Substituted N-(1,4,5,6,-tetrahydro-cyclopentapyrazol-3-yl) derivatives, their production and use as pharmaceutical agents

Abstract

Substituted N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives, their production, as well as intermediate products for their production, and the use as pharmaceutical agents for treating various diseases are described.

1 . Compounds of general formula I, in which  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  stands for linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio or C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 3 -C 12 -heterocycloalkyl, C 3 -C 12 -heterocycloalkenyl, aryl or heteroaryl, which optionally can be substituted in one or more places in the same way or differently,  
 R 2  and R 3  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently,  
 R 4  and R 5  are the same or different and stand for hydrogen, halogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal with O,O; N,O; O,S; or S,S, which optionally can be substituted with C 1 -C 6 -alkyl, or  
 R 2  and R 4  together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently,  
 R 6  and R 7  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkinyl, which optionally can be substituted in one or more places in the same way or differently, or together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently, or  
 R 5  and R 6  optionally together form a double bond, or  
 R 3  und R 5  together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently,  
 T stands for —CH 2 —, —O—, —CH 2 ═CH 2 —, —CH≡CH—, —CH 2 —O—CH 2 —, —CH 2 —O—, —O—CH 2 — or ═CO, and  
 n stands for 0-6, as well as tautomers, isomers and salts thereof.  
 
     
     
         2 . Compounds of general formula I, according to  claim 1 , in which 
 R 1  stands for linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio or C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 3 -C 12 -heterocycloalkyl, C 3 -C 12 -heterocycloalkenyl, aryl or heteroaryl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl, cyano, nitro, C 1-6 -alkylsulfanyl, C 1-6 -alkylsulfinyl, C 1-6 -alkylsulfonyl, or with the group —C(O)C 1-6 -alkyl, —NHC 1-6 -alkyl, —N-di-C 1-6 -alkyl, —CONH 2 , —CONHC 1-6 -alkyl or —CON-di-C 1-6 -alkyl, or can be substituted with another aryl radical or heteroaryl radical that optionally itself can be substituted in one or more places in the same way or differently,    R 2  and R 3  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl,    R 4  and R 5  are the same or different and stand for hydrogen, halogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal of the structure                           or    R 2  and R 4  together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or    R 3  and R 5  together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl,    R 6  and R 7  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkinyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or    R 5  and R 6  optionally together form a double bond,    T stands for —CH 2 —, —O—, —CH 2 ═CH 2 —, —CH≡CH—, —CH 2 —O—CH 2 —, —CH 2 —O—, —O—CH 2 — or ═CO, and    n stands for 0-6, as well as tautomers, isomers and salts thereof.    
     
     
         3 . Compounds of general formula I, according to claims  1  and  2 , in which 
 R 1  stands for linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio or C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 3 -C 12 -heterocycloalkyl, C 3 -C 12 -heterocycloalkenyl, aryl or heteroaryl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl, cyano, nitro, C 1-6 -alkylsulfanyl, C 1-6 -alkylsulfinyl, C 1-6 -alkylsulfonyl, or with the group —C(O)C 1-6 -alkyl, —NHC 1-6 -alkyl, —N-di-C 1-6 -alkyl, —CONH 2 , —CONHC 1-6 -alkyl or —CON-di-C 1-6 -alkyl, or can be substituted with another aryl or heteroaryl radical, which optionally itself can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl, cyano, nitro, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfanyl, C 1-6 -alkylsulfinyl, C 1-6 -alkylsulfonyl, or with the group —C(O)C 1-6 -alkyl, —NHC 1-6 -alkyl, —N-di-C 1-6 -alkyl, —CONH 2 , —CONHC 1-6 -alkyl or —CON-di-C 1-6 -alkyl,  
 R 2  and R 3  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl,  
 R 4  and R 5  are the same or different and stand for hydrogen, halogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal of the structure  
                     
  or  
 R 2  and R 4  together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or  
 R 3  and R 5  together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl,  
 R 6  and R 7  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkinyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or together form a C 3 -C 12 -cycloalkyl ring or a C 3 -C 12 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or  
 R 5  and R 6  optionally together form a double bond,  
 T stands for —CH 2 —, —O—, —CH 2 ═CH 2 —, —CH≡CH—, —CH 2 —O—CH 2 —, —CH 2 —O—, —O—CH 2 — or ═CO, and  
 n stands for 0-6, as well as tautomers, isomers and salts thereof.  
 
     
     
         4 . Compounds of general formula I, according to  claims 1  to  3 , in which 
 R 1  stands for linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, thiinyl, dihydroazetyl, cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, azulenyl, fluorenyl, anthracenyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, 1,3-benzodioxol-5-yl, phenoxazinyl or xanthenyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl, cyano, nitro, C 1-6 -alkylsulfanyl, C 1-6 -alkylsulfinyl, C 1-6 -alkylsulfonyl, or can be substituted with the group —C(O)C 1-6 -alkyl, —NHC 1-6 -alkyl, —N-di-C 1-6 -alkyl, —CONH 2 , —CONHC 1-6 -alkyl or —CON-di-C 1-6 -alkyl, or can be substituted with another aryl or heteroaryl radical, which optionally itself can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl, cyano, nitro, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfanyl, C 1-6 -alkylsulfinyl, C 1-6 -alkylsulfonyl, or with the group —C(O)C 1-6 -alkyl, —NHC 1-6 -alkyl, —N-di-C 1-6 -alkyl, —CONH 2 , —CONHC 1 -alkyl or —CON-di-C 1-6 -alkyl,  
 R 2  and R 3  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl,  
 R 4  and R 5  are the same or different and stand for hydrogen, halogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl or C 1 -C 6 -alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal of the structure  
                     
  or  
 R 2  and R 4  together form a C 3 -C 7 -cycloalkyl ring or a C 3 -C 7 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or  
 R 3  and R 5  together form a C 3 -C 7 -cycloalkyl ring or a C 3 -C 7 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way of differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl,  
 R 6  and R 7  are the same or different and stand for hydrogen, linear or branched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkinyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or together form a C 3 -C 7 -cycloalkyl ring or a C 3 -C 7 -cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C 1-6 -alkoxy, or with the group —NHC 1-6 -alkyl or —N-di-C 1-6 -alkyl, or  
 R 5  and R 6  optionally together form a double bond,  
 T stands for —CH 2 —, —O—, —CH 2 ═CH 2 —, —CH≡CH—, —CH 2 —O—CH 2 —, —CH 2 —O—, —O—CH 2 — or ═CO, and  
 n stands for 0-6, as well as tautomers, isomers and salts thereof.  
 
     
     
         5 . Compounds of general formula I, according to  claims 1  to  4 , in which 
 R 1  stands for C 1 -C 6 -alkylthio, phenyl, biphenyl, thienyl, cyclopropyl, cyclohexyl, pyridyl, naphthyl, 1,3-benzodioxol-5-yl or isoxazolyl, which optionally can be substituted in one or more places in the same way or differently with halogen, amino, cyano, C 1-6 -alkyl-sulfonyl, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, or with the group —C(O)C 1-6 -alkyl, or which can be substituted with phenyl, thienyl, naphthyl, pyridyl, furanyl or pyrimidinyl, which optionally itself can be substituted in one or more places in the same way or differently with C 1-6 -alkyl, C 1-6 -alkoxy, amino, C 1-6 -alkylsulfonyl, cyano or with the group —C(O)NH 2 ,  
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  stand for hydrogen or C 1-6 -alkyl,  
 T stands for the group —CH 2 —, —CH 2 —O—CH 2 — or —CH 2 —O—, and  
 n stands for 0-2, as well as tautomers, isomers and salts thereof.  
 
     
     
         6 . Compounds of general formula II  
       
         
           
           
               
               
           
         
       
       in which R 2 , R 3 , R 4 , R 5 , R 6  and R 7  have the meanings that are indicated in general formula I, as intermediate products for the production of the compounds of general formula I according to the invention.  
     
     
         7 . Use of the compounds of general formula I, according to  claims 1  to  5 , for the production of a pharmaceutical agent for treating cancer, auto-immune diseases, chemotherapy-agent-induced alopecia and mucositis, cardiovascular diseases, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections.  
     
     
         8 . Use according to  claim 7 , wherein cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, Hepatitis B and C, and HIV diseases.  
     
     
         9 . Pharmaceutical agents that contain at least one compound according to  claims 1  to  5 .  
     
     
         10 . Pharmaceutical agents according to  claim 9  for treating cancer, auto-immune diseases, cardiovascular diseases, infectious diseases, nephrological diseases, neurodegenerative diseases and viral infections.  
     
     
         11 . Compounds according to  claims 1  to  5  and pharmaceutical agents according to claims  9  and  10  with suitable formulation substances and vehicles.  
     
     
         12 . Use of the compounds of general formula I, according to  claims 1  to  5 , as inhibitors of the cyclin-dependent kinases.  
     
     
         13 . Use according to  claim 12 , wherein the kinase is CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9.  
     
     
         14 . Use of the compounds of general formula I, according to  claims 1  to  5 , as inhibitors of glycogen-synthase-kinase (GSK-3β).  
     
     
         15 . Use of the compounds of general formula I, according to  claims 1  to  5 , in the form of a pharmaceutical preparation for enteral, parenteral and oral administration.