MXPA01005197A - Substituted benzimidazoles and their use as parp inhibitors - Google Patents

Abstract

The invention relates to compounds of general formula (1a) or (1b) wherein R1 and R4 are hydrogen or defined substituents, A is a saturated or monoethenoid heterocyclic ring with 4 to 8 members which contains one or two nitrogen atoms, wherein additionally one oxygen or sulfur atom can be present. Said ring can be further substituted. The invention also relates to their tautomer forms, possible enantiomer and diastereomer forms, their prodrugs, as well as possible physiologically acceptable salts. The invention also relates to the use of said compounds for treating diseases related to a pathologically increased activity of PARP.

Description

SUBSTITUTE BENZYMIDAZOLES AND THEIR USE AS PARP INHIBITORS The present invention relates to the novel benzimidazoles, their preparation and their use as inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30) for the preparation of medicaments. Poly (ADP-ribose) polymerase (PARP) or, as it is also known, poly (ADP-ribose) tapesa (PARS) is a ^ fc 10 regulatory enzyme found in cell nuclei (K. Ikai et al. , J. Histochem, Cytochem, 31 (1983), 1261-1264). PARP is assumed to play a role in the repair of DNA breaks (M. S. Satoh et al., Na ture 356 (1992), 356-358). The damage to or breaks in the DNA strands activate the PARP enzyme, which, if activated, catalyzes the transfer of ADP-ribose from NAD (S. Shaw, Adv. Radia T. Biol. 11_ (1984), 1-69 ). Nicotinamide is released from NAD. Nicotinamide is converted back into NAD with the consumption of ATP energy carrier by other enzymes. Over-activation of PARP, therefore, would give rise to a high, non-physiological consumption of ATP, and this causes damage to cells and cell death in extreme cases. It is known that radicals such as superoxide anion NO and hydrogen peroxide can cause DNA damage in cells and therefore activate PARP. The formation of large amounts of radicals is observed under different pathophysiological conditions, and it is assumed that this accumulation of radicals causes or contributes to the cellular or organ damage observed. These include, for example, ischemic organ conditions, such as in cerebrovascular accident, myocardial infarction (C. Thiemermann et al., Proc. Na tl. Acad. Sci. USA 94 (1997), 679-783) or ischemia. the kidneys, as well as damage by reperfusion as occurs, for example, after lysis of myocardial infarction (see above: C. Thiemermann et al). The inhibition of the enzyme PARP could, therefore, be a means for the prevention or reduction of this damage at least in part. The PARP inhibitors could, therefore, constitute a new therapeutic principle for the treatment of various disorders. The PARP enzyme has an influence in the repair of DNA damage and thus it could also play a role in the treatment of cancer diseases, since it is observed a greater potential for action against tumor tissue in combination with cytostatic substances (G. Chen et al. Cancer Chemo, Pharmacol 22 (1988), 303). Non-limiting examples of tumors are leukemia, glioblastomas, lymphomas, melanomas, breast carcinomas and cervical carcinomas. ^ Fc It was also found that PARP inhibitors can have an immunosuppressive effect (D. Weltin et al., Int. Immunopharmacol 17 (1995), 265-271). It was also discovered that PARP is involved in immunological diseases or disorders in which the immune system plays an important role, for example rheumatoid arthritis and septic shock, and that PARP inhibitors can have an advantageous effect in the course of treatment. the disease (H. Kroger et al., Inflammation 20 (1996), 203-215; W. Ehrlich et al., Rheuma tol. Int. 15 (1995), 171-172; C. Szabo et al., Proc. Na tl. Acad. Sic. USA 95 (1998), 3867-3872; S. 15 Cuzzocrea et al., Eur. J. Pharmacol. 342 (1998), 67-76). For the purposes of this invention, PARP with meaning of isoenzymes of the PARP enzyme described above is also understood. ^ Furthermore, the PARP 3-aminobenzamide inhibitor showed protective effects in a model for circulatory shock (S. Cuzzocrea et al., Br. J. Pharmacol. 121 (1997), 1065-1074). PARP is also involved in diabetes mellitus (V. Burkhart et al., Nature Medicine (1999), 25 5314-19).

Benzimidazoles have been described extensively. The synthesis of 2-phenylbenzimidaz-4-ylamides which also carries an alkyl chain substituted on the amide radical and which is said to have a cytotoxic effect is mentioned in J. Med. Chem. 33: (1990), 814-819. WO 97/04771 mentions the 4-benzimidazolamides that inhibit PARS. In particular, derivatives carrying a phenyl ring at the 2-position, where the phenyl ring can also be substituted by simple substituents such as nitro, methoxy or CF3, are described therein as effective.

Although some of these substances exhibit good inhibition of the PARP enzyme, the derivatives described therein have the disadvantage that they have little or no solubility in aqueous solutions and therefore can not be applied as an aqueous solution. Benzimidazoles bearing a piperidine ring in the 2-position have also been described. So, in J. Het. Chem. 2_4 (1987), 31, derivatives have been reported as antihistaminic drugs. In J. Het. Chem. 3_2 (1995), 707 and J. Het. Chem. 26 (1989), 541, analogous compounds having the same use have been described. The 2-piperidinylbenzimidazoles are mentioned in EP 818454 as antihistamine drugs and in WO 9736554 as anti-hepatitis agents. In the same way the derivatives are mentioned in CA 80, 146143, Fr. 2103639 and in Khim. GeterotsikI. Soedin 1 (1974), 104. However, the importance of the substituents on the aromatic phenyl in the benzimidazole fragment has not been investigated. In addition, these benzimidazoles carrying a 4- to 8-membered heterocycle, in particular a piperidine ring, in the 2-position have not been described to date as PARP inhibitors. The present application describes the surprising finding that the introduction of a carboxamide radical in the aromatic benzimidazole provides benzimidazoles which are novel and highly effective PARP inhibitors, provided that these are substituted in the 2-position by a saturated heterocycle.

In various treatments, such as for cerebrovascular accident, the active compounds are applied intravenously as a solution for infusion. For this purpose, it is necessary to have substances, in this case PARP inhibitors, that have sufficient solubility in water at physiological or near physiological pH (ie, pH of 5-8), so that a solution for infusion can be prepared. However, many of the disclosed PARP inhibitors, in particular the most effective PARP inhibitors, have the disadvantage that they have only little or no solubility in water at pH values and are therefore not suitable for intravenous application. Such active compounds can be applied with excipients that are proposed to impart solubility in water (see WO 97/04771). These excipients, for example polyethylene glycol and dimethyl sulfoxide, often cause side effects and are even not tolerated. To date, highly effective PARP inhibitors having sufficient solubility in water have not been described. It was found, surprisingly, that the benzimidazoles bearing a piperidine ring in the imidazole ring are highly effective inhibitors and, due to the incorporation of the aliphatic amine radical, allow the formation of salts with acids, giving rise to a substantial water solubility. improved and thus allowing the preparation of a solution for infusion. The present invention describes the novel benzimidazole derivatives of the formula I which have the advantages over the above-described compounds and are potent PARP inhibitors and have sufficient water solubility thereto. When referring to the compounds of the formula I, it is understood that these mean the compounds of the formulas la and Ib. The present invention relates to the substituted benzimidazoles of the formula I: where R1 is hydrogen or straight-chain or branched Ci-Ce alkyl, where a carbon atom of the alkyl radical can further carry OR5 (where R5 is hydrogen or C1-C4 alkyl), or a carbon atom in the chain also can carry a group = 0 or a group NR8R9, where R8 and R9, independent of each other are each hydrogen or C1-C4 alkyl and NR8R9 together can be a cyclic amine having from 4 to 8 atoms in the ring, where the carbon chains in R8 or R9 or the ring formed by NR8R9 can also carry a radical R6 which, independently of R2, can have the same meaning as R2, R 4 is hydrogen, C 1 -C 6 alkyl, branched or straight chain, chlorine, bromine, fluorine, nitro, cyano NR8R9, NH-CO-R10 or OR8, where R8 and R9, independent of each other, are each hydrogen or C? -C4 alkyl, and NR8R9 together can be a cyclic amine having from 4 to 8 atoms in the ring, where the ring may furthermore bear a radical (branched or straight-chain C?-C6 alkyl, (C3-C7) cycloalkyl-Cal-C4 alkyl, CO-R41, COOR41 or phenyl), and R10 may be hydrogen, alkyl of C? ~ C4 or phenyl and R41 can have the same meaning as R21, A is a 4- to 8-membered, heterocyclic, saturated or nonounsaturated ring containing one or two nitrogen atoms, it being possible for an oxygen or sulfur atom to be incorporated, whose oxygen or sulfur atoms are substituted by R2 and R3 [sic], where R is hydrogen, branched or straight chain Ci-Cs alkyl which may also be substituted by R23, and a carbon atom of the chain may bear a = 0, cycloalkyl (C3-C7) -alkyl group of C1-C4 , -CO- (NH) 0.? - R21, COOR21 or phenyl, where R21 is hydrogen, branched or straight-chain C6-6 alkyl, cycloalkyl (from C3-C7) -alkyl of C? ~ C4, phenylalkyl of C1-C4, C3-C7 cycloalkyl or phenyl, and each radical can also carry (CH2) 0-2-R23, and the respective phenyl ring in turn can also be substituted by 1, 2 or 3 of the following radicals : chlorine, fluorine, bromine, iodine, branched and straight-chain C 1 -C 4 alkyl [sic], nitro, CF 3, cyano, - (CH 2) 0-2-NR 24 R 25, NH-CO-R 10, OR 10, COOR 10, S02-C1-C4 alkyl, S02Ph, S02NH, NHS02- Cx-C4 alkyl, NHS02Ph and CF3, where R24 and R25, independent of each other, are each hydrogen or C? -C4 alkyl and NR2R25 together can be a cyclic amine with 4 to 8 atoms in the ring, where the ring can also be e) carrying a branched or straight-chain C?-C6 alkyl radical, (C3-C7) cycloalkyl-C1-C4 alkyl, CO-R22, COOR22 (where R22 is hydrogen, branched C?-C6 alkyl or straight chain, cycloalkyl (C3-C7) C alquilo-C 4 alkyl, phenyl C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl or phenyl), and R 10 is hydrogen, C 1 -C 4 alkyl or phenyl, and R23 is NR26R27, wherein R26 and R27 each are hydrogen, C?-C6 alkyl, (C0-C4) alkyl phenyl, wherein the phenyl ring may also be substituted by up to three Cl, F, Br, I, alkyl radicals of C? -C4, CF3, CN, S02-C? -C alkyl, S02-phenyl, N02, NH2, NHCO-C1-C4 alkyl, NHCO-phenyl, OH, O-C1-C4 alkyl, -alkyl (from C? ~ C4) phenyl, and NR26R27 may also be a cyclic amine having from 3 to 8 members, where another heteroatom such as 0, N and S ^ may also be present, and the ring may also be substituted by a radical R28, wherein R28 5 can be C?-C4 alkyl and C (-C alkyl (phenyl) alkyl, R3 is hydrogen, branched or straight-chain C6-C6 alkyl, C3-C7 cycloalkyl-C4-C4 alkyl which is unsubstituted or substituted by C6-C6 alkyl, or C3-cycloalkyl; C7 which is unsubstituted or substituted by Ci-Ce alkyl, wherein one carbon atom of the radical may additionally bear a phenyl ring which in turn may also be substituted by 1, 2 or 3 of the following radicals: chloro, Fluorine, bromine, iodine, branched and straight-chain C1-C4 alkyl [sic], nitro, CF3, cyano, -C (H2) 0-2-NR32R33, NH-CO-R10, OR10, COOR10, S02- C1-C4 alkyl, S0? Ph, CH3, S02NH, NHS02-C1-C4 alkyl, ^ NHS02Ph and CF3, where R32 and R33, independent of Yes, each is hydrogen or C 1 -C 4 alkyl and NR 32 R 33 together can be a cyclic amine having from 4 to 8 ring atoms, where the ring can also carry a branched or straight chain Ci-Ce alkyl radical , cycloalkyl (from C3-C7) -C1-C4 alkyl, CO-R31, COOR31 or phenyl, and R10 is hydrogen, C? -C alkyl or phenyl, and R31 can have the same meaning as R21, B > and its tautomeric forms, the enantiomeric forms and possible diastereomers, its prodrugs and physiologically tolerated salts possible. Preferred are compounds of the formula I wherein R 1 is hydrogen. Preferred are compounds of the formula I wherein R2 is hydrogen. Preferred are the compounds of the formula I where R 4 is hydrogen S See pprreeffieren the compounds of the formula I where R 3 is attached to the nitrogen of A. The compounds of the formula I wherein R 3 is hydrogen, Ci-Ce alkyl, benzyl or phenethyl are preferred. The compounds of the formula I wherein R1, R2 and R4 are each hydrogen and A is piperidine which is attached to the Position 4 on the benzimidazole and R3 is hydrogen, Ci-Cß alkyl, benzyl or phenethyl and is attached in the 1-position on the piperidine ring are particularly preferred. The respective meanings of R5 to R10 are independent among themselves in R1 to R4.

Preferred meanings NR8R9, NR24R25 and NR32R33 as the cyclic amine are piperidine, pyrrolidine, piperazine and homopiperazine. In the case of piperazine and homopiperazine, the ring can also preferably carry a branched or straight-chain Ci-Cß alkyl radical, (C3-C7) cycloalkyl-C1-C4 alkyl, CO-R7 or phenyl. The preferred meaning of A is piperidine, pyrrolidine, piperazine, morpholine or homopiperazine. The compounds of the formula I wherein A is piperazine 0 piperidine are particularly preferred. The compounds of the formula I can be used in the form of racemates, enantiomerically pure compounds or diastereomers. If 15 enantiomerically pure compounds are desired, these can be obtained, for example, by carrying out a traditional resolution of the racemate with the compounds of the formula 1 or its intermediates used in a convenient or optically active base or acid. The saturated or monounsaturated cyclic structures A may be present as cis isomers, trans isomers or mixtures thereof. The present invention also relates to compounds that are mesomers or tautomers of the compounds of the formula I.

The present invention also relates to the physiologically tolerated salts of compound I, which can be obtained by reacting the compounds I with a suitable acid or base. Suitable acids and bases are listed, for example, in Fortschritte der Arzneimittelforschung, 1966, Birkhuser Verlag, vol. 10, pages 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, etc., and sodium hydroxide, lithium hydroxide, hydroxide. potassium and tris. It is understood that prodrugs means those compounds that are metabolized in vivo to obtain the compounds of formula I. Common prodrugs are phosphates, amino acid carbamates, esters and others. The preparation of the novel benzimidazoles I can be carried out in different ways that are shown in Synthesis Scheme 1.

Synthesis scheme 1 Vil ONHj Benzimidazole I or VII is obtained by condensation of the aldehyde V with phenylenediamines VI, the process preferably being carried out in polar solvents such as ethanol or dimethylformamide, and with the addition of acids such as acetic acid, at elevated temperatures as a general rule from 80 to 120 ° C. It is convenient to add weak oxidizing agents such as copper (II) salts, which are added as an aqueous solution, to the reaction.

Synthesis scheme 2 IX VI If, in the benzimidazole VII, R is NH2, the novel compounds I are formed directly in the condensation. Otherwise, if R is O-alkyl, these esters can react with ammonia, if required at elevated temperatures and superatmospheric pressure, to obtain amide I. Otherwise, esters VII can react with hydrazine in polar solvents such as alcohols butanol and ethanol or dimethylformamide, at elevated temperatures, preferably from 80 to 130 ° C, the result being hydrazide VII (R = NHNH2) which can then be reduced under reductive conditions, for example, with Raney nickel in refluxing alcohols, for obtain amide I. The radical R 1 in the benzimidazole radical in I (R 1 = H) is introduced under traditional alkylation conditions. The benzimidazoles I are alkylated with R1-L, where L is a leaving group, using a base at a temperature of from 25 to 150 ° C, but mainly at elevated temperatures such as from 60 to 130 ° C, obtaining the novel product I where R1 ? hydrogen. The procedure is carried out in solvents, for example dimethylformamide, dimethylsulfoxide, alcohols such as ethanol, ketones for example methyl ethyl ketone or acetone, aliphatic ethers such as tetrahydrofuran and hydrocarbons such as toluene, it being also possible to use mixtures. Suitable bases are, for example, alcoholates such as sodium ethanolate and potassium tert-butanolate, carbonates such as potassium carbonate, hydrides such as sodium hydride and hydroxides such as sodium hydroxide and potassium hydroxide.

It is possible to add different crowned ethers in catalytic amounts as 18-capped 6. It is possible to use phase transfer conditions (for the methods see, R. C. Larock, Comprehensive Organic Transformations, 1989, page 445 et seq.). The leaving group L which may be used may be a halide, for example bromide, chloride or iodide, or for example a tosylate or mesylate.

Synthesis scheme 3 XIII VI 15 R »^ R 'VII Otherwise for the aldehydes V shown in Scheme 1, it is possible to use benzoic acids such as IX (see Scheme 2), or benzonitriles such as XIII (see Scheme 3), instead of benzaldehyde. The preparation of these derivatives is carried out in the same way as the preparation of the substituted benzaldehydes V starting from IX, the condensation to obtain VII is carried out in two stages. First, the benzoic acid XI reacts with the aniline VI with a peptide-like coupling to obtain the amide II. The conditions used in this case are the traditional ones mentioned, for example, in Houben-Weyl, Methoden der Organischen Chemie, 4th edition, E5, chapter V, or CR Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972 et seq. The cyclization to the benzimidazole is then carried out at elevated temperatures, for example from 60 to 180 ° C, with or without solvents such as dimethylformamide, with the addition of acids such as acetic acid, or directly in the acetic acid itself. The reaction of phenylenediamine VI with a benzonitrile XIII in the same way is carried out under conventional conditions. It is possible to use solvents such as dimethylformamide, with the addition of acids at elevated temperatures, such as from 60 to 200 ° C. However, it is possible to use the traditional methods for the preparation of the amides from benzonitriles, as described in J. Amer. Chem. Soc. (1957), 427 and J. Org. Chem. (1987), 1017. The substituted I benzimidazoles contained in the present invention are inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30). The inhibitory effect of the substituted I benzimidazoles was determined by an enzymatic test already known in the literature, determining the Ki value as a measure of activity. The benzimidazoles I were measured in this way for an inhibitory effect of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30). The substituted benzimidazoles of the formula I are inhibitors of poly (ADP-ribose) polymerase (PARP) or, as it is known, poly (ADP-ribose) tapese (PARS) and, therefore, can be used for the treatment and Prophylaxis of disorders associated with increased activity in these enzymes. The compounds of the formula I can be used to prepare drugs for the treatment of damage followed by ischemia and for prophylaxis where ischemia of different organs is expected. The present benzimidazoles of the formula I can then be used for the treatment and prophylaxis of neurodegenerative diseases that occur after ischemia, trauma (cranial brain trauma), massive hemorrhage, subarachnoid hemorrhages and stroke, and of neurodegenerative diseases such as dementia by infarction Multiple, Alzheimer's disease and Huntington's disease, of epilepsies, in particular of generalized epileptic seizures, for example, petit mal and tonoclonic seizures and partial epileptic seizures such as temporal lobe, and complex partial seizures, and for the treatment and prophylaxis of cardiac damage followed by myocardial ischemia and damage to the kidneys followed by renal ischemia, for example, acute renal failure, acute kidney injury, damage that is caused by treatment with medications such as, for example, during treatment with cyclosporine or damage that occurs during or after transplant of kidney. In addition, the compounds of the formula I can be used for the treatment of acute myocardial infarction and damage occurring during and after their lysis under treatment with medicaments (for example, with TPA, reteplase or streptokinase or mechanically with a laser or Rotablator) and of microinfarcts such as, for example, during and after cardiac valve replacement, aneurysm resections and heart transplants. The benzimidazoles I present can also be used for the treatment of a revascularization of critically narrowed coronary arteries, for example, in PCTA and bypass operations, and critically narrowed peripheral arteries, for example, leg arteries. In addition, benzimidazoles I may be useful in the chemotherapy of tumors and their metastases and for the treatment of inflammations or rheumatic disorders, for example, rheumatoid arthritis. In addition, the compounds of formula I can be used to treat diabetes mellitus or to treat sepsis and multiple organ failure such as, for example, during septic shock and respiratory distress syndrome in adults (ARDS, lung shock). The novel drug formulations contain an effective amount for therapeutic use of the compounds I in addition to the excipients of traditional medicaments. For external, local application, for example in the form of powders, ointments or rubbers, the active compounds may be present in the traditional concentrations. As a general rule, the active compounds are present in an amount from 0.001 to 1, preferably from 0.001 to 0.1% by weight. In the case of internal use, the preparations are administered in individual doses. From 0.1 to 100 mg per kg of body weight is administered in individual doses. The formulation can be administered daily in one or more doses, depending on the type and severity of the disorder. Depending on the method of application desired, the novel drug formulations contain the traditional carriers and diluents in addition to the active compound. For external, local application, pharmaceutical excipients such as ethanol, isopropanol, oxyethylated castor oil, oxyethylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and lanolin are suitable. Suitable for internal use are, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinyl pyrrolidone. Antioxidants such as tocopherol and butylated hydroxyanisole, butylated hydroxytoluene, flavor enhancing additives, stabilizers, emulsifiers and lubricants may also be present. The substances contained in the formulation in addition to the active compound, and the substances used in the preparation of the pharmaceutical formulations are safe from the point of view of toxicity and compatible with the respective active compound. The preparation of the drug formulations is carried out in a traditional manner, for example, by mixing the active compound with other conventional carriers and diluents. The formulations and medicaments can be administered by different methods of application, for example, per-orally, parenterally, as it can be intravenous by infusion, subcutaneous, intraperitoneal and topical. Thus, formulations such as tablets, emulsions, infusion and solutions for injection, pastes, ointments, gels, creams, powder lotions and rubbers are possible. In addition to the substances mentioned in the examples, the following compounds are particularly preferred and can be synthesized according to the methods of preparation: 1. 2- (N- (O-tert-butoxycarbonyl) piperidin-4-yl) benzimidazole-4-carboxamide 2.2- (N-methylpiperidin-4-yl) benzimidazole-4-carboxamide 3.2- (N-isopropylpiperidin-4-yl) Benzimidazole-4-carboxamide 4.2- (N-cyclohexylpiperidin-4-yl) benzimidazole-4-carboxamide 5.2- (N- (trans-4-propylcyclohex-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 6.2- (N-benzylpiperidin-4-yl) benzimidazole-4-carboxamide 7. 2- (N- (2-phenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 8.2- (N- (2- (4-fluorophenyl) et-l-yl) piperidin-4- il) benzimidazole-4-carboxamide 9.2- (N- (2- (4-chlorophenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 10. 2- (N- (2- (4- bromophenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 11. 2- (N- (2- (4-iodophenyl) et-l-yl) piperidin-4-yl) benzimidazole-4- carboxamide 12. 2- (N- (2- (4-nitrophenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 13. 2- (N- (2- (4-cyanophenyl) et- 1-yl) piperidin-4-yl) benzimidazole-4-carboxamide 14. 2- (N- (2- (4- (trifluoromethyl) phenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 15. 2- (N- (2- (4-methylphenyl) et-1-yl) piperidin-4-yl) enimidazole-4-carboxamide 16. 2- (N- (2- (4-hydroxyphenyl) et-1 -yl) piperidin-4-yl) benzimidazole-4-carboxamide 17. 2- (N- (2- (4-methoxyphenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 18. 2- (N- (2- (4- (N ', N' -dimethylamino) phenyl) et-1-yl) piperidin-4-yl) benzimidazole-4-carboxamide to 19. 2- (N- (2- (4- (K '-acetylamino) phenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 20. 2- (N- (2- ( 4- (N '-phenylsulfonylamino) phenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 21. 2- (N- (2- (4- (phenylsulfonyl) phenyl) et-1-yl ) piperidin-4-yl) benzimidazole-4-carboxamide 22. 2- (N- (2- (4- (methoxycarbonyl) phenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 23. 2 - (N-acetylpiperidin-3-yl) benzimidazole-4-carboxamide 24. 2- (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide . 2- (N-isopropylpiperidin-3-yl) benzimidazole-4-carboxamide 26. 2- (N-cycloheptylperidin-3-yl) benzimidazole-4-carboxamide 27. 2- (N- (trans-4-propylcyclohex-1) -yl) piperidin-3-yl) benzimidazole-4-carboxamide 28. 2- (N- (2-phenyl) et-1-yl) piperidin-3-yl) benzimidazole-4-carboxamide 29. 2- (N- (4-chlorophenyl) et-l-yl) piperidin-3-yl) benzimidazole-4-carboxamide 30. 2-pyrrolidin-3-ylbenzimidazole-4-carboxamide 31. 2- (N-acetylpyrrolidin-3-yl) benzimidazole- 4-carboxamide 32. 2- (N- (O-tert-butoxycarbonyl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 33. 2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 3. 2- (N-isopropylpyrrolidin-3-yl) benzimidazole-4-carboxamide 35. 2- (N-cyclohexylpyrrolidin-3-yl) benzimidazole-4-carboxamide 36. 2- (N- (trans-4-propylcyclohex-l) pyrrolidin-3-yl) benzimidazole-4-carboxamide 37. 2- (N-benzylpyrrolidin-3-yl) benzimidazole-4-carboxamide 38. 2- (N- (2-phenyl) et-1-yl) pyrrolidin-3 -yl) benzimidazole-4-carboxamide 39. 2- (N- (2- (4-chlorophenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 40. 2- (N- (2- (4-nitrophenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 41. 2- (N- (2- (4-cyanophenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole 4-carboxamide 42. 2- (N- (2- (4- (trifluoromethyl) phenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 43. 2- (N- (2- ( 4-methylphenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 44. 2- (N- (2- (4-hydroxyphenyl) et-1-yl) pyrrolidin-3-yl) benzimidazole- 4-carboxamide 45. 2- (N- (2- (4-methoxyphenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 46. 2- (N- (2- (4- (N , N '-dimethylamino) phenyl) et-1-yl) p irrolidin-3-yl) benzimidazole-4-carboxamide 47. 2- (N- (2- (4- (M '-acetylamino) phenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 2- (N- (2- (4- (N '-phenylsulfonylamino) phenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 49. 2- (N- (2- (4- (phenylsulfonyl) phenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 50. 2- (N- (2- (4- (methoxycarbonyl) phenyl) et-l-yl) pyrrolidin- 3- il) benzimidazole-4-carboxamide 51. 2-pyrrolidin-2-ylbenzimidazole-4-carboxamide 52. 2- (N-acetylpiperazin-4-yl) benzimidazole-4-carboxamide 53. 2- (N- (O-tert-butoxycarbonyl) piperazin-4-yl) benzimidazole-4-carboxamide 5. 2- (N-methyl-piperazin-4-yl) -benzimidazole-4-carboxamide 55. 2- (N-propylpiperazin-yl) benzimidazole-4-carboxamide 56. 2- (N-isopropylpiperazin-4-yl) benzimidazole-4-carboxamide 57. 2- (N-cyclohexylpiperazin-4-yl) benzimidazole-4-carboxamide 58. 2- (N- (trans-4-propylcyclohex-1- il) piperazin-4-yl) benzimidazole-4-carboxamide 59. 2- (N-benzylpiperazin-4-yl) benzimidazole-4-carboxamide 60. 2- (N- (2-phenyl) et-l-yl) piperazine -4-yl) benzimidazole-4-carboxamide 61. 2- (N- (2- (4-fluorophenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 62. 2- (N- ( 2- (4-chlorophenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 63. 2- (N- (2- (4-bromophenyl) et-l-yl) piperazin-4-yl ) benzimidazole-4-carboxamide 64. 2- (N- (2- (4-iodophenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 65. 2- (N- (2- (4 -nitrophenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 66. 2- (N- (2- (4-cyanophenyl) et-l-yl) piperazin-4-yl) benzimidazole-4 -carboxamide 67. 2- (N- (2- (4- (trifluoromethyl) phenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 68. 2- (N- (2- (4- methylphenyl) et-l-yl) piperazin-4-yl) benzimid azole-4-carboxamide 69. 2- (N- (2- (4-hydroxyphenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 70. 2- (N- (2- (4- methoxyphenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 71. 2- (N- (2- (4- (N, N '-dimethylamino) phenyl) et-1-yl) piperazine- 4-yl) benzimidazole-4-carboxamide 72. 2- (N- (2- (4- (N '-acetylamino) phenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 73. 2 - (N- (2- (4- (N '-phenylsulfonylamino) phenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 74. 2- (N- (2- (4- (phenylsulfonyl ) phenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 75. 2- (N- (2- (4- (methoxycarbonyl) phenyl) et-l-yl) piperazin-4-yl) benzimidazole-4-carboxamide 76. 2-homopiperazin-4-ylbenzimidazole-4-carboxamide 77. 2- (N-acetylhomopiperazin-4-yl) benzimidazole-4-carboxamide 78. 2- (N- (O-tert-butoxycarbonyl) homopiperazin-4-yl) benzimidazole-4-carboxamide 79. 2- (N-methylhomopiperazin-4-yl) benzimidazole-4-carboxamide 80. 2- (N-propylhomopiperazin-4-yl) benzimidazole-4-carboxy Measure 81. 2- (N-isopropylhomopiperazin-4-yl) benzimidazole-4-carboxamide 82. 2- (N-cyclohexyl-homopyperazin-4-yl) benzimidazole-4-carboxamide 83. 2- (N- (trans-4-propylcyclohex -l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 84. 2- (N-benzylhomopiperazin-4-yl) benzimidazole-4-carboxamide 85. 2- (N- (2-phenyl) et-l- il) homopiperazin-4-yl) benzimidazole-4-carboxamide 86. 2- (N- (2- (4-fluorophenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 87. 2- ( N- (2- (4-Cl orophenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 88. 2- (N- (2- (4-bromophenyl) et-1-yl) homopiperazine 4-yl) benzimidazole-4-carboxamide 89. 2- (N- (2- (4-iodophenyl) et-l-yl) homopy? Ezin-4-yl) benzimidazole-4-carboxamide 90. 2- (N - (2- (4-nitrophenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 91. 2- (N- (2- (4-cyanophenyl) et-1-yl) homopiperazine-4 - il) benzimidazole-4-carboxamide 92. 2- (N- (2- (4-trifluorophenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 93. 2- (N- (2- (4-methylphenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 94. 2- (N- (2- (4-hydroxyphenyl) et-1-yl) homopiperazine-4- il) benzimidazole-4-carboxamide 95. 2- (N- (2- (4-methoxyphenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 96. 2- (N- (2- ( 4- (N ', N' -dimethylamino) phenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 97. 2- (N- (2- (4- (N '-acetylamino) phenyl) ) et-1-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 98. 2- (N- (2- (4- (N '-phenylsulfonylamino) phenyl) et-1-yl) homopiperazin-4-yl ) benzimidazole-4-carboxamide 99. 2- (N- (2- (4- (phenylsulfonyl) phenyl) et-1-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 100. 2- (N- (2 - (4- (methoxycarbonyl) phenyl) et-l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 101. l-methyl-2- (piperidin-4-yl) benzimidazole-4-carboxamide 102. 2- (N- (O-tert-butoxycarbonyl) piperidin-4-yl) -1- methylbenzimidazole-4-carboxamide 103. l-methyl-2- (N-methyl-piperidin-4-yl) benzimidazole-4-carboxamide 104. l-Methyl-2- (N-isopropyl-piperidin-4-yl) benzimidazole-4-carboxamide 105. 2- (N- (benzylpiperidin-4-yl) -l-methylbenzimidazole-4-carboxamide 106. l- methyl-2- (N- (2-phenyl) et-l-yl) piperidin-4-yl) benzimidazole-4-carboxamide 107. 2- (N- (2- (4-chlorophenyl) et-1-yl) piperidin-4-yl) -1- methylbenzimidazole-4-carboxamide 108. 2- (N-acetylpiperidin-3-yl) -l-methylbenzimidazole-4-carboxamide 109. l-methyl-2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 110. 2- (N-acetylpyrrolidin-3-yl) -l-methylbenzimidazole-4-carboxamide 111. 2- (N- (O-tert-butoxycarbonyl) pyrrolidin-3-yl) -1- methylbenzimidazole 4-carboxamide 112. l-methyl-2- (N-methylpyrrolidin-3-yl) benzimidazole-4-carboxamide 113. l-methyl-2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 114. l-methyl-2- (N-isopropylpyrrolidin-3-yl) benzimidazole-4-carboxamide 115. 2- (N-benzyl) pyrrolidin-3-yl) -l-methylbenzimidazole-4-carboxamide 116. l-methyl-2- (N- (2-phenyl) et-l-yl) pyrrolidin-3-yl) benzimidazole-4-carboxamide 117. 2 - (N- (2- (4-chlorophenyl) et-l-yl) pyrrolidin-3-yl) -1-methylbenzimidazole-4-carboxamide 118. l-methyl-2- (pyrrolidin-2-yl) benzimidazole-4 - carboxamide 119. 2- (N-acetylpyrrolidin-2-yl) -l-methylbenzimidazole-4-carboxamide 120. l-methyl-2-piperazin-4-ylbenzimidazole-4-carboxamide 121. 2- (N-Acetylpiperazin-4-yl) -l-methylbenzimidazole-4-carboxamide 122. 2- (N- (O-tert-butoxycarbonyl) piperazin-4-yl) -1- methylbenzimidazole-4-carboxamide 123. l methyl-2- (N-methylpiperazin-4-yl) benzimidazole-4-carboxamide 124. l-methyl-2- (N-propylpiperazin-4-yl) benzimidazole-4-carboxamide 125. l-methyl-2- ( N-isopropylpiperazin-4-yl) benzimidazole-4-carboxamide 126. 2- (N-benzylpiperazin-4-yl) -l-methylbenzimidazole-4-carboxamide 127. l-methyl-2- (N-phenyl) et-1 -yl) piperazin-4-yl) benzimidazole-4-carboxamide 128. 2- (N- (2- (4-chlorophenyl) et-l-yl) piperazin-4-yl) -1- methylbenzimidazole-4-carboxamide 129 2- (Homopiperazin-4-yl) -l-methylbenzimidazole-4-carboxamide 130. 2- (N-Acetylhomopiperazin-4-yl) -1-methylbenzimidazole-4-carboxamide 131. 2- (N- (O-ter -butoxycarbonyl) homopiperazin-4-yl) -1- methylbenzimidazole-4-carboxamide 132. l-methyl-2- (N-methylhomopiperazin-4-yl) benzimidazole-4-carboxamide 133. l-methyl-2- (N- propylhomopiperazin-4-yl) benzimidazole-4-carboxamide 134. l-methyl-2- (N-is opropylhomopiperazin-4-yl) enimidazole-4-carboxamide 135. 2- (N-benzylhomopiperazin-4-yl) -1-methylbenzimidazole-4-carboxamide 136. l-methyl-2- (N- (2-phenyl) et- l-yl) homopiperazin-4-yl) benzimidazole-4-carboxamide 137. 2- (N- (2- (4-chlorophenyl) et-l-yl) homopiperazin-4-yl) -1-methylbenzimidazole-4-carboxamide 138. 1-Ethyl-2- (piperidin-4-yl) -1-benzimidazole-4-carboxamide 139. 2- (piperidin-4-yl) -l-isopropylbenzimidazole-4-carboxamide 140. 1- (2- ( hydroxy) et-l-yl) -2- (piperidin-4-yl) benzimidazole-4-carboxamide 141. 1- (2- (methoxy) et-l-yl) -2- (piperidin-4-yl) benzimidazole -4-carboxamide 142. 1- (2- (amino) et-1-yl) -2- (piperidin-4-yl) benzimidazole-4-carboxamide 143. 1- (2- (N, N-dimethylamino) et -l-yl) -2- (piperidin-4-yl) benzimidazole-4-carboxamide 144. l- (2- (piperidin-1-yl) et-1-yl) -2- (piperidin-4-yl) benzimidazole-4-carboxamide 145. 2- (piperidin-4-yl) -1- (pyrrolidin-1-yl) et-l-yl) benzimidazole-4-carboxamide 146. 1- (2- (2-ethylpiperidin-1) -il) et-l-il) -2- (piperidin-4- i l) benzimidazole-4-carboxamide 147. l-ethyl-2- (piperidin-3-yl) benzimidazole-4-carboxamide 148. 2- (piperidin-3-yl) -l-isopropylbenzimidazole-4-carboxamide 149. 1- (2-hydroxy) et-1-yl) -2- (piperidin-3-yl) benzimidazole-4-carboxamide 150. 1 - (2-methoxy) et-l-yl) -2- (piperidin-3-yl) benzimidazole-4-carboxamide 151. 1- (2-amino) et-l-yl) -2- (piperidin-3- il) benzimidazole-4-carboxamide 152. 1- (2- (N, N-dimethylamino) et-l-yl) -2- (piperidin-3-yl) benzimidazole-4-carboxamide 153. 1- (2- ( piperidin-1-yl) et-l-yl) -2- (piperidin-3-yl) benzimidazole-4-carboxamide 154. 2- (piperidin-3-yl) -1- (pyrrolidin-1-yl) et-1-yl) benzimidazole-4-carboxamide 155. 1- (2- (2-ethyl-piperidin-1-yl) et -l-yl) -2- (piperidin-3-yl) benzimidazole-4-carboxamide 156. l-ethyl-2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 157. l-isopropyl-2- (pyrrolidine -3-yl) benzimidazole-4-carboxamide 158. 1- (2- (hydroxy) et-1-yl) -2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 159. 1- (2- (methoxy ) et-1-yl) -2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 5 160. 1- (2- (amino) et-1-yl) -2- (pyrrolidin-3-yl) benzimidazole -4-carboxamide 161. 1- (2- (N, N-dimethylamino) et-l-yl) -2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 162. 1- (2- (piperidin-1-yl) et-1-yl) -2- ( pyrrolidin-3-fc-10-yl) benzimidazole-4-carboxamide 163. 2- (pyrrolidin-3-yl) -1- (2- (pyrrolidin-1-yl) et-1-yl) benzimidazole-4-carboxamide 164. 1- (2- (2-ethylpiperidin-1-yl) et-1-yl) -2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 15 165. l-ethyl-2- (pyrrolidin-2-yl) ) benzimidazole-4-carboxamide 166. 1-isopropyl-2- (pyrrolidin-2-yl) benzimidazole-4-carboxamide 167. 1- (2- (hydroxy) et-1-yl) -2- (pyrrolidin-2-) il) benzimidazole-4-carboxamide 20 168. 1- (2- (methoxy) et-l-yl) -2- (pyrrolidin-2-yl) benzimidazole-4-carboxamide 169. 1- (2- (amino) et -l-yl) -2- (pyrrolidin-2-yl) benzimidazole-4-carboxamide 170. 1- (2- (N, N-dimethylamino) et-l-yl) -2- (pyrrolidin-2-yl) ) benzimidazole-4-carboxamide 171. 1- (2- (piperidin-1-yl) et-l-yl) -2- (pyrrolidin-2-yl) benzimidazole-4-carboxamide 172. 2- (pyrrolidin-2- il) -1- (2- (pyrrolidin-1-yl) et-1-yl) benzimidazole-4-carboxy Measure 173. l- (2- (2-ethyl-piperidin-1-yl) et-1-yl) -2- (pyrrolidin-2-yl) benzimidazole-4-carboxamide 174. l-ethyl-2- (piperazine -4-yl) benzimidazole-4-carboxamide 175. l-isopropyl-2- (piperazin-4-yl) benzimidazole-4-carboxamide 176. 1- (2- (hydroxy) et-1-yl) -2- (piperazin-4-yl) benzimidazole-4-carboxamide 177 1- (2- (methoxy) -et-l-yl) -2- (piperazin-4-yl) benzimidazole-4-carboxamide 178. 1- (2- (amino) -et-l-yl) -2 - (piperazin-4-yl) benzimidazole-4-carboxamide 179. 1- (2- (N, N-dimethylamino) et-1-yl) -2- (piperazin-4-yl) -benzimidazole-4-carboxamide 180 2- (piperazin-4-yl) -1- (2- (piperidin-1-yl) et-l-yl) benzimidazole-4-carboxamide 181. 2- (piperazin-4-yl) -l- (2 - (pyrrolidin-1-yl) et-l-yl) benzimidazole-4-carboxamide 182. 1- (2- (2-ethyl-piperidin-1-yl) et-1-yl) -2- (piperazin-4) - il) -benzimidazole-4-carboxamide 183. l-ethyl-2- (homopiperazin-4-yl) benzimidazole-4-carboxamide 184. l-isopropyl-2- (homopiperazin-4-yl) benzimidazole-4-carboxamide 185 1- (2- (hydroxy) et-1-yl) -2- (homopiperazin-4-yl) benzimidazole-4-carboxamide 186. 1- (2- (methoxy) et-1-yl) -2- ( homopiperazin-4-yl) benzimidazole-4-carboxamide 187. 1- (2- (amino) et-1-yl) -2- ( homopiperazin-4-yl) benzimidazole-4-carboxamide 188. 1- (2- (N, N-dimethylamino) et-1-yl) -2- (homopiperazin-4-yl) -benzimidazole-4-carboxamide 189. 2 - (homopiperazin-4-yl) -1- (2- (piperidin-1-yl) et-l-yl) -benzimidazole-4-carboxamide 190. 2- (homopipera zin-4-yl) -1- ( 2- (Pyrrolidin-1-yl) et-1-yl) -benzimidazole-4-carboxamide 191. 1- (2- (2-ethylpiperidin-1-yl) et-1-yl) -2- (homopiperazine- - il) benzimidazole-4-carboxamide 192. l-ethyl-2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide 193. l-isopropyl-2- (N-propylpiperidin-4-yl) benzimidazole- 4- carboxamide 194. 1- (2- (hydroxy) et-1-yl) -2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide 195. 1- (2- (methoxy) et-1-yl) -2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide 196. 1- (2- (amino) et-1-yl) -2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide 197. 1- (2- (N, N-dimethylamino) et-l-yl) -2- (N-propylpiperidin-4-yl) -benzimidazole-4-carboxamide 198. 1- (2- (piperidin-1- il) et-l-il) -2- (N-propylpiperidin-4-yl) -benzimidazole-4-carboxamide 199. 2- (N-propylpiperidin-4-yl) -1- (2- (pyrrolidin-1-yl) et-l-yl) -benzimidazole-4-carboxamide 200. 1- (2 - (2-ethylpiperidin-l-yl) et-l-yl) -2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide 201. l-ethyl-2- (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide 202. l-isopropyl-2- (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide 203. 1- (2- (hydroxy) et-l-yl) -2- (N-propylpiperidine -3-yl) benzimidazole-4-carboxamide 204. 1- (2- (methoxy) et-l-yl) -2- (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide 205. 1- (2- (amino) et-1-yl) -2- (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide 206. 1- (2- (N, N-dimethylamino) et-1-yl) -2- ( N-propylpiperidin-3-yl) benzimidazole-4-carboxamide 207. 1- (2- (piperidin-1-yl) et-1-yl) -2- (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide 208. 2- (N-propylpiperidin-1-yl) -1- (2- (pyrrolidin-1-yl) et-1-yl) -benzimidazole-4-carboxamide 209. 1- (2- (2-ethylpiperidin- l-il) et-l-il) -2- (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide 210. l-ethyl-2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 211. l-isopropyl-2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 212 1- (2- (hydroxy-et-1-yl) -2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 213. 1- (2- (methoxy-et-1-yl) -2 - (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 214. 1- (2- (amino-et-1-yl) -2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 215. 1- (2- (N, N-dimethylamino-et-l-yl) -2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 216. 1- (2- (piperid.in-1-yl) ) -et-1-yl) -2- (N-propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 217. 2- (N-propylpyrrolidin-3-yl) -1- (2- (pyrrolidin-1-yl) ) et-1-yl) benzimidazole-4-carboxamide 218. 1- (2- (2-ethylpiperidin-1-yl) et-1-yl) -2- (propylpyrrolidin-3-yl) benzimidazole-4-carboxamide 219. l-ethyl-2- (N-propylpyrrolidin-2-yl) benzimidazole-4-carboxamide 220. l-isopropyl-2- (N-propylpyrrolidin-2-yl) benzimidazole-4-carboxamide 221. 1- (2- ( hydroxy) et-1-yl) -2- (N-propylpyrrolidin-2-yl) benzimidazole-4-carboxamide 222. 1- (2- (methoxy) et-1-yl) -2- (N-propylpyrrolidin-2) - il) benzimidazole-4-carboxamide 223. 1- (2- (amino) et-1-yl) -2- (N-propylpyrrolidin-2-yl) benzimidazole-4-carboxamide 224. 1- (2- (N, N-dimethylamino) et-l-yl) -2- (N-propylpyrrolidi-2-yl) benzimidazole-4-carboxamide 225. 1- (2- (piperidin-1-yl) et-1-yl) -2 - (N-propylpyrrolidin-2-yl) benzimidazole-4-carboxamide 226. 2- (pyrrolidin-2-yl) -l- (2- (N-propylpyrrolidin-1-yl) et-1-yl) -benzimidazole- 4-carboxamide 227. 1- (2- (2-ethylpiperidin-1-yl) et-1-yl) -2- (N-propylpyrrolidin-l-2-yl) benzimidazole-4-carboxamide 228. l-ethyl-2- (N-propylpiperazin-4-yl) benzimidazole-4-carboxamide 229. 1-isopropyl-2- (N-propyl-piperazin-4-yl) -benzimidazole-4-carboxamide 230. 1- (2- ( hydroxy) et-l-yl) -2- (N-propylpiperazin-4-yl) benzimidazole-4-carboxamide 231. 1- (2- (methoxy) et-l-yl) -2- (N-propylpiperazin-4) - il) benzimidazole-4-carboxamide 232. 1- (2- (amino) et-1-yl) -2- (N-propylpiperazin-4-yl) benzimidazole-4-carboxamide 233. 1- (2- (N , N-dimethylamino) et-l-yl) -2- (N-propylpiperazin-4-yl) benzimidazole-4-carboxamide 234. 1- (2- (piperidin-1-yl) et-1-yl) -2 - (N-propylpiperazin-4-yl) benzimidazole-4-carboxamide 235. 2- (N-propyl-piperazin-4-yl) -1- (2-pyrrolidin-1-yl) et-1-yl) benzimidazole- 4-carboxamide 236. 1 - (2- (2-ethylpiperidin-1-yl) et-1-yl) -2- (N-propyl-piperazin-4-yl) -benzimidazole-4-carboxamide 237. 1-ethyl-2- (N-propylhomopiperazin-4-yl) benzimidazole-4-carboxamide 238. l-isopropyl-2- (N-propylhomopiperazin-4-yl) benzimidazole-4-carboxamide 239. 1- (2- (hydroxy) et-l- il) -2- (N-propylhomopiperazin-4-) ) benzimidazole-4-carboxamide 240. 1- (2- (methoxy) et-l-yl) -2- (N-propylhomopiperazin-4-yl) benzimidazole -4-carboxamide 241. 1- (2- (amino) et -l-il) -2- (N-propylhomopiperazin-4-yl) benzimidazole-4-carboxamide 242. 1- (2- (N, N-dimethylamino) et-1-yl) -2- (N- propylhomopiperazine- 4-yl) -benzimidazole-4-carboxamide 243. 1- (2- (piperidin-1-yl) et-1-yl) -2- (N-propylhomopiperazin-4-yl) benzimidazole-4-carboxamide 244. 2- (N-propylhomopiperazin-4-yl) -1- (2- (pyrrolidin-1-yl) et-1-yl) -benzimidazole-4-carboxamide 245. 1- (2- (2-ethylpiperidine-1 il) et-1-yl) -2- (N-propylhomopiperazin-4-yl) benzimidazole-4-carboxamide 246. 6-chloro-2- (piperidin-4-yl) benzimidazole-4-carboxamide 247. 6-chloro -2- (piperidin-3-yl) benzimidazole-4-carboxamide 248. 6-chloro-2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 249. 6-chloro-2- (piperazin-4-yl) benzimidazole-4-carboxamide 250. 6-chloro-2- (homopiperazin-4) -yl) benzimidazole-4-carboxamide 251. 6-ethyl-2- (piperidin-4-yl) benzimidazole-4-carboxamide 252. 6-Ethyl-2- (piperidin-3-yl) benzimidazole-4-carboxamide 253. 6-Ethyl-2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 254. 6-ethyl-2- (piperazin-4-yl) benzimidazole-4-carboxamide 255. 6-Ethyl-2- (homopiperazin-4-yl) benzimidazole-4-carboxamide 256. 6-amino-2- (piperidin-4-yl) benzimidazole-4-carboxamide 257. 6-amino-2- (piperidin-3-yl) benzimidazole-4-carboxamide 258. 6-amino-2- (pyrrolidin-3-yl) benzimidazole-4-carboxamide 259. 6-amino-2- (piperazin-4) -yl) benzimidazole-4-carboxamide 260. 6-amino-2- (hcmopiperazin-4-yl) benzimidazole-4-carboxamide 261. 2- (piperidin-4-yl) -6- (pyrrolidin-1-yl) benzimidazole-4-carboxamide 262. 2- (piperidine -3-yl) -6- (pyrrolidin-1-yl) benzimidazole-4-carboxamide 263. 2- (pyrrolidin-3-yl) -6- (pyrrolidin-1-yl) benzimidazole-4-carboxamide 264. 2- (piperazin-4-yl) -6- (pyrrolidin-1-yl) benzimidazole-4-carboxamide 265. 2- (homopiperazin-4-yl) -6- (pyrrolidin-1-yl) benzimidazole-4-carboxamide 266 2- (3-methylpiperidin-4-yl) benzimidazole-4-carboxamide 267. 2- (3-cyclohexylpiperidin-4-yl) benzimidazole-4-carboxamide 268. 2- (2-cyclohexylpiperidin-4-yl) benzimidazole-4-carboxamide 269. 2- (3-phenylpiperidin-4-yl) benzimidazole-4 -carboxamide 270. 2- (4-Phenylpiperidin-4-yl) benzimidazole-4-carboxamide 271. 2- (2- (hydroxycarbonyl) piperidin-4-yl) benzimidazole-4-carboxamide 272. 2- (2- (ethoxycarbonyl) piperidin-4-yl) benzimidazole-4-carboxamide 273. 2- (2- (cyclohexyloxycarbonyl) piperidin-4-yl) benzimidazole-4-carboxamide 274. 2- (2- (benoxycarbonyl) piperidin-4-yl) benzimidazole-4-carboxamide [sic] 275. 2- (2- (phenoxycarbonyl) piperidin-4-yl benzimidazole-4-carboxamide Example 1 2- (piperidin-4-yl) benzimidazole-4-carboxamide • 2 HCl a) N- (2-amino-3-ethoxycarbonyl) -1- (tert-butoxycarbonyl) -piperidine-4-carboxanilide . 5 g (24 mmol) of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 4.3 g (24 mmol) of ethyl 2-3-diaminobenzoate were dissolved with 6.0 g (60 mmol) of triethylamine and 3.2 g ( 24 mmol) of 1-hydroxybenzotriazole in 100 ml of anhydrous tetrahydrofuran. At 0 ° C4.6 g (24 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide were then added and the whole was stirred for one hour. Stirring was continued for 24 hours at room temperature. The reaction mixture was evaporated under reduced pressure and the residue obtained was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The ethyl acetate phase was also washed with a 5% aqueous solution of citric acid concentration, dried and evaporated under reduced pressure. 8.4 g of the product were obtained. b) Ethyl 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzimidazole-4-carboxylate 8. 1 g of the intermediate in 100 ml of concentrated acetic acid were refluxed for 30 minutes. The whole was then evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate phase was also washed with an aqueous solution of sodium bicarbonate and the water was then evaporated under reduced pressure. 4.6 g of the product were obtained. c) 2-piperidin-4-ylbenzimidazole-4-carboxylate x 2 HCl 3. 7 g (9.9 mmol) of intermediate lb were added to 50 ml of a 4M solution of hydrogen chloride in dioxane and stirred for one hour at room temperature. Then, the batch was diluted with a large amount of ether and the resulting precipitate was filtered with suction. 3.2 g of the product were obtained. d) 2-piperidin-4-ylbenzimidazole-4-carbohydrazide 2. 7 g (7.8 mmol) of the intermediary le and 2.7 g (54 mmol) of hydrazine in 30 ml of n-butanol were refluxed for 15 hours. Then, the whole was evaporated under reduced pressure and the residue obtained was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic phase was separated, dried and evaporated under reduced pressure. 0.9 g of the product was obtained. e) 2-piperidin-4-ylbenzimidazole-4-carboxamide x 2 HCl Approximately 2.4 g of Raney nickel in 20 ml of water were added to 0.8 g (3.1 mmol) of intermediate ld in 20 ml of dimethylformamide, and the total was heated at 100 ° C for 8 hours. Then the reaction mixture was filtered. The residue was taken up in ethanol and a crude product was precipitated by adding ether. The precipitate was dissolved in isopropanol, and a solution of hydrogen chloride in isopropanol was added. The resulting precipitate was filtered with suction. 0.52 g of the product was obtained.

XH-NMR (Dg-DMSO). d = 1.8-2.3 (4H), 2.8-3.5 (5H), 7.2 (1H), 7.7 (1H), 7.8 (1H), 8.5 (broad) and 9.2 (broad) ppm.

Example 2 2-piperidin-4-ylbenzimidazole-4-carboxamide The example was prepared in the same manner as Example 1. XH-NMR (D6-DMSO). d = 1.7 (1H), 1.9-2.2 (4H), 2.75 (1H), 3.8 (1H), 7.2 (1H), 7.6 (1H), 7.8 (1H) and 9.3 (broad) ppm.

Example 3 2- (N-Acetylpiperidin-4-yl) benzimidazole-4-carboxamide a) Methyl 2- (N-acetylpiperidin-4-yl) benzimidazole-4-carboxylate 3. 3 g (19.9 mmol) of methyl 2, 3-diaminobenzoate were dissolved in 100 ml of methanol, and a solution of 4.0 g (25.8 mmol) of N-acetylpiperidine-4-carbaldehyde in 100 g of methanol was added dropwise at room temperature. ml of methanol. The whole was stirred for approximately 10 minutes at room temperature. Then, 5.2 g (25.8 mmol) of copper (II) acetate, which was dissolved in 100 ml of water, were added dropwise and the whole was refluxed for 30 minutes. After cooling, 25 ml of concentrated hydrochloric acid were carefully added and the total was refluxed again. 7.15 g (29.8 mmol) of sodium sulphide nonahydrate, dissolved in 100 ml of water, were then added dropwise and the whole was boiled for another 10 minutes. After cooling, the reaction solution was evaporated under reduced pressure. The residue obtained was dispersed in water and filtered. The filtrate was made alkaline with an aqueous solution of sodium bicarbonate and extracted several times with ethyl acetate. The combined organic phases were washed with water, dried and evaporated under reduced pressure. 4.5 g of the product were obtained. b) 2- (N-acetylpiperidin-4-yl) benzimidazole-4-carbohydrazide 4. 3 g (14.9 mmol) of intermediate 3a were refluxed with 3.7 g (74.3 mmol) of hydrazine hydrate in 100 ml of ethanol for 2.5 hours. The total was then evaporated under reduced pressure, the crude product obtained was used directly in the next reaction step. 2- (N-Acetylpiperidin-4-yl) benzimidazole-4-carboxamide g of Raney nickel were added to a mixture of 100 ml of dimethylformamide and 50 ml of water. The residue of reaction step 3b, dissolved in water, was then carefully added dropwise at room temperature so that the observed gas evolution could be controlled. The total was then heated to 100 ° C for 2 hours. After cooling, filtration was carried out and the filtrate was evaporated under reduced pressure. The residue obtained was treated in little methylene chloride and the product was precipitated by carefully adding ether. 3.2 g of the product were obtained.

^ -NMR (D6-DMSO). d = 1.8-2.3 (4H), 2.8-3.5 (5H), 7.2 (1H), 7.7 (1H), 7.8 (1H), 8.5 (broad) and 9.2 (broad) ppm.

Example 4 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide 0. 25 g (1 mmol) of the product of Example 2, 59 mg (1 mmol) of n-propanal and 125 μl (2 mmol) of acetic acid were dissolved in 25 ml of ethanol. Then, 64 mg (1 mmol) of sodium cyanoborohydride were added at room temperature and the whole was stirred for 16 hours. The reaction solution was evaporated under reduced pressure and the residue partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase was washed with water, separated, dried and evaporated under reduced pressure. The residue obtained was purified by chromatography using the mobile phase ethyl acetate / methanol 4/1, obtaining 0.07 g of the product.

XH-NMR (D6-DMSO). d = 0.9 (3H), 1.5 (2H), 1.9 (2H), 2.3 (2H), 2.9 (2H), 3.3 (1H), 7.25 (1H), 7.6 (1H), 7.8 (1H), 9.3 (1H) and 12.8 (1H) ppm.

Example 5 2-piperidin-3-ylbenzimidazole-4-carboxamide x 2 HCl 1. 3 g (3.8 mmol) of the product of Example 6 were dissolved in 20 ml of isopropanol, and 50 ml of an isopropanolic hydrochloride solution was added. The whole was stirred for one hour at room temperature. The resulting precipitate was filtered with suction to obtain 1.1 g of the product.

^ -NMR (D6-DMSO). d = 1.95-2.3 (3H), 2.45 (1H), 3.2 (1H), 3.5 (1H), 3.9 (1H), 7.6 (1H) and 7.95 (2H) ppm.

Example 6 2- (N- (O-tert-butoxycarbonyl) piperidin-3-yl) benzimidazole-4-carboxamide a) Ethyl 2-amino-3- (N- (O-tert-butoxycarbonyl) piperidin-3-yl) amidobenzoate 4 g (17.4 mmol) of N- (O-tert-butoxycarbonyl) piperidine-3-carboxylic acid and 4.8 ml (34.9 mmol) of triethylamine were dissolved in 100 ml of anhydrous tetrahydrofuran. 1.7 ml (17.4 mmol) of ethyl chloroformate, dissolved in 10 ml of anhydrous tetrahydrofuran, were then added dropwise at -10 ° C. The total was stirred for one hour at 0 ° C. Then, 2.9 g (17.4 mmol) of methyl 2, 3-diaminobenzoate were added, once more at -10 ° C, and the whole was stirred for 16 hours at room temperature. The reaction solution was evaporated under reduced pressure and the residue obtained was partitioned between ethyl acetate and water. The organic phase was also washed with an aqueous solution of sodium bicarbonate and water, dried and evaporated under reduced pressure. 5.5 g of the product were obtained. b) 2- (methyl N- (O-tert-butoxycarbonyl) piperidin-3-yl) benzimidazole-4-carboxylate . 4 g (14.3 mmol) of the product of 6a in 100 ml of acetic acid were refluxed for 75 minutes. After cooling, the whole was evaporated under reduced pressure and the resulting residue was purified by chromatography using the 1/6 ethyl acetate / heptane mobile phase. 2.7 g of the product were obtained. c) 2- (N- (O-tert-butoxycarbonyl) piperidin-3-yl) benzimidazole-4-carbohydrazide 2. 3 g (6.4 mmol) of the 6b product were refluxed with 1.6 g (32 mmol) of hydrazine hydrate in 20 ml of ethanol for 2.5 hours. After cooling, the total was evaporated under reduced pressure. The residue was treated with water, the resulting precipitate was filtered with suction and dried. 1.6 g of the product were obtained. d) 2- (N-0-tert-butoxycarbonyl) piperidin-3-yl) benzimidazole-4-carboxamide 1. 6 g of the 6c product reacted similarly to the method of 3c. 1.3 g of the product were obtained.

XH-NMR (D6-DMSO). d = 1.4 (1H), 1.5 (1H), 2.9 (1H), 3.1 (1H), 3.9 (1H), 4.2 (1H), 7.3 (1H), 7.7 (1H), 7.8 (1H), 9.1 (broad) ) and 13 (broad) ppm.

The substances mentioned in the following examples were prepared in the same manner as Examples 1 to 6: Example 7 2- (N-Benzylpiperidin-3-yl) -benzimidazole XH-NMR (D6-DMS0): d = 1.6-1.8 (3H), 2.1 (1H), 2.3 (1H), 2.8 (1H), 3.1 ( 1H), 3.2 (1H), 3.5 (2H), 7.2-7.4 (6H), 7.6 (2H), 7.8 (2H) and 9.2 (broad) ppm.

Example 8 2- (N-Methylpiperidin-3-yl) -benzimidazole-4-carboxamide x 2 HCl ^ -NMR (D20): d = 2.1 (2H), 2.3 (1H), 2.5 (1H), 3.1 (3H) , 3.2 (1H), 3.5 (1H), 3.7 (1H), 4.0 (2H), 7.7 (1H) and 8.0 (2H) ppm.

Example 9 2-Piperazin-4-yl-benzimidazole-4-carboxamide XH-NMR (D6-DMSO): d = 2.5 (4H), 3.3 (4H), 7.2 (1H), 7.6-7.7 (2H), 7.8 ( 1H) and 9.3 (1H) ppm.

Example 10 2- (N-Propylpiperidin-3-yl) -benzimidazole-4-carboxamide x 2 HCL XH-NMR (D6-DMSO): d = 0.9 (3H), 1.5 (2H), 1.9 (2H), 2.0 ( 4H), 2.3 (2H), 2.9 (3H), 7.2 (1H), 7.6 (2H), 7.8 (1H) and 9.3 (broad) ppm.

Example 11 2- (N- (3-Phenylprop-1-yl) -piperidin-3-yl) benzimidazole-4-carboxamide x 2HC1 XH-NMR (D6-DMSO): d = 2.0-2.5 (6H), 2.8 ( 2H), 3.1 (1H), 3. 2-3.4 (3H), 3.7 (1H), 3.8-4.0 (2H), 7.3-7.5 (5H), 7.7 (1H) and 8.0 (2H) ppm.

Example 12 2- (N-Benzoylpiperidin-3-yl) -benzimidazole-4-carboxamide XH-NMR (CF3COOD): d = 1.9 (1H), 2.6 (1H), 3.8 (1H), 3.9-4.2 (4H), 4.3 (1H), 4.8 (1H) and 7.5-8.2 (8H) ppm.

Example 13 2- (N-Benzylpiperidin-4-yl) -benzimidazole-4-carboxamide x 2 HCl XH-NMR (D20): d = 2.3 (2H), 2.6 (2H), 3.3 (2H), 3.8 (3H) , 4.5 (2H) and 7.5-8.0 (8H) ppm.

Example 14 2- (1- (1-Methylpiperidin-4-yl) piper idin-4-yl) -benzimidazole-4-carboxamide x 3 HCl XH-NMR (D6-DMSO): d = 1.4 (2H), 1.6- 2.0 (6H), 2.0-2.4 (7H), 2.7-3.0 (6H), 7.2 (1H), 7.7 (2H), 7.8 (1H) and 9.4 (broad) ppm.

Example 15 2- (N-n-Pentylpiperidin-4-yl) -benzimidazole-4-carboxamide XH-NMR (D6-DMSO): d = 0.9 (3H), 1.2-1.5 (6H), 1.7-2.1 (6H), 2.3 (2H), 2.8-3.0 (4H), 7.3 (1H), 7.6-7.8 (3H), 9.4 (1H) and 12.8 (broad) ppm.

Example 16 2- (N-Isobut-l-yl-piperidin-4-yl) -benzimidazole-4-carboxamide XH-NMR (D6-DMSO): d = 0.9 (6H), 1.8-2.1 (10H), 2.9 ( 2H), 7.2 (1H), 7.6 (2H), 7.8 (1H), 9.2 (1H) and 12.5 (broad) ppm.

Example 17 2- (Nn-Butylpiperidin-4-yl) -benzimidazole-4-carboxamide x HCl ^ -NMR (Dg-DMSO): d = 0.9 (3H), 1.3 (2H), 1.7 (2H), 2.2-2.4 (4H), 3.0-3.2 (4H), 3.4-3.6 (3H), 7.5 (1H), 7.8-8.0 (2H), 8.0 (1H), 8.7 (broad) and 10.9 (broad) ppm.

Example 18 2- (N- (3-Methyl-but-l-yl) piperidin-4-yl) -benzimidazole-4-carboxamide x HCl XH-NMR (D6-DMSO): d = 0.9 (6H), 1.7 ( 3H), 2.2-2.4 (4H), 3. 1 (4H), 3.3 (1H), 3.7 (2H), 7.5 (1H), 7.8-8.0 (3H), 8.7 (broad) and 10.5 (broad) ppm.

Example 19 2- (1,4-Dimethyl-piperazin-2-yl) -benzimidazole-4-carboxamide x 2 HCl XH-NMR (D6-DMSO): d = 2.5 (3H), 2.9 (3H), 3.3-3.8 (5H) ), 3.9 (1H), 5.0 (1H), 7.4 (1H), 7.7 (1H), 7.8 (1H), 7.9 (1H) and 8.6 (broad) ppm Example 20 2-piperazin-2-yl-benzimidazole-4-carboxamide x 2 HCl 1. 83 g (3.67 mmol) of the product of Example 23 were introduced into 250 ml of methanol with 1 g of 10% palladium on carbon and hydrogenated with about 165 ml of hydrogen. The catalyst was filtered with suction, and the filtrate was concentrated. The residue was dissolved in 20 ml of isopropanol and 50 ml of an isopropanolic hydrochloric acid solution was added. The resulting precipitate was filtered with suction to obtain 1.1 g of the product. XH-NMR (Dg-DMSO): d = 3.2-3.7 (5H), 4-0 (1H), 5-2 (1H), 7.4 (1H), 7.8 (1H), 7.9 (1H) and 10.2 (broad) ) ppm.

Example 21 2- (N-Isopropylpiperidin-4-yl) -benzimidazole-4-carboxamide x HCl XH-NMR (Dg-DMSO): d = 1.25 (6H), 2.3 (4H), 3.1 (1H), 3.4- 3.6 (4H), 3.7 (1H), 7.5 (1H), 7.7-8.0 (3H), 8.7 (1H) and . 7 (broad) ppm.

Example 22 2- (4- (2-Ethyl-prop-1-yl) piperidin-4-yl) -benzimidazole-4-carboxamide Example 23 2- (1,4-Dibenzylpiperazin-2-yl) -benzimidazole-4-carboxamide x 2 HCl XH-NMR (Dg-DMSO): d = 2.95-3.7 (7H). 3.8-4.9 (4H), 7.1-7.55 (8H), 7.65 (2H), 7.85 (2H), 7.94 (1H), 8.7 (broad) and 12.2 (broad) ppm Example 24 2- (N-Benzylpiperidin-4-yl) -1- (l-benzylpiperidin-4-ylcarbonyl) -benzimidazole-4-carboxamide ^ -NMR (Dg-DMSO): d = 1.7 (2H), 1.8-2.0 (6H), 2.1 (4H), 2.5-2.7 (2H), 2.8-3.0 (4H), 3.5 (4H), 7.2-7.5 (11H), 7.7 (1H), 8.6 (1H), 9.5 (1H) and 12.3 (broad) ppm.

Example A: Inhibition of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30) A 96-well microtiter plate (Falcon) was coated with histones (type II-AS, SIGMA H7755).

In addition, the histones were dissolved in a bicarbonate buffer (0.05M NaHCO3, pH 9.4) to a concentration of 50 μg / ml. The individual wells of the microtiter plate were incubated overnight, each with 100 μl of the histone solution. Then, the histone solution was removed and the individual wells were incubated with 200 μl of a 1% solution of BSA (bovine serum albumin) in a carbonate buffer for 2 hours at room temperature. The wash was then washed three times with washing buffer (0.05% Tween 10 in PBS). For the enzymatic reaction, 50 μl of the solution for enzymatic reaction per well (5 μl of the buffer for reaction (Tris-HCl IM, pH 8.0, 100 mM MgCl 2, 10 mM DTT), 0.5 μl of PARP (c = 0.22 μg / μl), 4 Rl of activated DNA (SIGMA D-4522, 1 mg / ml in water) 40.5 μl of H20) were pre-incubated with 10 μl of an inhibitor solution for 10 minutes. The enzymatic reaction was started by adding 40 μl of a solution of the substrate (4 μl of the buffer for reaction (see above), 8 μl of a NAD solution (100 μm in H20), 28 μl of H20). The reaction time was 20 minutes at room temperature. The reaction was stopped by washing three times with buffer for washing (see above). This was followed by incubation for one hour at room temperature with a specific anti-poly-ADP-ribose antibody. Anti-poly (ADP-ribose) "10H" monoclonal antibodies (Biomol SA-276) were used. The antibodies were used in a 1: 5000 dilution in buffer for antibodies (1% BSA and PBS, 0.05% Tween 20). Washing three times with buffer for washing was followed by incubation for one hour at room temperature with the secondary antibody. In this case. An anti-mouse IgG coupled with peroxidase (Boehringer Mannheim) was used for the monoclonal antibody and an anti-rabbit IgG coupled with peroxidase (SIGMA A-6154) was used for the rabbit antibody, each at a 1: 10,000 dilution in a buffer solution for antibody. After washing three times with the buffer for washing, the colored reaction was carried out using 100 μl / well of the color reagent (SIGMA, TMB ready-mix, T8540) for approximately 15 minutes at room temperature. The color reaction was interrupted by 100 μl of 2 M H2SO4. The measurement was then performed immediately (450 against 620 nm, ELISA "Easy Reader" EAR340AT, SLT-Lab instruments, Austria). The Kx can be determined in a traditional way from the inhibition curves at different substrate concentrations.

Example B: Determination of solubility in water One of the compounds to be measured was dissolved directly in a specified volume of water and the resulting solution was brought to a pH from 5 to 6 with a solution of sodium acetate to reach the concentration of the active compound that was to be tested. If the test substance was not present as a water-soluble salt, it was dissolved in a very small amount of dimethylsulfoxide and then diluted with water (final concentration of dimethylsulfoxide <1%), after which the pH was adjusted as well. In this case, Example 1 according to the invention gave a solubility of > 0.5%

Claims (1)

1. CLAIMS The compound of the formula la or Ib Wherein R1 is hydrogen "or branched or straight-chain C6-6 alkyl, wherein a carbon atom of the alkyl radical may additionally carry OR5 (where R5 is hydrogen or C1-C4 alkyl), or a carbon atom in the chain t (can also carry a group = 0 or a group NR8R9, where R8 and R9, independent of each other are each hydrogen or C-C4 alkyl and NR8R9 together can be a cyclic amine having from 4 to 8 atoms in the ring, where the carbon chains in R8 or R9 or the ring formed by NR8R9 can also carry a radical R6 which, independently of R2, can have the same meaning as R2, R is hydrogen, Ci-Cg alkyl, branched or straight chain, chloro, bromo, fluoro, nitro, cyano NR8R9, NH-CO-R10 or OR8, where R8 and R9, independent of each other, are each hydrogen or C1-C4 alkyl, and NR8R9 together can be a cyclic amine having from 4 to 8 ring atoms, wherein the ring can further bear a radical (branched or straight chain Ci-Cg alkyl, cycloalkyl (from C3-C7) ) -C1-C4 alkyl, CO-R41, COOR41 or phenyl), and R10 can be hydrogen, C? -C alkyl or phenyl and R41 can have the same meaning as R21, A is a ring of 4 to 8 members, heterocyclic, saturated or monounsaturated containing one or two nitrogen atoms, it is possible that an oxygen or sulfur atom is also incorporated, whose oxygen or sulfur atoms is substituted by R2 and R3 [ sic], where R 2 is hydrogen, branched or straight chain C 1 -C 8 alkyl which may furthermore be substituted by R 23, and a carbon atom of the chain may bear a = 0, C 3 -C 7 cycloalkyl-C 1 alkyl group C4, -CO- (NH) 0 /? -R21, COOR21 or phenyl, where R21 is hydrogen, branched or straight-chain Ci-C alkyl, (C3-C7) cycloalkyl-C4-C4 alkyl, phenylalkyl of C1-C4, C3-C7 cycloalkyl or phenyl, and each radical can also carry (CH2) 0-2-R23, and the respective phenyl ring in turn can also be substituted by 1, 2 or 3 of the following radicals : chlorine, fluorine, bromine, iodine, branched and straight-chain C 1 -C 4 alkyl [sic], nitro, CF 3, cyano, - (CH 2) 0-2-NR 2 R 25, NH-CO-R 10, OR 10, COOR 10, S02-alkyl? of C1-C4, S02Ph, S02NH, NHS02-C1-C4 alkyl, NHS02Ph and CF3, where R24 and R25, independent of each other, are each hydrogen or C? -C4 alkyl and NR24R25 together can be a cyclic amine with from 4 to 8 ring atoms, wherein the ring may furthermore bear a branched or straight-chain Ci-C alkyl radical, (C3-C7) cycloalkyl-C1-C4 alkyl, CO-R22, COOR22 (where R22 is hydrogen, C? C6 branched or straight chain, cycloalkyl (from C3-C7) alkyl of C1-C4, phenylalkyl of C 1 -C 4, cycloalkyl of C 3 -C 7 or phenyl) or phenyl, and R 10 is hydrogen, C 1 -C 4 alkyl or phenyl, and is NR26R27, wherein R26 and R27 each are hydrogen, C?-C6 alkyl, (C0-C4) alkyl phenyl, wherein the phenyl ring may further be substituted by up to three Cl, F, Br, I, alkyl, C1-C4, CF3, CN, S02-C1-C4 alkyl, S02-phenyl, N02, NH2, NHCO-C1-C4 alkyl, NHCO-phenyl, OH, O-C1-C4 alkyl, 0-alkyl ( of C1-C4) phenyl, and NR26R27 may also be a cyclic amine having from 3 to 8 members, where another heteroatom such as 0, N and S may also be present, and the ring may further be substituted by a radical R28, where R 28 can be C 1 -C 4 alkyl and C 1 -C 4 alkyl phenyl, is hydrogen, branched or straight chain C?-Cg alkyl, (C3-C7) cycloalkyl-C1-C4 alkyl which is unsubstituted or substituted by Ci-Cg alkyl or C3-C7 cycloalkyl which is unsubstituted or substituted by Ci-Cg alkyl, where a carbon atom of the radical can also carry a phenyl ring which in turn can also be substituted by 1, 2 or 3 of the following radicals: chlorine, fluorine, bromine, iodine, alkyl of branched and straight chain C1-C4 [sic], nitro, CF3, cyano, -C (H2) or-2-NR32R33, NH-CO-R10, OR10, COOR10, S02- C1-C4 alkyl, S02Ph, CH3, S02NH, NHS02- C1-C4 alkyl, NHS02Ph and CF3, where R32 and R33, independent of each other, are each hydrogen or C1-C4 alkyl and NR32R33 together can be a cyclic amine having from 4 to 8 atoms in the ring, wherein the ring can further bear a branched Ci-Cg alkyl radical or straight-chain, (C3-C7) cycloalkyl-C1-C4 alkyl, CO-R31, COOR31 or phenyl, and R10 is hydrogen, C? -C4 alkyl or phenyl, and R31 may have the same meaning as R21 , and its tautomeric forms, possible enantiomeric and diastereomeric forms, its prodrugs and possible physiologically tolerated salts. The compound as claimed in claim 1, wherein R1, R2 and R4 are each hydrogen and A is piperidine, pyrrolidine, piperazine, morpholine or homopiperazine and R3 is attached to the nitrogen of A. The compound as claimed in any of claims 1 and 2, wherein A can be piperidine which has been attached to the 4-position in the benzimidazole and R3 can be hydrogen, C-C4 alkyl, benzyl or phenylethyl and is in the position 1 on the piperidine ring. 4. A medicament comprising a compound as claimed in any of claims 1 to 3 in addition to the traditional carriers and excipients. 5. The use of a compound of formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for treating disorders in which activities increased from the pathological point of view of PARP. 6. The use of a compound of formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for treating neurodegenerative disorders and neuronal damage. 7. The use as claimed in claim 6 to treat those neurodegenerative disorders and neuronal damage that are caused by ischemia, trauma or massive hemorrhage. The use as claimed in claim 6 for the treatment of stroke and craniocerebral trauma. The use as claimed in claim 6 for the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease. The use of a compound of formula I as claimed in any of claims 1 to 3 for preparing medicaments for the treatment or prophylaxis of ischemia damage. The use of a compound of formula I as claimed in any of claims 1 to 3 for preparing medicaments for treating epilepsies, in particular generalized epileptic seizures, for example, petit mal and tonoclonic seizures, and partial epileptic seizures such as the temporal lobe and complex partial attacks. The use of a compound of the formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for treating kidney damage after renal ischemia, damage that is caused by drug treatments, and for the treatment during and after of kidney transplants. The use of a compound of formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for the treatment of cardiac damage after myocardial ischemia and damage that is caused by reperfusion of narrowed or closed vessels. The use of a compound of the formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for treating micro-infarcts. The use of a compound of the formula I as claimed in any of claims 1 to 3 for preparing medicaments for the treatment associated with revascularization of critically-constricted coronary arteries. The use of a compound of the formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for treating acute myocardial infarction and damage during or after their lysis by means of medicaments or mechanics. The use of a compound of formula I as claimed in any of claims 1 to 3 for preparing medicaments for the treatment of tumors and their metastases. The use of a compound of formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for treating sepsis and multiple organ failure. The use of a compound of formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for the treatment of immunological disorders such as inflammations and rheumatic diseases. The use of a compound of formula I as claimed in any of claims 1 to 3 for preparing medicaments for the treatment of diabetes mellitus.