Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-25
2004-02-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S249000, C514S256000, C514S255050, C514S365000, C514S367000, C514S374000, C514S378000, C514S383000, C514S307000, C514S314000, C514S300000, C514S248000, C514S252030, C514S266230, C514S218000, C514S254060, C514S234500, C514S322000, C514S338000, C514S394000, C544S333000, C544S353000, C544S405000, C544S237000, C544S238000, C544S284000, C544S370000, C544S139000, C546S144000, C546S167000, C546S199000, C546S273400, C548S215000, C548S257000, C548S240000, C548S305100, C548S305400, C548S304700, C548S306100, C548S
Reexamination Certificate
active
06696437
ABSTRACT:
The present invention relates to novel benzimidazoles, their preparation and their use as inhibitors of the enzyme poly-(ADP-ribose) polymerase or PARP (EC 2.4.2.30) for producing drugs.
Poly(ADP-ribose) polymerase (PARP) or, as it is also known, poly(ADP-ribose) synthase (PARS), is a regulatory enzyme found in cell nuclei (K. Ikai et al.,
J. Histochem. Cytochem
. 1983, 31, 1261-1264). It is assumed that PARP is involved in the repair of DNA breaks (M. S. Satoh et al.,
Nature
1992, 356, 356-358). Damage or breaks in DNA strands activate the enzyme PARP which, when it is activated, catalyzes the transfer of ADP-ribose from NAD (S. Shaw,
Adv. Radiat. Biol
., 1984, 11, 1-69). During this, nicotinamide is released from NAD. Nicotinamide is converted back into NAD by other enzymes with consumption of the energy carrier ATP. Overactivation of PARP would accordingly result in a nonphysiologically large consumption of ATP, and this leads in the extreme case to cell damage and cell death.
It is known that free radicals such as superoxide anion, NO and hydrogen peroxide may lead to DNA damage in cells and thus activate PARP. The formation of large amounts of free radicals is observed in a number of pathophysiological states, and it is assumed that this accumulation of free radicals leads or contributes to observed cell or organ damage. This includes, for example, ischemic states of organs as in stroke, myocardial infarct (C. Thiemermann et al.,
Proc. Natl. Acad. Sci. USA
, 1997, 94, 679-683) or ischemia of the kidneys, but also reperfusion damage has occurred, for example, after lysis of myocardial infarct (see above: C. Thiemermann et al.). Inhibition of the enzyme PARP might accordingly be a means of at least partly preventing or moderating this damage. PARP inhibitors might thus represent a novel therapeutic principle for treating a number of diseases.
The enzyme PARP influences the repair of DNA damage and might thus also play a part in the therapy of cancers since a greater action potential on tumor tissue was observed (G. Chen et al.
Cancer Chemo. Pharmacol
. 1988, 22, 303) in combination with substances with cytostatic activity. Nonlimiting examples of tumors are leukemia, glioblastomas, lymphomas, melanomas and carcinomas of the breast and cervix.
In addition, it has been found that PARP inhibitors may show an immunosuppressant effect (D. Weltin et al.
Int.J.Immunopharmacol
. 1995, 17, 265-271).
It has likewise been discovered that PARP is involved in immunological disorders or diseases in which the immune system plays an important part, such as, for example, rheumatoid arthritis and septic shock, and that PARP inhibitors may show a beneficial effect on the course of the disease (H. Kröger et al.
Inflammation
1996, 20, 203-215; W. Ehrlich et al.
Rheumatol. Int
. 1995, 15, 171-172; C. Szabo et al.,
Proc. Natl. Acad. Sci. USA
1998, 95, 3867-3872; S. Cuzzocrea et al.
Eur. J. Pharmacol
. 1998, 342, 67-76). PARP is understood to include for the purpose of this invention isoenzymes of the PARP enzyme described above.
In addition, the PARP inhibitor 3-aminobenzamide showed protective effects in a model of circulatory failure (S. Cuzzocrea et al.,
Br. J. Pharmacol
. 1997, 121, 1065-1074).
There is likewise experimental evidence that inhibitors of the enzyme PARP might be useful as agents for treating diabetes mellitus (V. Burkart et al.
Nature Med
. 1999, 5, 314-319).
Benzimidazoles have been described many times. Thus, DE 38 30 060 discloses alkylated derivatives as inhibitors of erythrocyte aggregation. DE 35 22 230 mentions an ester derivative of 2-phenylbenzimidazole as inhibitor of platelet aggregation. Halogen-substituted 2-phenylbenzimidazoles having substituted amine radicals on the phenyl ring have been described in WO 98/06703 as MCP-1 antagonists.
Likewise known are 2-phenylbenzimidazoles in which the benzimidazole group is substituted by an amide group. 5-amido derivatives of 2-phenylbenzimidazole with alkyloxy radicals on the phenyl ring have been described in WO 94/12461 as inhibitors of cAMP phosphodiesterase. It was found in DE 35 46 575 (e.g. Example 15) for analogous derivatives that these compounds induce positive inotropic effects. 4-Amido derivatives having a pyridyl radical in position 3 are likewise mentioned in WO 97/48697 as inhibitors of cAMP phosphodiesterase.
Benzimidazoles with amido groups in position 4 and with heterocyclic rings in position 2 are likewise known, for example from Denn W. A. et al., J. Med. Chem. 1990, 33, 814-819. Described therein are, for example, benzimidazoles with thiophene ring, with pyridine rings, furan rings and pyrrole rings in position 2, although the amido groups in position 4 on the benzimidazole carry other alkylamino radicals, which is important for the cytotoxic effect mentioned therein, but these substitutions on the amide residue are extremely unfavorable for an inhibitory effect on the enzyme PARP and usually lead to inactive compounds (see page 728 in M. J. Suto et al., Drugs of the Future, 1991, 16, 723-739).
The synthesis of 2-phenyl-benzimidazole-4-carboxamides has been described in J. Chem. Soc. Perkin Trans 1, 1979, 2303-2307. Analogous compounds which have a substituted alkyl chain on the amide residue and are said to have a cytotoxic effect are mentioned in J. Med. Chem. 1990, 33, 814-819. WO 97/04771 mentions, on the other hand, benzimidazole-4-carboxamides which inhibit PARS. In particular, derivatives described therein as active have a phenyl ring in position 2, and the phenyl ring may also be substituted by simple substituents such as nitro, methoxy and CF
3
. Although some of these substances show good inhibition of the enzyme PARP, the derivatives described therein have the disadvantage that they show little or no solubility in aqueous solutions and thus cannot be administered as aqueous solution.
In a number of therapies, such as stroke, the active ingredients are administered intravenously as infusion solution. For this purpose it is necessary to have available substances, in this case PARP inhibitors, which have adequate solubility in water at physiological pH values or close pH values (for example pH values of 5-8) so that an infusion solution can be prepared. Many of the PARP inhibitors described, especially the more effective PARP inhibitors, have the disadvantage, however, that they have only low or no solubility in water at these pH values and thus are not suitable for intravenous administration. Active ingredients of this type can be administered only with excipients intended to confer solubility in water (cf. WO 97/04771). These excipients, for example polyethylene glycol and dimethyl sulfoxide, frequently cause side effects or are not tolerated. Very effective PARP inhibitors with adequate solubility in water have not previously been described.
Benzimidazoles with a carboxylic ester group or a carboxamide group in position 5 and, at the same time, heteroaromatic rings in position 2 have seldom been described, examples being thiazoles (JP 4001631) and quinolines (WO 9820007). Benzimidazoles having, for example, methyl groups on the benzo ring, or having further benzo rings fused on the benzo ring, or even being unsubstituted thereon, have frequently been described with heteroaromatic rings in position 2, for example indoles (V. Ketarev et al., Chem. Heterocycl. Comp. 1980, 16, 501-506), quinolines (J. Gosh, J. Ind. Chem. Soc. 1938, 15, 89), pyridines (T. Hisano, Chem. Pharm. Bull 1982, 30, 2996-3004), Pyrimidines (H. Bredereck et al., Chem. Ber. 1960, 93, 2410-2414) and pyrroles (GB 966,796).
Benzimidazoles with heteroaromatic rings such as pyridine, furan, thiophene and pyrrole in position 2 and with carboxylic acid derivatives in position 4 have been described in W. A. Denny et al., J. Med. Chem. 1990, 33, 814-819 as potential cytostatics. However, the carboxylic acid derivatives prepared and mentioned in this case are only the carboxylic acid itself and amides with alkylamine residues on the N atom.
It has been found, surprisingly, that benzimidazoles also having heteroaromatic r
Grandel Roland
Hoeger Thomas
Holzenkamp Uta
Kock Michael
Lubisch Wilfried
Abbott & GmbH & Co. KG
Habte Kahsay
Shah Mukund J.
Wood Phillips Katz Clark & Mortimer
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