Use of CSAIDTM compounds as inhibitors of angiogenesis

Abstract

The present invention is to the novel use of a cytokine inhibitor for the treatment of chronic diseases which are caused by excessive, undesired or inappropriate angiogenesis.

What is claimed is:  
     
         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 which inhibits the production, transcription or translation of a cytokine.  
     
     
         2 . The method according to  claim 1  wherein the cytokine is inhibited by inhibition of the kinase CSBP/p38/RK.  
     
     
         3 . The method according to  claim 1  wherein the cytokine is IL-1β.  
     
     
         4 . The method according to  claim 1  wherein the cytokine is TNF-α.  
     
     
         5 . The method according to  claims 1  to  4  wherein the disease is diabetic retinopathy and other ocular neovasularizations.  
     
     
         6 . The method according to  claims 1  to  4  wherein the disease is tumor growth and metastosis.  
     
     
         7 . The method according to  claims 1  to  4  wherein the disease is atherosclerosis.  
     
     
         8 . The method according to  claims 1  to  4  wherein the disease is arthritis.  
     
     
         9 . The method according to  claim 1  wherein the compound is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  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, NHR a , optionally substituted C 1-4  alkyl, halogen, hydroxyl, optionally substituted C 1-4  alkoxy, optionally substituted C 1-4  alkylthio, C 1-4  alkylsulfinyl, CH 2 OR 12 , amino, mono and di-C 1-6  alkyl substituted amino, or N(R 10 )C(O)R b ;  
 Y is OR a ;  
 R 4  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)NR 7 R 17 , —C(Z)OR 16 , —(CR 10 R 20 ) v COR 12 , —SR 5 , —SOR 5 , —OR 12 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, —C(Z)R 12 , —NR 10 C(Z)R 16 , or —(CR 10 R 20 ) v NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, —C(Z)NR 13 R 14 , —C(Z)OR 3 , —(CR 10 R 20 ) m ″COR 3 , —S(O) m R 3 , —OR 3 , halo-substituted-C 1-4  alkyl, —C 1-4  alkyl, —(CR 10 R 20 ) m″ NR 10 C(Z)R 3 , —NR 10 S(O) m′ R 8 , —NR 10 S(O) m″ NR 7 R 17 , —ZC(Z)R 3  or —(CR 10 R 20 ) m′ NR 13 R 14 ;  
 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;  
 R 2  is —(CR 10 R 20 ) n′ OR 9 , heterocyclyl, heterocyclylC 1-10  alkyl, C 1-10 alkyl, halo-substituted C 1-10  alkyl, C 2-10 alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 3-7 cycloalkylC 1-10  alkyl, C 5-7  cycloalkenyl, C 5-7  cycloalkenylC 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10 alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 , (CR 10 R 20 ) n NO 2 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n′ SO 2 R 18 , (CR 10 R 20 ) n S(O) m′ NR 13 R 14 , (CR 10 R 20 ) n C(Z)R 11 , (CR 10 R 20 ) n OC(Z)R 11 , (CR 10 R 20 ) n C(Z)OR 11 , (CR 10 R 20 ) n C(Z)NR 13 R 14 , (CR 10 R 20 ) n C(Z)NR 11 R 9 , (CR 10 R 20 ) n NR 10 C(Z)R 11 , (CR 10 R 20 ) n NR 10 C(Z)NR 13 R 14 , (CR 10 R 20 ) n N(OR 6 )C(Z)NR 13 R 14 , (CR 10 R 20 ) n N(OR 6 )C(z)R 11 , (CR 10 R 20 ) n C(═NOR 6 )R 11 , (CR 10 R 20 ) n NR 10 C(═NR 19 )NR 13 R 14 , (CR 10 R 20 ) n OC(Z)NR 13 R 14 , (CR 10 R 20 ) n NR 10 C(Z)NR 13 R 14 , (CR 10 R 20 ) n NR 10 OC(Z)OR 10 , 5-(R 18 )-1,2,4-oxadizaol-3-yl or 4-(R 12 )-5-(R 18 R 19 )-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;  
 R a  is C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 16  alkyl, heteroaryl, or heteroarylC 1-6 alkyl, wherein each of these moieties may be optionally substituted,  
 R b  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, or heterocyclylC 1-4  alkyl;  
 R 3  is heterocyclyl, heterocyclylC 1-10  alkyl or R 8 ;  
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 7 R 17 , excluding the moieties —SR 5  being —SNR 7 R 17  and —SOR 5  being —SOH;  
 R 6  is hydrogen, a pharmaceutically acceptable cation, C 1-10  alkyl, C 3-7  cycloalkyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4  alkyl, heterocyclic, aroyl, or C 1-10  alkanoyl;  
 R 7  and R 17  is each independently selected from hydrogen or C 1-4  alkyl or R 7  and R 17  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 NR 15 ;  
 R 8  is C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;  
 R 9  is hydrogen, —C(Z)R 11  or optionally substituted C 1-10  alkyl, S(O) 2 R 18 , optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl;  
 R 10  and R 20  is each independently selected from hydrogen or C 1-4  alkyl;  
 R 11  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl or heteroarylC 1-10  alkyl;  
 R 12  is hydrogen or R 16 ;  
 R 13  and R 14  is each independently selected from hydrogen or optionally substituted C 1-4  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  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 NR 9 ;  
 R 15  is R 10  or C(Z)—C 1-4  alkyl;  
 R 16  is C 1-4  alkyl, halo-substituted-C 1-4  alkyl, or C 3-7  cycloalkyl;  
 R 18  is C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or heteroarylalkyl;  
 R 19  is hydrogen, cyano, C 1-4  alkyl, C 3-7  cycloalkyl or aryl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         10 . The compound according to  claim 9  wherein R 1  is a substituted 4-pyridyl or 4-pyrimindyl.  
     
     
         11 . The compound according to  claim 9  wherein R a  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.  
     
     
         12 . The compound according to  claim 11  wherein R a  is benzyl, halosubstituted benzyl, napthylmethyl, phenyl, halosubstituted phenyl, morpholinopropyl, 2-hydroxy ethyl, ethyl-1-piperidinecarboxylate, piperonyl, piperidin-4-yl, alkyl substituted piperidine, chlorotryptamine, and tetrathiohydropyranyl.  
     
     
         13 . The compound according to  claim 9  wherein R 4  is an optionally substituted phenyl.  
     
     
         14 . The compound according to  claim 9  wherein R 2  is selected from optionally substituted heterocylcyl, optionally substituted heterocyclylC 1-10  alkyl, (CR 10 R 20 ) n NS(O) 2 R 18 , (CR 10 R 20 ) n S(O) m R 18 , arylC 1-10  alkyl, (CR 10 R 20 ) n NR 13 R 14 , optionally substituted C 3-7 cycloalkyl, or optionally substituted C 3-7 cycloalkyl C 1-10  alkyl.  
     
     
         15 . The compound according to  claim 14  wherein R 2  is morpholino propyl, piperidine, N-methylpiperidine, N-benzylpiperidine, 2,2,6,6-tetramethylpiperidine, 4-aminopiperidine, 4-amino-2,2,6,6-tetramethyl piperidine, 4-hydroxycyclohexyl, 4-methyl-4-hydroxy cyclohexyl, 4-pyrrolinindyl-cyclohexyl, 4-methyl-4-aminocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-keto cyclohexyl, 4-oxiranyl, or 4-hydroxy-4-(1-propynyl)cyclohexyl.