Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-24
2002-09-10
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S211080, C514S253090, C514S254060, C514S316000, C514S394000, C540S575000, C544S364000, C544S370000, C546S187000, C546S199000, C548S306100
Reexamination Certificate
active
06448271
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 the preparation of drugs.
Poly(ADP-ribose)polymerase (PARP) or, as it is also known, poly(ADP-ribose)synthase (PARS) is a regulatory enzyme which is found in cell nuclei (K. Ikai et al.,
J. Histochem. Cytochem.
31 (1983), 1261-1264). It is assumed that PARP plays a role in repairing DNA breaks (M. S. Satoh et al.,
Nature
356 (1992), 356-358). Damage to or breaks in the DNA strands activate the enzyme PARP which, if it has been activated, catalyses the transfer of ADP-ribose from NAD (S. Shaw,
Adv. Radiat.Biol.
11 (1984), 1-69). Nicotinamide is liberated from NAD. Nicotinamide is converted back into NAD with consumption of the energy carrier ATP by other enzymes. Overactivation of PARP would accordingly result in an unphysiologically high consumption of ATP, and this leads to cell damage and cell death in extreme cases.
It is known that radicals such as the superoxide anion, NO and hydrogen peroxide can lead to DNA damage in cells and hence activate PARP. The formation of large amounts of radicals is observed in a number of pathophysiological conditions, and it is assumed that this accumulation of radicals leads or contributes to the observed cell or organ damage. These include, for example, ischemic conditions of organs, as in stroke, myocardial infarct (C. Thiemermann et al.,
Proc. Natl. Acad. Sci. USA
94 (1997), 679-683) or ischemia of the kidneys, as well as reperfusion damage as occurs, for example, following the lysis of myocardial infarct (see above: C. Thiemermann et al.). The inhibition of the enzyme PARP might accordingly be a means for preventing or reducing this damage at least in part. PARP inhibitors might therefore constitute a new therapeutic principle for treating a number of disorders.
The enzyme PARP influences the repair of DNA damage and could thus also play a role in therapy of cancer diseases, since the higher action potential against tumor tissue was observed in combination with cytostatic substances (G. Chen et al.
Cancer Chemo. Pharmacol.
22 (1988), 303).
Nonlimiting examples of tumors are leukemia, glioblastomas, lymphomas, melanomas, carcinomas of the breast and cervical carcinomas.
It was also found that PARP inhibitors can have an immunosuppressive effect (D. Weltin et al.
Int. J. 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 on the course of the disorder (H. Kröger et al.
Inflammation
20 (1996), 203-215; W. Ehrlich et al.
Rheumatol. Int.
15 (1995), 171-172; C. Szabo et al.,
Proc. Natl. Acad. Sci. USA
95 (1998), 3867-3872; S. Cuzzocrea et al.
Eur. J. Pharmacol.
342 (1998), 67-76).
For the purposes of this invention, PARP is also understood as meaning isoenzymes of the PARP enzyme described above.
Furthermore, the PARP inhibitor 3-aminobenzamide exhibited 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), 5314-19).
Benzimidazoles have been widely described.
The synthesis of 2-phenylbenzimidaz-4-ylamides which also carry a substituted alkyl chain on the amide radical and which are said to have a cytotoxic effect is mentioned in J. Med. Chem. 33 (1990), 814-819. WO 97/04771 mentions 4-benzimidazolamides which inhibit PARS. In particular, derivatives which carry a phenyl ring in the 2-position, where the phenyl ring may furthermore be substituted by simple substituents such as nitro, methoxy or CF
3
, are described there as being effective. Although some of these substances exhibit good inhibition of the enzyme PARP, the derivatives described there have the disadvantage that they have little or no solubility in aqueous solutions and hence cannot be applied as an aqueous solution.
Benzimidazoles which carry a piperidine ring in the 2-position have also been described. Thus, in J. Het. Chem. 24 (1987), 31, derivatives have been prepared as antihistamine drugs. In J. Het. Chem. 32 (1995), 707 and J. Het. Chem. 26 (1989), 541, analogous compounds having the same use have been described. 2-Piperidinylbenzimidazoles are mentioned in EP 818454 as antihistamine drugs and in WO 9736554 as agents against hepatitis. Derivatives are likewise mentioned in CA 80, 146143, Fr. 2103639 and in Khim. Geterotsikl. Soedin 1 (1974), 104.
However, the importance of substituents on the phenylaromatics in the benzimidazole fragment has not been investigated. Furthermore, those benzimidazoles which carry a 4- to 8-membered heterocycle, in particular a piperidine ring, in the 2-position have not been described to date as being PARP inhibitors.
The present application describes the surprising finding that the introduction of a carboxamide radical on the benzimidazole aromatic gives benzimidazoles which constitute novel and highly effective PARP inhibitors, provided that they are substituted in the 2-position by a saturated heterocycle.
In a number of treatments, such as for stroke, the active compounds are applied intravenously as an infusion solution. For this purpose, it is necessary to have substances, in this case PARP inhibitors, which have sufficient water solubility at or about physiological pH (i.e. pH of 5-8), so that an infusion solution can be prepared. However, many of the PARP inhibitors described, in particular the more effective PARP inhibitors, have the disadvantage that they exhibit only little or no water solubility at the pH values and are therefore not suitable for intravenous application. Such active compounds can be applied only with excipients which are intended to impart water solubility (cf. WO 97/04771). These excipients, for example polyethylene glycol and dimethyl sulfoxide, frequently cause side effects or are even not tolerated. No highly effective PARP inhibitors having sufficient water solubility have been described to date.
It was surprisingly found that benzimidazoles which carry a piperidine ring on the imidazole ring are highly effective inhibitors and, owing to the incorporation of the aliphatic amine radical, permit salt formation with acids, resulting in substantially improved water solubility and hence permitting the preparation of an infusion solution.
The present invention describes novel benzimidazole derivatives of the formula I which have advantages over the compounds described above and constitute potent PARP inhibitors and at the same time have sufficient water solubility. When compounds of the formula I are referred to, they are understood as meaning the compounds of the formulae Ia and Ib. The present invention relates to substituted benzimidazoles of the formula I:
where
R
1
is hydrogen or branched or straight-chain C
1
-C
6
-alkyl, where one carbon atom of the alkyl radical may furthermore carry OR
5
(where R
5
is hydrogen or C
1
-C
4
-alkyl), or one carbon atom in the chain may also carry an ═O group or a group NR
8
R
9
, where R
8
and R
9
, independently of one another, are each hydrogen or C
1
-C
4
-alkyl and NR
8
R
9
together may be 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 a radical R
6
which, independently of R
2
, may have the same meaning as R
2
,
R
4
is hydrogen, branched or straight-chain C
1
-C
6
-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 and NR
8
R
9
together may be a cyclic amine having 4 to 8 ring atoms, where the ring may furthermore carry a radical (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 phenyl), and R
10
may be hydrogen, C
1
-C
4
-alkyl or phenyl a
Grandel Roland
Höger Thomas
Kock Michael
Lubisch Wilfried
Müller Reinhold
BASF - Aktiengesellschaft
Keil & Weinakuf
Stockton Laura L.
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