Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-17
2003-01-21
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S309700
Reexamination Certificate
active
06509365
ABSTRACT:
The present invention relates to novel 2-phenylbenzimidazoles and 2-phenylindoles, their preparation and their use as inhibitors of the enzyme poly(ADP-ribose)polymerase or PARP (EC 2.4.2.30) for the production of drugs.
Poly(ADP-ribose)polymerase (PARP) or poly(ADP-ribose)synthase (PARS), as it is also known, is a regulatory enzyme which is found in cell nuclei (K. Ikai et al.,
J. Histochem. Cytochem.
1983, 31, 1261-1264). It is assumed that PARP plays a part in the repair of DNA bridges (M. S. Satoh et al.,
Nature
1992, 356, 356-358). Damage to or breaks in the DNA strands activate the enzyme PARP which, when it is activated, catalyzes the conversion of ADP-ribose from NAD (S. Shaw,
Adv. Radiat. Biol.,
1984, 11, 1-69). During the course of this, nicotinamide is released from NAD. Nicotinamide is converted into NAD again with consumption of the energy carrier ATP of other enzymes. Overactivation of PARP would accordingly have resulted in an unphysiologically high consumption of ATP and this leads, in extreme cases, to cell damage and cell death.
It is known that free radicals such as the superoxide anion, NO and hydrogen peroxide can 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 conditions and it is assumed from this that this accumulation of free radicals leads or contributes to the observed cell and organ damage. This includes, for example, ischemic conditions of organs such as in stroke, cardiac infarct (C. Thiemermann et al.,
Proc. Natl. Acad. Sci. USA,
1997, 94, 679-683) or ischemia of the kidneys, but also reperfusion damage such as occurs, for example, after lysis of cardiac infarct (see above: C. Thiemermann et al.). The inhibition of the enzyme PARP could accordingly be a means of preventing or alleviating this damage at least partly. PARP inhibitors could thus be a new therapeutic principle for the treatment of a number of diseases.
The enzyme PARP affects the repair of DNA damage and could thus also play a part in the therapy of carcinomatous disorders, since in combination with cytostatically active substances a higher potential of action against tumor tissue was observed (G. Chen et al.
Cancer Chemo. Pharmacol.
1988, 22, 303).
Nonlimiting examples of tumors are leukemia, glioblastoma, lymphoma, melanoma, mastocarcinoma and cervical carcinoma.
Moreover, it has been found that PARP inhibitors can show immunosuppressant action (D. Weltin et al.
Int. J. Immunopharmacol.
1995, 17, 265-271).
It was also 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 can show a favorable 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).
Within the meaning of this invention, PARP is understood as also meaning isoenzymes of the above-described PARP enzyme.
Furthermore, the PARP inhibitor 3-aminobenzamide showed protective effects in a model for circulatory shock (S. Cuzzocrea et al.,
Br. J. Pharmacol.
1997, 121, 1065-1074).
There are likewise experimental indications that inhibitors of the enzyme PARP could be useful as an agent for the treatment of diabetes mellitus (V. Burkart et al.
Nature Med.
1999, 5, 314-319).
2-Phenylbenzimidazoles have been widely described. Thus, in DE 38 30 060 alkylated derivatives are disclosed as inhibitors of erythrocyte aggregation. In DE 35 22 230, an ester derivative of 2-phenylbenzimidazole is mentioned as an inhibitor of platelet aggregation. Halogen-substituted 2-phenylbenzimidazoles which carry substituted amine radicals on the phenyl ring have been described as MCP-1 antagonists in WO 98/06703.
2-Phenylbenzimidazoles are also known in which the benzimidazole group is substituted by an amide group. 5-Amido derivatives of 2-phenylbenzimidazole, which carry alkyloxy radicals on the phenyl ring, have been described as inhibitors of cAMP phosphodiesterase in WO 94/12461. For analogous derivatives, it was found in DE 35 46 575 (e.g. Example 15) that these compounds induce positively inotropic effects. 4-Amido derivatives which carry a pyridyl radical in the 3-position are also described as inhibitors of cAMP phosphodiesterase in WO 97/48697.
The synthesis of 2-phenylbenzimidazyl-4-amides has been described in J. Chem. Soc. Perkin Trans 1, 1979, 2303-2307. Analogous compounds which carry a further substituted alkyl chain on the amide radical, and which are said to have cytotoxic action, are mentioned in J. Med. Chem. 1990, 33, 814-819. In WO 97/04771, however, benzimidazole-4-amides which inhibit PARS are mentioned. In particular, derivatives which carry a phenyl ring in the 2-position are described as active there, it additionally being possible to substitute the phenyl ring with simple substituents such as nitro, methoxy and CF
3
. Although these substances in some cases show good inhibition of the enzyme PARP, the derivatives described there have the disadvantage that they only show little or no solubility in aqueous solutions and thus cannot be administered as an aqueous solution.
In a number of therapies such as stroke, the active compounds are administered intravenously as an infusion solution. To this end, it is necessary to have available substances, in this case PARP inhibitors, which have sufficient water solubility at physiological pHs or approximate pHs (e.g.: pHs of 5-8) so that an infusion solution can be prepared. Many of the described PARP inhibitors, in particular the better active PARP inhibitors, have the disadvantage, however, that they only show low or no water solubility at these pHs and are thus not suitable for intravenous administration. Active compounds of this type can only be administered with auxiliaries which are intended to mediate the water solubility (cf. WO 97/04771). These auxiliaries, for example polyethylene glycol and dimethyl sulfoxide, often cause side effects or are even intolerable. Highly efficacious PARP inhibitors having adequate water solubility have not been described until now.
It has surprisingly been found that 2-phenylbenzimidazoles which additionally carry an amine radical on the phenyl ring are highly efficacious inhibitors which, however, make possible salt formation with acids due to the incorporation of the aliphatic amine radical and as a result show a markedly improved water solubility.
In the present invention, novel 2-phenylbenzimidazole and 2-phenylindole derivatives of the general formula I are described which, compared with the compounds already described, show advantages and are potent PARP inhibitors and at the same time also show adequate water solubility, which makes possible administration as an infusion solution.
The present invention relates to substituted 2-phenylbenzimidazoles and 2-phenylindoles of the general formula I:
in which
A is N or CH,
R
1
is hydrogen, branched or unbranched C
1
-C
6
-alkyl, where one C atom of the alkyl radical can further carry OR
11
, where
R
11
is hydrogen or C
1
-C
4
-alkyl, and
R
2
is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C
1
-C
6
-alkyl, nitro, CF
3
, CN, NR
21
R
22
, NH—CO—R
23
, OR
21
, where
R
21
and R
22
independently of one another are hydrogen or C
1
-C
4
-alkyl and
R
23
is hydrogen, C
1
-C
4
-alkyl or phenyl, and
R
3
is —(CH
2
)
q
—NR
31
R
32
, (CH
2
)
q
—NR
33
R
34
, where q can be 0, 1, 2 or 3
R
31
is hydrogen, C
1
-C
6
-alkyl, (CH
2
)
4
NR
33
R
34
,
R
32
is (CH
2
)
r
NR
33
R
34
, in which, if R
31
and R
32
are independent of one another, r is 2, 3, 4, 5 or 6 and R
33
and R
34
independently of one another are hydrogen, C
1
-C
6
-alkyl, together with the nitrogen atom are a ring of 3 to 8 atoms which can carry an additional heteroatom selected from O, N—C
1
-C
4
-alkyl, N—C
0
-C
2
-phenyl or NH, phenyl-C
1
-C
4
Höger Thomas
Kock Michael
Lubisch Wilfried
BASF - Aktiengesellschaft
Keil & Weinkauf
Shameem Golam M M
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