Claims
- 1. A method of treating a chronic disease in a mammal in need thereof, which disease is characterized by excessive, undesired or inappropriate angiogenesis, with an effective amount of a compound of Formula (I) which inhibits the production, transcription or translation of a cytokine, which cytokine is inhibited by inhibition of the kinase CSBP/p38/RK: wherein:R1 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently one to three times with Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amnino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb; Y is ORa; R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7R17, C(Z)OR16, (CR10R20)vCOR12, SR5, SOR5, OR12, halo-substituted-C1-4 alkyl, C1-4 alkyl, ZC(Z)R12, NR10C(Z)R16, or (CR10R20)vNR10R20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR13R14, C(Z)OR3, (CR10R20)m″COR3, S(O)mR3, OR13, halo-substituted-C1-4 alkyl, C1-4 alkyl, (CR10R20)m″NR10C(Z)3, NR10S(O)m′R8, NR10S(O)m′NR7R17, ZC(Z)3 or (CR10R20)m″NR13R14; v is 0, or an integer having a value of 1 or 2; m is 0, or the integer 1 or 2; m′ is an integer having a value of 1 or 2, m″ is 0, or an integer having a value of 1 to 5; R2 is (CR10R20)n′OR9, heterocyclyl, heterocyclylC1-10 alkyl, C1-10alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenylC1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14, (CR10R20)nNO2, (CR10R20)nCN, (CR10R20)n′SO2R18, (CR10R20)nS(O)m′NR13R14, (CR10R20)nC(Z)R11, (CR10R20)nOC(Z)R11, (CR10R20)nC(Z)OR11, (CR10R20)nC(Z)NR13R14, (CR10R20)nC(Z)NR11OR9, (CR10R20)nNR10C(Z)R11, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nN(OR6)C(Z)NR13R14, (CR10R20)nN(OR6)C(Z)R11, (CR10R20)nC(═NOR6)R11, (CR10R20)nNR10C(═NR19)NR13R14, (CR10R20)nOC(Z)NR13R14, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nNR10C(Z)OR10, 5-(R18)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10; n′ is 0, or an integer having a value of 1 to 10; Z is oxygen or sulfur; Ra is C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl, wherein each of these moieties may be optionally substituted; Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl; R3 is heterocyclyl, heterocyclylC1-10 alkyl or R8; R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties —SR5 being —SNR7R17 and —SOR5 being —SOH; R6 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclic, aroyl, or C1-10 alkanoyl; R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R8 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, —C(Z)R11 or optionally substituted C1-10 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl; R10 and R20 is each independently selected from hydrogen or C1-4 alkyl; R11 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl; R12 is hydrogen or R16; R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; R15 is R10 or C(Z)-C1-4 alkyl; R16 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-7 cycloalkyl; R18 is C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl; R19 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.
- 2. The method according to claim 1 wherein R1 is a substituted 4-pyridyl or 4-pyrimidinyl.
- 3. The method according to claim 1 wherein Ra is aryl, arylalkyl, halosubstituted arylalkyl, halosubstituted aryl, heterocyclic alkyl, hydroxy alkyl, alkyl-1-piperidine-carboxylate, heterocyclic, alkyl substituted heterocyclic, halosubstituted heterocyclic, or aryl substituted heterocyclic.
- 4. The method according to claim 3 wherein Ra is benxyl, halosubstituted benzyl, napthylmethyl, phenyl, halosubstituted phenyl, morpholinopropyl, 2-hydroxy ethyl, ethyl-1-piperidinecarboxylate, piperonyl, piperidin-4-yl, alkyl substituted piperidine, chlorotryptamine, and tetrathiohydropyranyl.
- 5. The method according to claim 1 wherein R4 is an optionally substituted phenyl.
- 6. The method according to claim 1 wherein R2 is selected from optionally substituted heterocylcyl, optionally substituted heterocyclylC1-10 alkyl, (CR10R20)nNS(O)2R18, (CR10R20)nS(O)mR18, arylC1-10 alkyl, (CR10R20)nNR13R14, optionally substituted C3-7cycloalkyl, or optionally substituted C3-7cycloalkyl C1-10 alkyl.
- 7. The method according to claim 6 wherein R2 is morpholino propyl, piperidine, N-methylpiperidine, N-benzylpiperidine, 2,2,6,6-tetramethylpiperidine, 4-aminopiperidine, 4-amino-,2,6,6-tetramethyl piperidine, 4-hydroxycyclohexyl, 4-methyl-4-hydroxy cyclohexyl, 4-pyrrolinindyl-cyclohexyl, 4-methyl-4-arninocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-keto cyclohexyl, 4-oxiranyl, or 4-hydroxy-4-(1-propynyl)cyclohexyl.
- 8. The method according to claim 1 wherein the cytokine is IL-1β.
- 9. The method according to claim 1 wherein the cytokine is TNF-α.
- 10. The method according to claim 1 wherein the disease is diabetic retinopathy and other ocular neovascularizations.
- 11. The method according to claim 1 wherein the disease is tumor growth and metastasis.
Parent Case Info
This application is the §371 national stage entry of PCT/US97/03626, filed Mar. 7, 1997 which claims the benefit of U.S. Ser. No. 60/013,138 filed Mar. 8, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US97/03626 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/32583 |
9/12/1997 |
WO |
A |
US Referenced Citations (6)
Foreign Referenced Citations (5)
Number |
Date |
Country |
WO9314081 |
Jul 1993 |
WO |
WO9314082 |
Jul 1993 |
WO |
WO 9502591 |
Jan 1995 |
WO |
WO9509841 |
Apr 1995 |
WO |
WO9531451 |
Nov 1995 |
WO |
Non-Patent Literature Citations (2)
Entry |
Soni Chem. Abstract 97:216082., 1982.* |
Ben Ezra et al., “In vivo angiogenetic activity of interleukins”, Archives of Ophthalmology, 108(4), pp. 573-576 (1990). |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/013138 |
Mar 1996 |
US |