Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-04
2004-05-18
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254060, C514S322000, C514S338000, C514S394000, C540S553000, C540S574000, C544S370000, C546S199000, C546S273400, C548S306100, C548S309700
Reexamination Certificate
active
06737421
ABSTRACT:
The present invention relates to novel benzimidazoles, their preparation and the 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 called, 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 non-physiologically 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 the 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 as occurs, 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 modifying this damage. PARP inhibitors might thus represent a novel therapeutic principle for treating a number of diseases.
PARP influences the repair of DNA damage and thus might also play a part in the therapy of cancers, since a greater action potential on tumor tissues was observed (G. Chen et al.
Cancer Chemo. Pharmacol
. 1988, 22, 303) in combination with substances with cytostatic activity.
Non-limiting examples of tumors are leukemia, glioblastomas, lymphomas, melanomas, and carcinomas of the breast and cervix.
It has also 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 inhibits 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.
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 also experimental evidence that inhibitors of the enzyme PARP might be of benefit 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 disclosed 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 residues on the phenyl ring have been described in WO 98/06703 as MCP-1 antagonists.
Also known are 2-phenylbenzimidazoles in which the benzimidazole group is substituted by an amide group. 5-Amido derivatives of 2-phenylbenzimidazole with alkoxy 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 for cAMP phosphodiesterase.
The synthesis of 2-phenylbenzimidazole-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 amid residue and are said to have a cytotoxic effect are mentioned in J. Med. Chem. 1990, 33, 814-819. WO 97/04771 on the other hand mentions 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.
Benzimidazoles with cycloalkyl radicals in position 2 have likewise been described. Thus, 2-cyclohexyl derivatives which may also have alkylamides in position 1 are mentioned in F. Pellicciari et al.,
Arch. Pharm
. 1985, 318, 393-399, or in
Ann
. 1952, 575, 162, which also described methyl derivatives in which the methyl group is located on the benzimidazole aromatic system. 2-Cycloalkylbenzimidazoles in which the aromatic ring is substituted by chlorine or nitro groups are described, for example, in DE 2649125, E. Seuer et al.,
Farmaco
1997, 52, 99 and M. Benchidmi et al.,
Bull. Soc. Chim. Belg
. 1995, 104, 605-612. Derivatives of benzimidazole-5-carboxylic acid with cyclopentanedione residues in position 2 are mentioned in
Ann
., 1893, 273, 320. Benzimidazoles with lactam rings fused to the aromatic ring have been described in DE 2732951 and in W. Saal et al.,
J. Med. Chem
. 1989, 32, 1481-1491. However, benzimidazoles with carbocyclic rings in position 2 having an amide group on the benzimidazole ring or, in particular, position 4 on the benzimidazole ring have not yet been described.
In a number of therapies, such as strokes, the active substances 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 unsuitable for intravenous administration. Active substances of this type can be administered only with excipients intended to promote solubility in water (cf. WO 97/04771). These excipients, for example polyethylene glycol and dimethyl sulfoxide, often cause side effects or are not tolerated. Very effective PARP inhibitors with adequate solubility in water have not previously been described.
Surprisingly, it has been found that benzimidazoles having a saturated or monounsaturated carbocyclic system on the imidazole ring are very effective inhibitors but, owing to the further incorporation of aliphatic amine residues, they can form salts with acids and thus show distinctly improved solubility in water.
The present invention describes benzimidazole derivatives of th general formula I or II which are potent PARP inhibitors and also show adequate solubility in water to allow administration as infusion solution.
The present invention relates to substituted benzimidazoles of the general formula I and II:
in which
A is a saturated or monounsaturated carbocyclic system which has 3 to 8 carbon atoms and may additionally have a fused-on benzene ring, it being possible for the rings also to be substituted by one or two different or identical radicals R
3
and also the radical R
4
, and
Grandel Roland
Hoeger Thomas
Kock Michael
Lubish Wilfried
Mueller Reinhold
Abbott & GmbH & Co. KG
Rao Deepak
Wood Phillips Katz Clark & Mortimer
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