Substituted benzimidazoles and their use as PARP inhibitors

Abstract

Compounds of the formula Ia or IB where A is a saturated or monounsaturated heterocyclic, 4 - to 8-membered ring which contains one or two nitrogen atoms, and their tautomeric forms, possible enantiomeric and diastereomeric forms, their prodrugs and possible physiologically tolerated salts are useful as inhibitors of the enzyme poly(ADP-ribose)polymerase.

1. The compound of the formula Ia or Ib 
                 
 R 1  is hydrogen or branched or straight-chain C 1 -C 8 -alkyl, where one carbon atom of the alkyl radical may furthermore carry  is optionally substituted by OR 5  (  where R 5  is hydrogen or C 1 -C 4 -alkyl) , or one carbon atom in the chain may also carry  alkyl radical is optionally substituted by an ═O group NR 8 R 9 , where R 8  and R 9 , independently of one another, are each hydrogen or C 1 -C 4 -alkyl or NR 8 R 9  together may be  form a cyclic amine having 4 to 8 ring atoms, where the carbon chains in R 8  or R 9  or the ring formed by NR 8 R 9  may furthermore carry  are optionally substituted by a radical R 6  which, independently of R 2 , may have  has the same meaning as R 2 ,  
 R 4  is hydrogen, branched or straight-chain C 1 -C 8 -alkyl, chlorine, bromine, fluorine, nitro, cyano, NR 8 R 9 , NH—CO—R 10  or OR 8 , where R 8  and R 9 , independently of one another, are each hydrogen or C 1 -C 4 -alkyl or NR 8 R 9  together may be  form a cyclic amine having 4 to 8 ring atoms, where the ring may furthermore carry  is optionally substituted by a radical (  selected from the group consisting of branched or straight-chain C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, CO—R 41 , COOR 41  or  and phenyl) , and R 10  may be  is hydrogen, C 1 -C 4 -alkyl or phenyl and R 41  may have  has the same meanings as R 21 ,  
 A is a saturated or monounsaturated heterocyclic, 4- to 8-membered ring which contains one or two nitrogen atoms, and optionally, an oxygen or sulfur atom which ring is substituted by R 2  and R 3 , where  
 R 2  is hydrogen,  or branched or straight-chain C 1 -C 8 -alkyl which may furthermore be  is optionally substituted by R 23 , and a carbon atom of the chain may carry  is optionally substituted by an ═O group, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, —CO—(NH) 0.1 — R 21 , COOR 21  or phenyl, where R 21  is hydrogen, branched or straight-chain C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl or phenyl, and each radical may furthermore carry  is optionally substituted by (CH 2 ) 0-2 —R 23 , and the respective phenyl ring in turn may furthermore be  is optionally substituted by 1, 2 or 3 of the following radicals:  selected from the group consisting of chlorine, fluorine, bromine, iodine, branched and straight-chain C 1 -C 4 -alkyl, nitro, CF 3 , cyano, —(CH 2 ) 0-2 —NR 24 R 25 , NH—CO—R 10 , OR 10 , COOR 10 , SO 2 —C 1 -C 4 -alkyl, SO 2 Ph, SO 2 NH 2 , NHSO 2 —C 1 -C 4 -alkyl, NHSO 2 Ph and CF 3 , where R 24  and R 26  R 25 , independently of one another, are each hydrogen or C 1 -C 4 -alkyl or NR 24 R 25  together may be  are a cyclicamine  cyclic amine having 4 to 8 ring atoms, where the ring may furthermore carry  is optionally substituted by a radical selected from the group consisting of branched or straight-chain C 1 -C 8 -alkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, CO—R 22 , COOR 22  (  where R 22  is hydrogen, branched or straight-chain C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 - alkyl, C 3 -C 7 -cycloalkyl or phenyl) or  and phenyl, and R 10  is hydrogen, C 1 -C 4 -alkyl or phenyl, and  
 R 23  is NR 26 N 27  where R 26  and R 27  are each hydrogen, C 1 -C 6 -alkyl, C 0 -C 4 -alkylphenyl, where the phenyl ringmay furthermore be  is optionally substituted by up to 3 radicals selected from the group consisting of Cl, F, Br, I, C 1 -C 4 -alkyl, CF 3 , CN, SO 2 -C 1 -C 4 -alkyl, SO 2 -phenyl, NO 2 , NH 2 , NHCO—C 1 -C 4 -alkyl, NHCO-phenyl, OH, O—C 1 -C 4 -alkyl, and O—C 1 -C 4 -alkylphenyl, or NR 26 R 27  may also be  together are a cyclicamine  cyclic amine having 3 to 8 members, in which O, N and S as a further hetero atom may additionally be  are optionally present, and the ring may furthermore be  is optionally substituted by a radical R 23  where R 26  may be  is C 1 -C 4 -alkyl and  or C 1 -C 4 -alkylphenyl,  
 R 3  is hydrogen, branched or straight-chain C 1 -C 6 alkyl,  or C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl which is unsubstituted or substituted by C 1 -C 6 -alkyl or C 3 -C 7 -cycloalkyl which is unsubstituted or substituted by C 1 -C 6 -alkyl, where one carbon atom of the radical may furthermore carry  is optionally substituted by a phenyl ring which in turn may also be  is optionally substituted by 1, 2 or 3 of the following  radicals:  selected from the group consisting of chlorine, fluorine, bromine, iodine, branched and straight-chain C 1 -C 4 -alkyl, nitro, CF 3 , cyano, (CH 2 ) 0-2 —NR 32 R 33 , NH—CO—R 10 , OR 10 , COOR 10 , SO 2 —C 1 -C 4 -alkyl, SO 2 Ph, CH 3 , SO 2 NH 2 , NHSO 2 - —C 1 -C 4 -alkyl, NHSO 2 Ph and CF 3 , where R 32  and R 33 , independently of one another, are each hydrogen or C 1 -C 4 -alkyl or NR 32 R 33  together may be  are a cyclicamine having 4 to 8 ring atoms, where the ring may furthermore carry  is optionally substituted by a radical selected from the group consisting of branched or straight-chain C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, CO—R 31 , COOR 31  or  and phenyl, and R 10  is hydrogen, C 1 -C 4 -alkyl or phenyl, and R 31  may have  has the same meaning as R 21 ,  
 
       or a tautomeric enantiomeric or diastereomeric form, a prodrug or a physiologically tolerated salt thereof. 
     
     
       2. A compound as claimed in  claim 1 , wherein R 1 , R 2  and R 4  are each hydrogen and A is piperidine, pyrrolidine, piperazine, morpholine and homopiperazine and R 3  is bonded to the nitrogen of A. 
     
     
       3. A compound as claimed in  claim 1 , wherein A may be piperdine  is piperidine which has bonded to the 2-position on the benzimidazole and R 3  may be  is hydrogen, C 1 -C 4 -alkyl, benzyl or phenyl ethyl and is in the 1-position on the piperidine ring. 
     
     
       4. A composition for treating disorders in which pathologically increased PARP activities occur which comprises an effective amount of a compound as described in  claim 1  and a pharmaceutical carrier or excipient. 
     
     
       5. A method of treating patients having disorders in which pathologically increased PARP activities occur comprising administering a therapeutically effective amount of a compound of  claim 1  to said patient. 
     
     
       6. The method of  claim 5 , wherein the disorders are neurodegenerative disorders and neuronal damage. 
     
     
       7. The method of  claim 6 , wherein the disorders are neurodegenerative disorders and neuronal damage which are caused by ischemia, trauma or massive bleeding. 
     
     
       8. The method of  claim 6 , wherein the neurodegenerative disorders and neuronal damage are caused by stroke and  or craniocerebral trauma. 
     
     
       9. The method of  claim 6 , wherein the neurodegenerative disorders and neuronal damage are caused by Alzheimer's disease, Parkinson's disease or Huntington's disease. 
     
     
       10. A method for the treatment or prophylaxis of damage through ischemias comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       11. A method for treating epilepsies comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       12. A method for treating renal damage following renal ischemias, damage which is caused by drug therapy, and  or for treatment during and after kidney transplantations comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       13. A method for treating cardiac damage following myocardial ischemias and damage which is caused by reperfusion of narrowed or closed vessels comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       14. A method for treating microinfarcts comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       15. A method for treatment associated with revascularization of critically narrowed coronary arteries comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       16. A method for treating acute myocardial infarction and  or damage during or after its lysis by means of drugs or mechanically comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       17. A method for treating tumors and their metastasis comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       18. A method for treating sepsis and  or multiorgan failure comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       19. A method for treating immunological disorders comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       20. A method for treating diabetes mellitus comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
       21. A compound as claimed in  claim 1  wherein A is piperidine. 
     
     
       22. A compound as claimed in  claim 1  wherein A is pyrrolidine. 
     
     
       23.  2 -( N - Propylpiperidin -   4   - yl ) benzimidazole -   4   - carboxamide.   
     
     
       24.  2 -( N - Isopropylpiperidine -   4   - yl ) benzimidazole -   4   - carboxamide HCl.   
     
     
       25. A composition for treating disorders in which pathologically increased PARP activities occur which comprises an effective amount of a compound as described in  claim 22  and a pharmaceutical carrier or excipient. 
     
     
       26. A composition for treating disorders in which pathologically increased PARP activities occur which comprises an effective amount of a compound as described in  claim 23  and a pharmaceutical carrier or excipient. 
     
     
       27. A composition for treating disorders in which pathologically increased PARP activities occur which comprises an effective amount of a compound as described in  claim 24  and a pharmaceutical carrier or excipient. 
     
     
       28. A method of treating patients having disorders in which pathologically increased PARP activities occur which comprising administering a therapeutically effective amount of a compound of  claim 22  to said patient. 
     
     
       29. A method of treating patients having disorders in which pathologically increased PARP activities occur which comprising administering a therapeutically effective amount of a compound of  claim 23  to said patient. 
     
     
       30. A method of treating patients having disorders in which pathologically increased PARP activities occur which comprising administering a therapeutically effective amount of a compound of  claim 24  to said patient. 
     
     
       31. A method for treating tumors and their metastasis comprising administering a therapeutically effective amount of a compound of  claim 22  to a patient in need thereof. 
     
     
       32. A method for treating tumors and their metastasis comprising administering a therapeutically effective amount of a compound of  claim 23  to a patient in need thereof. 
     
     
       33. A method for treating tumors and their metastasis comprising administering a therapeutically effective amount of a compound of  claim 4  to a patient in need thereof. 
     
     
       34. A compound of  claim 21  wherein the  4  position of the piperidine ring is bound to the  2  position of the benzimidazole ring. 
     
     
       35. A compound of  claim 34  wherein R 1    and R   4    are hydrogen.   
     
     
       36. A compound of  claim 22  wherein one of R 2    and R   3    are bound to the ring nitrogen of A.   
     
     
       37. A compound of  claim 36  wherein R 2    is hydrogen and R   3  is bound to the ring nitrogen of A. 
     
     
       38. A compound of  claim 2  wherein A is homopiperazine. 
     
     
       39. A method for treating tumors and their metastasis comprising administering a therapeutically effective amount of a compound of  claim 23  in combination with one or more chemotherapeutic agents to a patient in need thereof. 
     
     
       40. A method for treating tumors and their metastasis comprising administering a therapeutically effective amount of a compound of  claim 24  in combination with one or more chemotherapeutic agents to a patient in need thereof.