7/00 : Drugs for disorders of the ...A61P 7/02 : Antithrombotic agents; Anti...A61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...C07D 239/47 : One nitrogen atom and one o...C07D 471/04 : Ortho-condensed systems