CA2352194A1

CA2352194A1 - Azepinoindole derivatives, the production and use thereof

Info

Publication number: CA2352194A1
Application number: CA002352194A
Authority: CA
Inventors: Wilfried Lubisch; Michael Kock; Thomas Hoger; Roland Grandel; Reinhold Muller; Sabine Schult
Original assignee: Individual
Current assignee: Abbott GmbH and Co KG
Priority date: 1999-09-28
Filing date: 2000-09-15
Publication date: 2001-04-05
Also published as: WO2001023390A3; HK1048999A1; CZ20012373A3; CN1374961A; HUP0104917A3; WO2001023390A2; BR0007174A; SK8842001A3; AU1271201A; JP2003510328A; BG105650A; PL347885A1; TR200101499T1; EP1183259A2; NO20012567D0; KR20010087401A; NO20012567L; HUP0104917A2; IL143349A0

Abstract

The invention relates to compounds of formula (I) as well as to the tautomer ic forms thereof, possible enantiomeric and diastereomeric forms and the prodru gs thereof, the production and use thereof, whereby the values have the meaning as given in the description.

Description

AZEPINOINDOLE DERIVATIVES, THE PRODUCTION AND USE THEREOF
The present invention relates to novel azepinoindole derivatives, their preparation and use as inhibitors of the enzyme poly(ADP-ribose) polymerase or PARP (EC 2.4.2.30) for the production of pharmaceuticals.
Poly(ADP-ribose) polymerase (PARP) or, as it is also called, poly(ADP-ribose) synthase (PARS) 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 role in the repair of DNA breaks (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 transfer of ADP-ribose from NAD (S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69). In this process, nicotinamide is released from NAD.
Nicotinamide is converted again into NAD by other enzymes using the energy carrier ATP. Overactivation of PARP would accordingly have resulted in a nonphysiologically high consumption of ATP and in the extreme case this leads 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 that this accumulation of free radicals leads or contributes to the observed cell or organ damage. This counts, 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 after the 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 partially. PARP inhibitors could thus be a novel therapy principle for the treatment of a number of diseases.
The enzyme PARP influences the repair of DNA damage and could thus also play a role in the therapy of carcinomatous diseases, as a higher potential of action against tumor tissue has been observed in combination with cytostatically active substances (G.
Chen et al. Cancer Chemo. Pharmacol. 1988, 22, 303).
Nonlimiting examples of tumors are leukemia, glioblastoma, lymphoma, melanoma, mammary and cervical carcinoma.

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Moreover, it has been found that PARP inhibitors can show immunosuppressant action (D. Weltin et al. Int. J.
Immunopharmacol. 1995, 17, 265-271).
It has likewise been discovered that PARP is invoved in immunological disorders or diseases in which the immune system plays an important role, such as rheumatoid arthritis and septic shock, and that PARP inhibitors can show a favorable effect on the course of the disease (H. Kroger 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 within the meaning of this invention is also understood as meaning isoenzymes of the PARP enzyme described above.
The PARP inhibitor 3-aminobenzamide furthermore showed protective effects in a model of 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 a means for the treatment of diabetes mellitus (V. Burkart et al. Nature Med. 1999, 5, 314-319).
WO 00/42040 mentions azepinoindoles which inhibit the PARP
enzyme. In particular, derivatives are described there as active which carry a phenyl ring in the 2 position, which can additionally be substituted by simple substituents.
The compounds of the general formula I according to the invention here have not been described until now and are accordingly novel.
In the present invention, novel azepinoindole derivatives of the general formula I are described which are potent PARP inhibitors.
The present invention relates to substituted azepinoindole derivatives of the general formula I

~N-A

I
R 1 ~ ~~ B
~ \ X3 in which BASF Aktiengesellschaft 992956 o.Z. 0050/51636 DE

can be a C1-C3 chain, where each carbon atom can additionally carry one or two of the following substituents: C1-C4-alkyl, OH, O-C1-C4-alkyl, COON, C00-C1-C4-alkyl and phenyl or a C
atom can also carry an =O group and X1 can be S, 0 or NH and X2 can be a carbon atom which can additionally carry a Ci-C4 chain, and N and X3 can be N or C-R2, where R2 can be hydrogen, branched or unbranched C1-C6-alkyl, C1-C9-alkylphenyl, phenyl and XZ and X3 cannot simultaneously be N, and R1 can be hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C1-C6-alkyl, OH, vitro, CF3, CN, NR11R12. NH-CO-R13. O-C1-C4-alkyl, where R11 and R12 independently of one another are hydrogen or C1-C4-alkyl and Ri3 is hydrogen, C1-C4-alkyl, C1-C4-alkylphenyl or phenyl, and g can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi-or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, which in each case are additionally substituted by one R4 and at most 3 different or identical radicals R5, and can carry one or two carbon or sulfur atoms and also one or two =O
groups such as keto groups, sulfones or sulfoxides, R4 is -(D)p-(E)s-(F1)q-G1-(FZ)r-(GZ) G3' where G1, G2 and G3 cannot simultaneously be hydrogen or a bond and if p = s = 0 and q or r = 1 or p, q and r = 0, then two radicals G1, G2 and G3 cannot simultaneously be a bond or hydrogen, and D can be S, NR43 or 0 can be phenyl, -S02-, -SOZNH-, -NHCO-, -CONH-, NHS02-, C=O , -NHCOCHZX4, and BASF Aktiengesellschaft 992956 O.Z. 0050/51636 DE

g4 can be S, 0 or NH, and F1 can be a straight-chain or branched saturated or unsaturated carbon chain of 1 to 8 C atoms and F2 independently of F1 has the same meaning as F1.
G1 is a bond or can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, which in each case are additionally substituted by at most 3 different or identical radicals R5 and can carry one or two carbon or sulfur atoms and one or two =O groups, and G2 is NR41Ra2 or R~
R~
R~ R7 N N~ N
R~

NJ N O
N~NwR9 U
or a bond and G3 can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which in each case are additionally substituted by at most 3 different or identical radicals g5, and one or two carbon or sulfur atoms can also carry one or two =0 groups, or hydrogen, and p can be 0 or 1 and s can be 0 or 1 and q can be 0 or 1 and BASF Aktiengesellschaft 992956 O.Z. 0050/51636 DE
r can be 0 or 1 and R41 can be hydrogen, C1-C6-alkyl, where each carbon atom can additionally carry up to two radicals R6, phenyl which can 5 additionally carry at most two radicals R6, and (CHz)t-K and -C6-alkyl, -CO-R8~ C02-R8. SOzNHz, SOz-R8~
Raz can be hydrogen, C1 -(C=N)-R8 and -(C=N)-NHRg and R43 can be hydrogen or C1-C4-alkyl and t can be 1, 2, 3 or 4 and K can be NRllRiz, NR11-Ci-C9-alkylphenyl, pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidine, piperazine, which can additionally be substituted by an alkyl radical C1-C6-alkyl, and homopiperazine which can additionally be substituted by an alkyl radical C1-C6-alkyl, and 5 can be hydrogen, chlorine, fluorine, bromine, iodine, OH, R
NR11R1z~ NH-CO-R13, Ci-C4-alkyl-CO-NH-R13, CORE, nitro, CF3, CN, Co-C4-alkyl-O-CO-R13, Ci-Ca-alkylphenyl, phenyl, COz-Ci-Ca-alkyl, and branched or unbranched C1-C6-alkyl, O-C1-C4-alkyl, S-C1-C4-alkyl, where each C atom of the alkyl chains can carry up to two radicals R6 and the alkyl chains can also be unsaturated, and R6 can be hydrogen, chlorine, fluorine,OH ron tro, CF ,n CN, branched or unbranched C1-C6-alkyl, NR11R1z, NH-CO-R13, 0-C1-C4-alkyl R~ can be hydrogen, C1-C6-alkyl, phenyl, where the ring can additionally be substituted by up to two radicals R~1, and one amine NR11Ri2 or a cyclic saturated amine having 3 to 7 members, which can additionally be substituted by an alkyl radical C1-C6-alkyl, and homopiperazine which can additionally be substituted by an alkyl radical C1-C6-alkyl, and where the radicals R11, Riz and R13 in K, R5, R6 and R~
independently of one another can assume the same meaning as R1, and R~1 can be OH, C1-C6-alkyl, 0-C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NHz, and BASF Aktiengesellschaft 992956 O.Z. 0050/51636 DE

R8 can be C1-C6-alkyl, CF3, phenyl, C1-C4-alkylphenyl, where the ring can additionally be substituted by up to two radicals R81, and R81 can be OH, C1-C6-alkyl, O-C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NHz, and R9 can be hydrogen, C1-C6-alkyl, C1-C4-alkylphenyl, COZ-C1-C4-alkylphenyl, COZ-C1-C4-alkyl, S02-phenyl, COR$ and phenyl, where the phenyl rings can additionally be substituted by up to two radicals R91, and R91 can be OH, C1-C6-alkyl, 0-C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, - and their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.
Preferred compounds of the formula I are those where A is a C2 chain which can be substituted, and X1 is O and R1 is hydrogen.
Preferred compounds of the formula I are those as indicated above, in which B can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi-or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which in each case are additionally substituted by an R4 and at most 3 different or identical radicals R5, and can carry one or two carbon or sulfur atoms and also one or two =0 groups.
Particularly preferred radicals for B are the following:
B is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which can additionally be substituted by one R4 or at most 2 R5.

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Very particularly preferred compounds of the formula I are those where R4 is D-Flo,1-G2-G3 where G3 is hydrogen and D is 0 or NR93, where R43 is hydrogen or C1-C3-alkyl and F1 is Cz-C4-alkyl.
The compounds of the formula I can be employed as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are desired, these can be obtained, for example, by carrying out a classical resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid.
Alkyl chains can in each case be branched or unbranched.
Unbranched alkyl chains are preferred.
The invention also relates to compounds which are mesomeric or tautomeric to compounds of the formula I.
The invention further relates to the physiologically tolerable salts of the compounds I, which can be obtained by conversion of compounds I using a suitable acid or base. Suitable acids and bases are listed, for example, in Fortschritte der Arzneimittelforschung, 1966, Birkhauser Verlag, Vol. 10, pp. 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, malefic acid, fumaric acid etc. or sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.
Prodrugs are understood as meaning those compounds which are metabolized in vivo to compounds of the general formula I.
Typical prodrugs are phosphates, carbamates of amino acids, esters and others.
The azepinoindole derivatives I according to the invention can be prepared in various ways, such as described in WO 00/42040.
The substituted azepinoindole derivatives I obtained in the present invention are inhibitors of the enzyme poly(ADP-ribose)polymerase or PARP (EC 2.4.2.30).

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The inhibitory action of the substituted azepinoindole derivatives I can be determined using an enzyme test which is already known in the literature, the measure of activity determined being a Ki value. The azepinoindole derivatives I were measured in this way for inhibitory action of the enzyme poly(ADP-ribose)polymerase or PARP (EC 2.4.2.30).
The substituted azepinoindole derivatives of the general formula I are inhibitors of poly(ADP-ribose)polymerase (PARP) or, as it is also called, polY(~P-ribose)synthase (PARS) and can thus be used for the treatment and prophylaxis of diseases which are connected with an increased enzyme activity of these enzymes.
The compounds of the formula I can be employed for the production of pharmaceuticals for the treatment of damage after ischemia and for prophylaxis in the case of expected ischemia of various organs.
The present azepinoindole derivatives of the general formula I
can accordingly be used for the treatment and prophylaxis of neurodegenerative diseases which occur after ischemia, trauma (craniocerebral trauma), mass hemorrhages, subarachnoid hemorrhages and stroke, and of neurodegenerative diseases.such as multiple infarct dementia, Alzheimer's disease, Huntington's disease and of epilepsy, in particular of generalized epileptic attacks, such as petit mal and tonic-clonic attacks and partially epileptic attacks, such as temporal lobe, and complex/partial attacks, and furthermore for the treatment and prophylaxis of damage to the heart after cardiac ischemia and damage to the kidneys after renal ischemia, for example of acute renal insufficiency caused by medicinal therapies such as in the case of cyclosporin treatment, of acute kidney failure or of damage which occurs during and after a kidney transplantation.
Furthermore, the compounds of the general formula I can be used for the treatment of acute myocardial infarct and damage which occurs during and after medicinal lysis thereof (for example using TPA, reteplase, streptokinase or mechanically using a laser or rotablator) and of microinfarcts during and after heart valve replacement, aneurysm resection and heart transplantation.
Likewise, the present azepinoindole derivatives I can be used for the treatment of a revascularization of critically constricted coronary arteries, for example in PCTA and bypass operations, and critically constricted peripheral arteries, for example leg arteries. Moreover, the azepinoindole derivatives I can be useful for the treatment of tumors and metastasis thereof and for the treatment of inflammation and rheumatic disorders, such as rheumatoid arthritis and also for the treatment of diabetes BASF Aktiengesellschaft 992956 O.Z. 0050/51636 DE

mellitus, for the treatment of multiorgan failure, e.g. in septic shock and for the treatment of ARDS (acute respiratory distress syndrome, shock lung).
In addition to the customary pharmaceutical excipients, the pharmaceutical preparations according to the invention contain a therapeutically active amount of the compound I.
For local external application, for example in powders, ointments or sprays, the active compounds can be present in the customary concentrations. As a rule, the active compounds are present in an amount from 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.
In the case of internal administration, the preparations are administered in individual doses. In an individual dose, 0.1 to 100 mg are given per kg of body weight. The preparations can be administered daily in one or more doses, depending on the nature and severity of the disorders.
Corresponding to the desired manner of administration, the pharmaceutical preparations according to the invention contain the customary vehicles and diluents in addition to the active compound. For local external application, pharmaceutical excipients, such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid paraffin, petroleum jelly and wool fat can be used. For internal administration, for example, lactose, 30.propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable.
Antioxidants such as tocopherol and butylated hydroxyanisole and also butylated hydroxytoluene, flavor-improving additives, stabilizers, emulsifieres and lubricants can furthermore be present.
The substances contained in the preparation in addition to the active compound and the substances used in the production of the pharmaceutical preparations are toxicologically innocuous and compatible with the respective active compound. The pharmaceutical preparations are produced in a customary manner, for example by mixing the active compound with other customary vehicles and diluents.

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The pharmaceutical preparations can be administered in various modes of administration, for example perorally. parenterally, such as intravenously, by infusion, subcutaneously, intraperitoneally and topically. Thus, preparation forms such as 5 tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.
Pharmacological Example:

10 Inhibition of the enzyme poly(ADP-ribose)polymerase or PARP
(EC 2.4.2.30) A 96-well microtiter plate (Flacon) is coated with histories (type II-AS; SIGMA H7755). For this purpose, histories are dissolved in carbonate buffer (0.05 M NaHC03; pH 9.4) to give a concentration of 50 ~g/ml~ The individual wells of the microtiter plates are incubated overnight with 100 ~1 each of this histone solution.
The histone solution is then removed and the individual wells are incubated at room temperature for 2 hours with 200 ~1 of a 1%
strength BSA (bovine serum albumin) solution in carbonate buffer.
The wells are then washed three times with wash buffer (0.05%
Tween 10 in PBS). For the enzyme reaction, 50 ~1 of the enzyme reaction solution (5 ~1 of reaction buffer (1 M tris HCl pH 8.0, 100 mM MgClz, 10 mM DTT), 0.5 ~1 of PARP (c = 0.22 ~g/~1). 4 ~1 of activated DNA (SIGMA D-4522, 1 mg/ml in water), 40.5 ~1 of H20) are preincubated with 10 ~1 of an inhibitor solution per well for 10 minutes. The enzyme reaction is started by addition of 40 ~.1 of a substrate solution (4 ~1 of reaction buffer (see above), 8 ~1 of NAD solution (100 ~M in H20), 28 ~1 of HZO). The reaction time is 20 minutes at room temperature. The reaction is stopped by washing three times with wash buffer (see above). A one-hour incubation at room temperature with a specific anti-poly-ADP-ribose antibody then follows. The antibodies used were monoclonal anti-poly-(ADP-ribose) antibodies "lOH"
(Kawamaitsu H et al. (1984) Monoclonal antibodies to poly (adenosine diphosphate ribose) recognize different structures.
Biochemistry 23, 3771-3777). Polyclonal antibodies can also be used.
The antibodies were employed in a 1:5 000 dilution in antibody buffer (1% BSA in PBS; 0.05% Tween 20). After washing three times with wash buffer, a one-hour incubation at room temperature with secondary antibody follows. Here, for the monoclonal antibody, an anti-mouse IgG coupled to peroxidase (Boehringer Mannheim) and, for the rabbit antibody, an anti-rabbit IgG coupled to peroxidase (SIGMA A-6154), in each case in a 1:10 000 dilution in antibody buffer, were used. After washing three times with wash buffer, BASF Aktiengesellschaft 992956 O.Z. 0050/51636 DE

the color reaction was carried out using 100 p.l/well of color reagent (SIGMA, TMB ready-to-use mix, T8540) for about 15 min at room temperature. The color reaction is stopped by addition of 100 ~1 of 2 M H2S04. The color is then immediately measured (450 nm against 620 nm; ELISA "Easy Reader" EAR340AT plate reader, SLT-Labinstruments, Austria). The IC50 value of an inhibitor to be measured is the inhibitor concentration where a half-maximal color concentration change occurs.
The following compounds according to the invention can be prepared analogously to the methods described above:
1. 2-(4-(4-n-Propylpiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 2. 2-(4-Piperazin-1-ylphenyl)-1,3,4,5-tetrahydro-6H-azepino-[5,4,3-c,d]indol-6-one 3. 2-(4-(4-Isopropylpiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 4. 2-(4-(4-Benzylpiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 5. 2-(4-(4-n-Butylpiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 6. 2-(4-(4-Ethylpiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 7. 2-(4-(2-N,N-Dimethylaminoeth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 8. 2-(4-(2-Pyrrolidinyleth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 9. 2-(4-(2-Piperidin-1-yleth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 10. 2-(4-(2-Piperazin-1-yleth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 11. 2-(4-(2-(4-Methylpiperazin-1-yl)eth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one BASF Aktiengesellschaft 992956 O.Z. 0050/51636 DE

12. 2-(4-(2-(4-Propyl-piperazin-1-yl)eth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 13. 2-(4-(2-(4-Ethyl-piperazin-1-yl)eth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 14. 2-(4-(2-(4-Benzylpiperazin-1-yl)eth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 15. 2-(4-(2-(4-Acetamidopiperazin-1-yl)eth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 16. 2-(4-(2-(4-Benzamidopiperazin-1-yl)eth-1-yloxy)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 17. 2-(4-Homopiperazin-1-yl-phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 18. 2-(4-(4-Methylhomopiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 19. 2-(4-(4-Benzylhomopiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 20. 2-(4-(4-n-Butylhomopiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 21. 2-(4-(4-Ethylhomopiperazin-1-yl)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 22. 2-Piperidin-4-yl-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]-indol-6-one 23. 2-(1-Methylpiperidin-4-yl)-1,3,4,5-tetrahydro-6H-azepino-[5,4,3-c,d]indol-6-one 24. 2-(1-n-Propylpiperidin-4-yl)-1,3,4,5-tetrahydro-6H-azepino-[5,4,3-c,d]indol-6-one 25. 2-(1-Benzylpiperidin-4-yl)-1,3,4,5-tetrahydro-6H-azepino-[5,4,3-c,d]indol-6-one 26. 2-(1-n-Butylpiperidin-4-yl)-1,3,4,5-tetrahydro-6H-azepino-[5,4,3-c,d]indol-6-one BASF Aktiengesellschaft 992956 O.Z. 0050/51636 DE

27. 2-(1-Isopropylpiperidin-4-yl)-1,3,4,5-tetrahydro-6H-azepino-[5,4,3-c,d]indol-6-one 28. 2-(2-(N,N-Dimethylamino)eth-1-ylamino)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 29. 2-(2-(N,N-Diethylamino)eth-1-ylamino)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 30. 2-(2-Piperidin-1-yleth-1-ylamino)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 31. 2-(2-Pyrrolidin-1-yleth-1-ylamino)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 32. 2-(3-(N,N-Dimethylamino)prop-1-ylamino)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 33. 2-(3-(N,N-Diethylamino)prop-1-ylamino)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 34. 2-(3-Piperidin-1-yl-prop-1-ylamino)phenyl)-1,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one 35. 2-(3-Pyrrolidin-1-yl-prop-1-ylamino)phenyl)-I,3,4,5-tetrahydro-6H-azepino[5,4,3-c,d]indol-6-one

Claims

We claim:

1, A compound of the formula I
in which A can be a C1-C3 chain, where each carbon atom can additionally carry one or two of the following substituents: C1-C4-alkyl, OH, O-C1-C4-alkyl, COOH, COO-C1-C4-alkyl and phenyl or a C atom can also carry an =O group and X1 can be S, O or NH and X2 can be a carbon atom which can additionally carry a C1-C4 chain, and N and X3 can be N or C-R2, where R2 can be hydrogen, branched or unbranched C1-C6-alkyl, C1-C4-alkylphenyl, phenyl and X2 and X3 cannot simultaneously be N, and R1 can be hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C1-C6-alkyl, OH, nitro, CF3, CN, NR11R12, NH-CO-R13, O-C1-C4-alkyl, where R11 and R12 independently of one another are hydrogen or C1-C4-alkyl and R13 is hydrogen, C1-C4-alkyl, C1-C4-alkylphenyl or phenyl, and B can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, which in each case are additionally substituted by one R4 and at most 3 different or identical radicals R5, and can carry one or two carbon or sulfur atoms and also one or two =O groups, R4 is -(D)p-(E)s-(F1)q-G1-(F2)r-(G2)-G3. where G1, G2 and G3 cannot simultaneously be hydrogen or a bond and if p = s = 0 and q or r = 1 or p, q and r = 0, then two radicals G1, G2 and G3 cannot simultaneously be a bond or hydrogen, and D can be S, NR43 or O
E can be phenyl, , -SO2-, -SO2NH-, -NHCO-, -CONH-, NHSO2-, -NHCOCH2X4, and X4 can be S, O or NH, and F1 can be a straight-chain or branched saturated or unsaturated carbon chain of 1 to 8 C atoms and F2 independently of F1 has the same meaning as F1, G1 is a bond or can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, which in each case are additionally substituted by at most 3 different or identical radicals R5 and can carry one or two carbon or sulfur atoms and one or two =O groups, and G2 is NR41R42 or or a bond and G3 can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which in each case are additionally substituted by at most 3 different or identical radicals R5, and one or two carbon or sulfur atoms can also carry one or two =O groups, or hydrogen, and p can be 0 or 1 and s can be 0 or 1 and q can be 0 or 1 and r can be 0 or 1 and R41 can be hydrogen, C1-C6-alkyl, where each carbon atom can additionally carry up to two radicals R6, phenyl which can additionally carry at most two radicals R6, and (CH2)t-K and R42 can be hydrogen, C1-C6-alkyl, -CO-R8, CO2-R8, SO2NH2, SO2-R8, -(C=N)-R8 and -(C=N)-NHR8 and R43 can be hydrogen or C1-C4-alkyl and t can be 1, 2, 3 or 4 and K can be NR11R12, NR11-C1-C4-alkylphenyl, pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidine, piperazine, which can additionally be substituted by an alkyl radical C1-C6-alkyl, and homopiperazine which can additionally be substituted by an alkyl radical C1-C6-alkyl, and R5 can be hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF3, CN, NR11R12, NH-CO-R13, C1-C4-alkyl-CO-NH-R13, COR8, Co-C4-alkyl-O-CO-R13, C1-C4-alkylphenyl, phenyl, CO2-C1-C4-alkyl, and branched or unbranched C1-C6-alkyl, O-C1-C4-alkyl, S-C1-C4-alkyl, where each C atom of the alkyl chains can carry up to two radicals R6 and the alkyl chains can also be unsaturated, and R6 can be hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C1-C6-alkyl, OH, nitro, CF3, CN, NR11R12, NH-CO-R13, O-C1-C4-alkyl R7 can be hydrogen, C1-C6-alkyl, phenyl, where the ring can additionally be substituted by up to two radicals R71, and one amine NR11R12 or a cyclic saturated amine having 3 to 7 members, which can additionally be substituted by an alkyl radical C1-C6-alkyl, and homopiperazine which can additionally be substituted by an alkyl radical C1-C6-alkyl, and where the radicals R11, R12 and R13 in K, R5, R6 and R7 independently of one another can assume the same meaning as R1, and R71 can be OH, C1-C6-alkyl, O-C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, and R8 can be C1-C6-alkyl, CF3, phenyl, C1-C4-alkylphenyl, where the ring can additionally be substituted by up to two radicals R81, and R81 can be OH, C1-C6-alkyl, O-C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, and R9 can be hydrogen, C1-C6-alkyl, C1-C4-alkylphenyl, CO2-C1-C4-alkylphenyl, CO2-C1-C4-alkyl, SO2-phenyl, COR8 and phenyl, where the phenyl rings can additionally be substituted by up to two radicals R91, and R91 can be OH, C1-C6-alkyl, O-C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, or its tautomeric forms, possible enantiomeric and diastereomeric forms, and its prodrugs.

2. A compound of the formula I as claimed in claim 1, where A is a C2 chain which can be substituted, and X1 is 0 and R1 is hydrogen.

3. A compound of the formula I as claimed in one of claims 1 and 2, in which B can be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having at most 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which in each case are additionally substituted by an R4 and at most 3 different or identical radicals R5, and can carry one or two carbon or sulfur atoms and also one or two =O groups.

4. A compound of the formula I as claimed in claim 3, where B is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which can additionally be substituted by one R4 or at most 2 R5.

5. A compound of the formula I as claimed in claim 4, where R4 is D-F1 0,1-G2-G3 where G3 is hydrogen and D is O or NR43, where R43 is hydrogen or C1-C3-alkyl and F1 is C2-C4-alkyl.

6. A pharmaceutical comprising, in addition to customary carriers and excipients, compounds of the formula I as claimed in one of claims 1 to 5.

7. The use of compounds of the general formula I as claimed in one of claims 1 to 5 for the production of pharmaceuticals having PARP-inhibitory action.

8. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of neurodegenerative diseases and neuronal damage.

9. The use as claimed in claim 7 for the treatment of those neurodegenerative diseases and that neuronal damage which are/is caused by ischemia, trauma or mass hemorrhages.

10. The use as claimed in claim 7 for the treatment of stroke and of craniocerebral trauma.

11. The use as claimed in claim 7 for the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease.

12. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment or prophylaxis of damage due to ischemias.

13. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of epilepsy, in particular of generalized epileptic attacks, such as, for example, petit mal and tonic/clonic attacks and partially epileptic attacks, such as temporal lobe and complex/partial attacks.

14. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of damage to the kidneys after renal ischemia, damage which is caused by medicinal therapy, such as during cyclosporin therapy, and for treatment during and after kidney transplantation.

15. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of damage to the heart after cardiac ischemia.

16. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of microinfarcts such as during and after heart valve replacement, aneurysm resection and heart transplantation.

17. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for treatment during revascularization of critically constricted coronary arteries such as in PTCA and bypass operations or critically constricted peripheral arteries, in particular leg arteries.

18. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of acute myocardial infarct and of damage during and after its medicinal or mechanical lysis.

19. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of tumors and metastases thereof.

20. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of multiorgan failure sepsis such as during septic shock and acute respiratory distress syndrome.

21. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of immunological diseases such as inflammation and rheumatic disorders, such as rheumatoid arthritis.

22. The use of compounds of the formula I as claimed in claim 7 for the production of pharmaceuticals for the treatment of diabetes mellitus.