EP1183259A2

EP1183259A2 - Azepinoindole derivatives, the production and use thereof

Info

Publication number: EP1183259A2
Application number: EP00974379A
Authority: EP
Inventors: Wilfried Lubisch; Michael Kock; Thomas Höger; Roland Grandel; Reinhold Müller; Sabine Schult
Original assignee: BASF SE
Current assignee: Abbott GmbH and Co KG
Priority date: 1999-09-28
Filing date: 2000-09-15
Publication date: 2002-03-06
Also published as: SK8842001A3; PL347885A1; BG105650A; HUP0104917A3; HUP0104917A2; BR0007174A; CA2352194A1; WO2001023390A3; TR200101499T1; HK1048999A1; NO20012567L; WO2001023390A2; NO20012567D0; CN1374961A; IL143349A0; CZ20012373A3; JP2003510328A; AU1271201A; KR20010087401A

Abstract

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

Description

Azepinoindole derivatives, their production and application

description

The present invention relates to novel azepinoindole derivatives, their preparation and their use as inhibitors of the enzyme poly (ADP-ribose) poly erase or PARP (EC 2.4.2.30) for the production of medicaments.

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. Histo- Chem. Cytochem. 1983, 31, 1261-1264). PARP is believed to play a role in repairing DNA breaks (M.S. Satoh et al., Nature 1992, 356, 356-358). Damage or breakage of the DNA strands activate the enzyme PARP, which, when activated, catalyzes the transfer of ADP-ribose from NAD (S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69). This releases nicotinamide from NAD. Nicotinamide is converted back into NAD by other enzymes using the energy source ATP. Overactivation of PARP would accordingly result in an unphysiologically high consumption of ATP and in extreme cases this leads to cell damage and cell death.

It is known that radicals such as superoxide anion, NO and hydrogen peroxide can lead to DNA damage in cells and thus 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 to or contribute to the observed damage to the cells or organs. These include, for example, ischemic conditions of organs such as in stroke, heart attack (C. Thiemermann et al., Proc. Natl. Acad. Sei. USA, 1997, 94, 679-683) or ischemia of the kidneys, but also reperfusion damage such as this for example, after lysis of a heart attack (see above: C. Thiemermann et al.). Inhibition of the PARP enzyme could therefore be a means to at least partially prevent or mitigate this damage. PARP inhibitors could thus represent a new therapeutic principle for the treatment of a number of diseases.

The enzyme PARP influences the repair of DNA damage and could therefore also play a role in the therapy of cancer diseases, since in combination with cytostatically active substances a higher activity potential against tumor tissue was observed (G. Chen et al. Cancer Chemo. Pharmacol 1988, 22, 303). Non-limiting examples of tumors are leukemia, glioblassomas, lymphomas, melanomas, mom and cervical cancers.

In addition, it has been found that PARP inhibitors can show immunosuppressive activity (D. Weltin et al. Int. J. Immunopharmacol. 1995, 17, 265-271).

It was also discovered that PARP is involved in immunological diseases or diseases in which the immune system plays an important role, such as rheumatoid arthritis and septic shock, and that PARP inhibitors can have a favorable effect on the course of the disease (H Kroger et al. Infammation 1996, 20, 203-215; W. Ehrlich et al. Reumatol. Int. 1995, 15, 171-172; C. Szabo et al., Proc. Natl. Acad. Sei. USA 1998, 95, 3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol. 1998, 342, 67-76).

PARP in the sense of this invention is also understood to mean isoenzymes of the PARP enzyme described above.

Furthermore, the PARP inhibitor 3-aminobenzamide was protective

Effects in a model for circulatory shock (S. Cuzzocrea et al., Br. J. Pharmacol. 1997, 121, 1065-1074).

There are also experimental indications that inhibitors of the enzyme PARP could be useful as agents for the treatment of diabetes mellitus (V. Burkart et al. Nature Med. 1999, 5,

314-319).

WO 00/42040 lists azepinoindoles which inhibit the PARP enzyme. In particular, there derivatives are described as effective which carry a phenyl ring in the 2-position which can still be substituted with simple substituents.

The compounds of general compound I according to the invention here have not been described so far and are therefore new.

In the present invention, new 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.

wherein

A is a chain -C-C ₃ , where each carbon atom can also carry one or two of the following substituents: -C-C ₄ alkyl, OH, 0-Cι-C ₄ alkyl, COOH, COO-Cι-C ₄ - Alkyl and phenyl or a carbon atom can also carry a = 0 group and

X ^{1 can be} S, 0 and NH and

X ^{2 is} a carbon atom that can still carry a chain C ₁ -C ₄ , and N and

X ^{3 can be} N and CR ² , where

R ^{2 is} hydrogen, branched and unbranched Ci-Cβ-alkyl, -C-C ₄ alkylphenyl, phenyl and

X ² and X ³ cannot be N at the same time, and

R ^{1 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ -alkyl, OH, nitro, CF ₃ , CN, NR ^{1: 1} R ¹² ,

NH-CO-R ¹³ , 0-Cχ-C ₄ alkyl, where R ¹¹ and R ¹² independently of one another are hydrogen or C 1 -C ₄ -alkyl and R ^{13 is} hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ - Alkyl-phenyl or phenyl mean, and

B an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially-unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, each of which is still substituted by one R ⁴ and a maximum of 3 different or identical radicals R ⁵ , and one or two carbon or sulfur atoms also one or two = 0- Can carry groups such as keto groups, sulfones or sulfoxides, - (D) _p - (E) _s - (F ¹ ) _q -G ¹ - (F ² ) _r - (G ² ) -G ³ , where G ¹ , G ² and G ³ do not simultaneously represent hydrogen or a Can be bond ind if p = s = 0 and q or r = 1 or p, q and r = 0, then two radicals G ¹ , G ² and G ³ cannot simultaneously be a bond or hydrogen, and

DS, NR ⁴³ and 0

E phenyl,

^ C 0, -S0 ₂ -. -S0 ₂ NH-, -NHCO-, -CONH-, NHS0 ₂ -,

-NHC0CH ₂ X, and

X ⁴ can mean S, 0 or NH, and

F ^{1 can be} a straight-chain or branched saturated or unsaturated carbon chain of 1 to 8 carbon atoms and

F ^{2 has} the same meaning as F ¹ independently of F ¹ ,

G ^{1 represents} a bond or an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which are each still substituted with a maximum of 3 different or identical radicals R ⁵ , and one or two carbon or sulfur atoms also one or two = 0 -Groups can carry, and

G ² NR ⁴¹ R ⁴² and

or means a bond and G ^{3 is} an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially-unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms , Can mean 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, each of which is still substituted with a maximum of 3 different or identical radicals R ⁵ , and one or two carbon or sulfur atoms can also carry one or two = 0 groups , or means hydrogen, and

p can mean 0 and 1 and

s 0 and 1 and

q can be 0 and 1 and

r can be 0 and 1 and

R ^{41 is} hydrogen, Ci-Cg-alkyl, where each carbon atom can still carry up to two radicals R ⁶ , phenyl, which can still carry a maximum of two radicals R ⁶ , and (CH ₂ ) _t -K and

R ^{42 is} hydrogen, -CC ₆ alkyl, -CO-R ⁸ , C0 ₂ -R ⁸ , S0 ₂ NH ₂ , S0 ₂ -R ⁸ , - (C = N) -R ⁸ and - (C = N) -NHR ⁸ and

R ^{43 is} hydrogen and -C ₄ alkyl and

t 1, 2, 3, 4 and

K NR ^ R ¹² , NR ^{1: l} -Cι-C ₄ alkylphenyl, pyrrolidine, piperidine, 1,2,5, 6-tetrahydropyridine, morpholine, homopiperidine, piperazine, which is still with an alkyl radical Ci-Cβ -Alkyl may be substituted, and homopiperazine, which may also be substituted with an alkyl radical Cχ-C ₆ -alkyl, and

R ⁵ hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF ₃ , CN, NR ^ll R ^l2 , NH-CO-R ¹³ , Cι-C-alkyl-CO-NH-R ¹³ , COR ⁸ , Co -C -alkyl-0-CO-R ¹³ , -C-C -alkyl-phenyl, phenyl,

C0 ₂ -C ₄ -alkyl, and branched and unbranched Ci-Cε-alkyl, 0-Cι-C ₄ alkyl, S-Cι-C alkyl, each carbon atom of the alkyl chains having up to two radicals R ⁶ can wear and the alkyl chains can also be unsaturated, and R ⁶ hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched Ci-Cβ-alkyl, OH, nitro, CF ₃ , CN, NR ^{1: L} R ¹ , NH-CO-R ¹³ , 0-Cι-C - alkyl

R ^{7 is} hydrogen, Ci-Cg-alkyl, phenyl, where the ring can still be substituted with up to two radicals R ⁷¹ , and an amine NR ^ R ¹² or a cyclic saturated amine with 3 to 7 members, still with an alkyl -Ri Ci-Cg-alkyl may be substituted, and homopiperazine, which may also be substituted with an alkyl radical Ci-C _ß- alkyl, and

where the radicals R ¹¹ , R ¹² and R ¹³ in K, R ⁵ , R ⁶ and R ^{7 can} independently assume the same meaning as R ¹ , and

R ⁷ ^ OH, C _! -C ₆ alkyl, 0-Cι-C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and

R ⁸ Ci-C _δ- alkyl, CF ₃ , phenyl, -CC ₄ -alkyl-phenyl, where the ring can be substituted with up to two radicals R ⁸¹ , and

R ⁸¹ OH, Cx-Cg-alkyl, 0-Cι-C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and

R ⁹ are hydrogen, C ₆ alkyl, C ₁ -C ₄ alkyl, phenyl, C0 ₂ -Cι-C alkyl, phenyl, C0 ₂ -Cι-C ₄ alkyl, S0 ₂ -phenyl, COR ⁸ and Phenyl, where the phenyl rings can also be substituted with up to two radicals R ⁹¹ , and

R ^{91 can be} OH, -C ₆ alkyl, 0 -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ ,

as well as their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.

The compounds of formula I are preferred, wherein

A is a Cχ-C ₂ chain, which may be substituted, and

X ^{1 represents} 0 and

R ^{1 is} hydrogen. The compounds of the formula I are preferably as indicated above, in which

B is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially-unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 can mean oxygen atoms or 0 to 2 sulfur atoms, each of which is still substituted by one R ⁴ and a maximum of 3 different or identical radicals R ⁵ , and one or two carbon or sulfur atoms also carry one or two = 0 groups can,

means.

The radicals for B are particularly preferred:

B phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine,

Quinoline, pyrazine, which can also be substituted by one R ⁴ or a maximum of 2 R ⁵ .

Compounds of the formula I are very particularly preferred, wherein

R ⁴ DF ¹ o, ι-G ² -G ³ with G ³ is hydrogen and

DO and NR ⁴³ , where R ^{43 is} hydrogen and C _! -C ₃ alkyl and

F ¹ C ₂ -C alkyl.

The compounds of the formula I can be used 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 classic resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid.

Alkyl chains can each be branched or unbranched. Unbranched alkyl chains are preferred.

The invention also relates to compounds of the formula I which are mesomeric or tautomeric. The invention further relates to the physiologically tolerable salts of the compounds I, which can be obtained by reacting compounds I with a suitable acid or base. Suitable acids and bases are listed, for example, in Progress in Pharmaceutical Research, 1966, Birkhäuser 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, maleic acid, fumaric acid etc. or sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.

Prodrugs are understood to mean those compounds which are metrabolized in vivo into 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, e.g. described in WO 00/42040.

The substituted azepinoindole derivatives I contained in the present invention are inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30).

The inhibitory effect of the substituted azepinoindole derivatives I can be determined using an enzyme test already known in the literature, a Ki value being determined as the yardstick. The azepinoindole derivatives I were measured in this way for the inhibitory effect of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30).

The substituted azepinoindole derivatives of the general formulas I are inhibitors of poly (ADP-ribose) polymerase (PARP) or, as it is also called, poly (ADP-ribose) synthase (PARS), and can therefore be used for the treatment and prophylaxis of diseases, which are associated with an increased enzyme activity of these enzymes serve.

The compounds of the formulas I can be used for the production of medicaments 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 then be used for the treatment and prophylaxis of neurodegenerative diseases following ischemia, trauma (craniocerebral trauma), mass bleeding, subarachnoid bleeding and stroke occur, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease, Huntington's disease and epilepsy, in particular of generalized epileptic seizures such as petit mal and tonic-clonic seizures and partially epileptic seizures such as temporal lope and complex-partial Seizures, and further for the treatment and prophylaxis of damage to the heart after cardiac ischemia and damage to the kidneys after renal ischemia, for example acute renal insufficiency, caused by drug therapies such as cyclosporin treatment, the acute

Kidney failure or damage that occurs during and after a kidney transplant. Furthermore, the compounds of the general formulas I can be used for the treatment of acute myocardial infarction and damage which occurs during and after its drug lysis (for example with TPA, reteplase, streptokinase or mechanically with a laser or rotablator) and of micro-infarcts during and after heart valve replacement, aneurysm resections and serve heart transplants. The present azepinoindole derivatives I can also be used to treat a revascularization of critically narrowed coronary arteries, for example in PCTA and bypass operations, and critically narrowed peripheral arteries, for example leg arteries. In addition, the azepinoindole derivatives I can be useful for the treatment of tumors and their metastasis and for the treatment of inflammation and rheumatic diseases such as e.g. rheumatoid arthritis and also for the treatment of diabetes mellitus, for the treatment of multi-organ failure e.g. in septic shock and for the treatment of ARDS (acute respiratory distress syndrome shock lung).

In addition to the usual pharmaceutical excipients, the pharmaceutical preparations according to the invention contain a therapeutically effective amount of the compounds I.

For local external use, for example in powders, ointments or sprays, the active compounds can be present in the usual concentrations. As a rule, the active substances are contained in an amount of 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.

For internal use, the preparations are administered in single doses. 0.1 to 100 mg per kg body weight are given in a single dose. The preparation can be administered daily in one or more doses depending on the type and severity of the diseases. In accordance with the desired type of application, the pharmaceutical preparations according to the invention contain the usual carriers and diluents in addition to the active ingredient. For local external use, pharmaceutical-technical auxiliaries such as ethanol, isopropanol, oxyethylated castor oil, oxyethylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat can be used. Milk sugar, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable for internal use.

Antioxidants such as tocopherol and butylated hydroxyanisole and butylated hydroxytoluene, taste-improving additives, stabilizers, emulsifiers and lubricants can also be present.

The substances contained in the preparation in addition to the active substance and the substances used in the manufacture of the pharmaceutical preparations are toxicologically harmless and compatible with the respective active substance. The pharmaceutical preparations are produced in a customary manner, for example by mixing the active ingredient with other customary excipients and diluents.

The pharmaceutical preparations can be in different

Application modes are administered, for example, orally, parenterally and intravenously by infusion, subcutaneously, intraperitoneally and topically. Forms of preparation such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.

Phar acological example:

Inhibition of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30)

A 96-well microtiter plate (flacon) is coated with histones (Type II-AS; SIGMA H7755). For this, histones are dissolved in carbonate buffer (0.05 M NaHC0 ₃ ; pH 9.4) to a concentration of 50 μg / ml. The individual wells of the microtiter plates are incubated overnight with 100 μl of this histone solution. The histone solution is then removed and the individual wells are incubated with 200 μl of a 1% BSA (Bovine Serum Albumine) solution in carbonate buffer for 2 hours at room temperature. It is then washed three times with washing buffer (0.05% Tween10 in PBS). For the enzyme reaction, 50 μl of the enzyme reaction solution (5 μl reaction buffer (1 M Tris-HCl pH 8.0, 100 mM MgCl ₂ , 10 mM DTT), 0.5 μl PARP (c = 0.22 μg / μl), 4 μl activated DNA (SIGMA D-4522, 1 mg / ml in water), 40.5 μl H ₂ 0) with 10 μl of an inhibitor solution for 10 minutes. The enzyme reaction is started by adding 40 μl of a substrate solution (4 μl reaction buffer (see above), 8 μl NAD solution (100 μM in H ₂ 0), 28 μl H ₂ 0). Response time is 20 minutes at room temperature. The reaction is stopped by washing three times with washing buffer (see above). This is followed by a one-hour incubation at room temperature with a specific anti-poly-ADP-Ribose antibody. A monoclonal anti-poly (ADP-ribose) antibody "10H" (Kawamaitsu H et al. (1984) Monoclonal antibodies to poly (adenosine diphosphate ribose) recognize different structures. Biochemistry 23, 3771-3777) was used as the antibody. Polyclonal antibodies can also be used.

The antibodies were used in a 1: 5000 dilution in antibody buffer (1% BSA in PBS; 0.05% Tween20). After washing three times with washing buffer, there is a one-hour incubation at room temperature with the secondary antibody. Here, an anti-mouse IgG coupled with peroxidase (Boehringer Mannheim) was coupled for the monoclonal antibody and an anti-rabbit IgG coupled with peroxidase (SIGMA A-6154) for the rabbit antibody, each in a 1: 10,000 dilution in antibody buffer used. After washing three times with wash buffer, the color reaction is carried out using 100 μl / well color reagent (SIGMA, TMB ready mix, T8540) for approx. 15 min. at room temperature. The color reaction is stopped by adding 100 ul 2 M HS0 ₄ . Then the measurement is carried out immediately (450 nm against 620 nm; ELISA plate reader "Easy Reader" EAR340AT, SLT-Labinstruments, Austria). The IC50 value of an inhibitor to be measured lies at the inhibitor concentration, where a half-maximum change in color concentration occurs.

The following compounds according to the invention can be prepared analogously to the methods described above:

1. 2- (4- (4-n-propyl-piperazin-l-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5, 4, 3-c, d] indole -6-on

2. 2- (4-piperazin-l-yl-phenyl) -1,3,4,5-tetrahydro-6iϊ-azepino- [5,4,3-c, d] -indol-6-one

3. 2- (4- (4-isopropyl-piperazin-l-yl) phenyl) -1, 3,4,5-tetrahydro-

6H-azepino [5,4, 3-c, d] indol-6-one

4. 2- (4- (4-benzyl-piperazin-l-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indole-6 -one 5. 2- (4- (4-n-butyl-piperazin-l-yl) phenyl) -1,3,4,5-tetrahydro-6Jf-azepino [5, 4, 3-c, d] indole -6-on

6. 2- (4- (4-ethyl-piperazin-l-yl) phenyl) -1, 3, 4, 5-tetrahydro-6tf- 5 azepino [5, 4, 3-c, d] -indole- 6-one

7. 2- (4- (2-N, IV-dimethylamino-eth-1-yloxy) phenyl) -1,3,4,5-tetra-hydro-6if-azepino [5,4,3-c, d] -indole-6-one

10 8. 2- (4- (2-pyrrolidinl-yl-eth-l-yloxy) phenyl) -1,3,4,5-tetra-hydro-6ff-azepino [5, 4, 3-c, i.e. ] indole-6-one

9. 2- (4- (2-piperidin-1-yl-eth-1-yloxy) phenyl) -1, 3, 4, 5-tetra-hydro-6H-azepino [5,4, 3-c, d] -indole-6-one 15

10. 2- (4- (2-piperazin-l-yl-eth-l-yloxy) phenyl) -1, 3, 4, 5-tetra-hydro-6H-azepino [5, 4, 3-c, d] -indole-6-one

11. 2- (4- (2- (4-Methyl-piperazin-l-yl) -eth-1-yloxy) phenyl) - 20 1,3,4,5-tetrahydro-6H-azepino [5, 4 , 3-c, d] indole-6-one

12. 2- (4- (2- (4-Propyl-piperazin-l-yl) -eth-1-yloxy) phenyl) - 1,3,4,5-tetrahydro-6H-azepino [5, 4, 3-c, d] indole-6-one

25 13. 2- (4- (2- (4-Ethylpiperazin-l-yl) -eth-1-yloxy) phenyl) - 1,3,4,5-tetrahydro-6if-azepino [5, 4 , 3-c, d] indole-6-one

14. 2- (4- (2- (4-Benzyl-piperazin-1-yl) -eth-1-yloxy) -phenyl) - 1,3,4,5-tetrahydro-6H-azepino [5, 4, 3-c, d] indole-6-one 30

15. 2- (4- (2- (4-Acetamido-piperazin-l-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-Benzamido-piperazin-l-yl) -eth-1-yloxy) phenyl) - 35 1,3, 4,5-tetrahydro-6H-azepino [5.4 , 3-c, d] indole-6-one

17. 2- (4-homopiperazin-l-ylphenyl) -1, 3, 4, 5-tetrahydro-6iϊ-azepino [5, 4, 3-c, d] -indol-6-one

40 18. 2- (4- (4-Methylhomopiperazin-l-yl) phenyl) -1,3,4,5-tetra-hydro-6fl-azepino [5, 4, 3-c, d] -indole- 6-one

19. 2- (4- (4-Benzylhomopiperazin-l-yl) phenyl) -1, 3,4,5-tetrahydro-6H-azepino [5, 4, 3-c, d] -indole-6 -on 45 20. 2- (4- (4-n-butyl-homopiperazin-l-yl) phenyl) -1, 3, 4, 5-tetra-hydro-6H-azepino [5,4, 3-c, d] indole-6-one

21. 2- (4- (4-ethylhomopiperazin-l-yl) phenyl) -1, 3, 4, 5-tetra- 5 hydro-6H-azepino [5,4, 3-c, d] - indole-6-one

22. 2-piperidin-4-yl-l, 3,4, S-tetrahydro-δH-azepino [5, 4, 3-c, d] - indol-6-one

10 23. 2- (l-methyl-piperidin-4-yl) -l, 3,4,5-tetrahydro-6iϊ-azepino- [5, 4, 3-c, d] -indol-6-one

24. 2- (l-n-propyl-piperidin-4-yl) -1, 3, 4, 5-tetrahydro-6ff-azepino-

[5,4, 3-c, d] indol-6-one 15

25. 2- (l-benzyl-piperidin-4-yl) -1, 3, 4, 5-tetrahydro-6.ϊ-azepino-

[5,4, 3-c, d] indol-6-one

26. 2- (1-n-Butyl-piperidin-4-yl) -1,3,4,5-tetrahydro-6if-azepino-20 [5, 4, 3-c, d] -indol-6-one

27. 2- (l-isopropyl-piperidin-4-yl) -1, 3, 4, 5-tetrahydro-6H-azepino- [5,4, 3-c, d] -indol-6-one

25 28. 2- (2- (iV, iV-Dimethylamino) -eth-l-ylamino) -phenyl) -l, 3,4,5-tetrahydro-6iϊ-azepino [5, 4, 3-c, d] indole-6-one

29. 2- (2- (, -V-diethylamino) -eth-1-ylamino) -phenyl) -1, 3, 4, 5-tetra-hydro-6H-azepino [5, 4, 3-c, i.e. ] -indole-6-one

30

30. 2- (2-piperidin-l-yl-eth-l-ylamino) phenyl) -1, 3, 4, 5-tetra-hydro-6iϊ-azepino [5, 4, 3-c, d] - indole-6-one

31. 2- (2-pyrrolidin-l-yl-eth-l-ylamino) phenyl) -1,3,4,5-tetra- 35 hydro-6tf-azepino [5, 4, 3-c, d] indole-6-one

32. 2- (3- (-V, iV-dimethylamino) prop-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5, 4, 3-c, d] indole-6-one

40 33. 2- (3- (iV, iV-diethylamino) -prop-l-ylamino) -phenyl) -l, 3, 4, 5-tetrahydro-6H-azepino [5, 4, 3-c, d] indole-6-one

34. 2- (3-piperidin-l-yl-prop-l-ylamino) phenyl) -1,3,4,5-tetra-hydro-6H-azepino [5, 4, 3-c, d] - indole-6-one

45

35. 2- (3-pyrrolidin-l-yl-prop-l-ylamino) phenyl) -1,3,4,5-tetra-hydro-6H-azepino [5, 4, 3-c, d] - indole-6-one

Claims

claims

1. Compounds of formula I.

wherein

A is a chain C ₁ -C ₃ , where each carbon atom can also carry one or two of the following substituents: C 1 -C ₄ -alkyl, OH, 0-C 1 -C ₄ -alkyl, COOH, C00-Cι-C ₄ - Alkyl and phenyl or a carbon atom can also carry a = 0 group and

X ^{1 can be} S, 0 and NH and

X ^{2 is} a carbon atom that can still carry a chain C ₁ -C ₄ , and N and

X ^{3 can be} N and CR ² , where

R ^{2 is} hydrogen, branched and unbranched Cχ-C ₆ alkyl, C ₁ -C ₄ alkyl phenyl, phenyl and

X ² and X ³ cannot be N at the same time, and

R ^{1 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ -alkyl, OH, nitro, CF ₃ , CN, NR ^ R ¹² , NH-CO-R ¹³ , 0-Cι-C alkyl , where R ¹¹ and R ¹² independently of one another are hydrogen or C 1 -C ₄ -alkyl and R ^{13 is} hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ ~ alkylphenyl or phenyl, and B an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially-unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and

0 to 5 stic atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, each of which is still substituted by one R ⁴ and a maximum of 3 different or identical radicals R ⁵ , and one or two carbon or sulfur atoms also can carry one or two = 0 groups,

R ⁴ - (D) _p - (E) _s - (F ¹ ) _q -G ¹ - (F ² ) _r - (G ² ) -G ³ means, whereby G ¹ , G ² and G ³ do not simultaneously represent hydrogen or can be a bond and if p = s = 0 and q or r = 1 or p, q and r = 0, then two radicals G ¹ , G ² and G ³ cannot simultaneously be a bond or hydrogen, and

DS, NR ⁴³ and O

E phenyl,

^ - _c __ _{0 /} -S0 ₂ - -S0 ₂ NH-, -NHCO-, -CONH-, NHS0 ₂ -,

I -NHCOCH ₂ X ⁴ , and

X ⁴ can mean S, 0 or NH, and

F ^{2 has} the same meaning as F ¹ independently of F ¹ ,

G ^{1 represents} a bond or an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially-unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which are each still substituted with a maximum of 3 different or identical radicals R ⁵ , and one or two carbon or. Sulfur atoms can also carry one or two = 0 groups, and G ² NR ⁴¹ R ⁴² and

or means a bond and

G ^{3 is} an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially-unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 can mean up to 2 oxygen atoms or 0 to 2 sulfur atoms, each of which is still substituted with a maximum of 3 different or identical radicals R ⁵ , and one or two carbon or sulfur atoms can also carry one or two = 0 groups, or Means hydrogen, and

Can mean 0 and 1 and

0 and 1 and

Can be 0 and 1 and

R ^{41 is} hydrogen, Ci-Cg-alkyl, where each carbon atom can carry up to two radicals R ⁶ , phenyl, which can carry a maximum of two radicals R ⁶ , and (CH) _t -K and

R ^{42 is} hydrogen, Ci-Cg-alkyl, -CO-R ⁸ , C0 ₂ -R ⁸ , S0 ₂ NH ₂ , S0 ₂ -R ⁸ , - (C = N) -R ⁸ and - (C = N) - NHR ⁸ and R ^{43 is} hydrogen and -C ~ C ₄ alkyl and

t 1, 2, 3, 4 and

K NR ^{1: L} R ¹² , NR ^{1: L} -C -C ₄ alkylphenyl, pyrrolidine, piperidine, 1,2,5, 6-tetrahydropyridine, morpholine, homopiperidine, piperazine, which is still with an alkyl radical Cχ -Cg-alkyl may be substituted, and homopiperazine, which may also be substituted with an alkyl radical Ci-Cg-alkyl, and

R ^{5 is} hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF ₃ , CN, NRUR ¹² , NH-CO-R ¹³ , -C-C ₄ alkyl-CO-NH-R ¹³ , COR ⁸ , C ₀ -C ₄ -Alkyl-O-CO-R ¹³ , -C-C ₄ -alkyl-phenyl, phenyl, C0 ₂ -Cι-C ₄ -alkyl, and branched and unbranched Ci-Cg-alkyl, 0-Cι-C- Alkyl, C 1 -C ₄ alkyl, each

C atom of the alkyl chains can carry up to two radicals R ⁶ and the alkyl chains can also be unsaturated, and

R ^{6 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched Ci-Cg-alkyl, OH, nitro, CF ₃ , CN, NR ^ R ¹² , NH-CO-R ¹³ , 0 -CC-C ₄ alkyl

R ^{7 is} hydrogen, Ci-Cg-alkyl, phenyl, where the ring can still be substituted with up to two radicals R ⁷¹ , and an amine NR ¹³ -R ¹² or a cyclic saturated amine with 3 to 7 members, which still has one Alkyl radical Ci-Cβ-alkyl can be substituted, and homopiperazine, which can also be substituted with an alkyl radical Ci-Cβ-alkyl, and

R ⁷¹ OH, Ci-Cg-alkyl, 0-Cι-C ₄ alkyl, chlorine, bromine, iodine, fluorine,

CF ₃ , nitro, NH ₂ , and

R ⁸ Ci-Cg-alkyl, CF ₃ , phenyl, -C-C ₄ alkyl phenyl, wherein the

Ring can still be substituted with up to two radicals R ⁸¹ , and

R ⁸¹ OH, -C -C ₆ alkyl, 0 -C -C alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and

R ^{9 is} hydrogen, Ci-Cg-alkyl, Ci-C-alkylphenyl,

C0 ₂ -C ₄ alkyl phenyl, C0 ₂ -C ₄ alkyl, S0 ₂ phenyl, COR ⁸ and phenyl, where the phenyl rings can also be substituted with up to two R ⁹¹ radicals, and R ^{91 can be} OH, Ci-Cg-alkyl, 0-Cι-C alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ ,

2. Compounds of formula I according to claim 1, wherein

A is a C ~ C ₂ chain, which may be substituted, and

X ^{1 represents} 0 and

R ^{1 is} hydrogen.

3. Compounds of formula I according to one of claims 1 or 2, wherein

means.

4. Compounds of formula I according to claim 3, wherein

B phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which can also be substituted by one R ⁴ or a maximum of 2 R ⁵ .

5. Compounds of formula I according to claim 4, wherein

R ⁴ DF ¹ _{0 (} ι-G ² -G ³ with G ³ is hydrogen and

D 0 and NR ⁴³ , where R ^{43 is} hydrogen and -CC ₃ alkyl and

F ¹ C ₂ -C ₄ alkyl.

F ^{1 is} C -C ₄ alkyl.

6. Medicaments containing, in addition to conventional carriers and auxiliaries, compounds of the formula I according to one of claims 1 to 5.

5 7. Use of compounds of general formula I according to one of claims 1 to 5 for the manufacture of medicaments with PARP-inhibiting action.

8. Use of compounds of formula I according to claim 7

10 for the manufacture of medicaments for the treatment of neurodegenerative diseases and neuronal damage.

9. Use according to claim 7 for the treatment of such neurodegenerative diseases and neuronal damage, the

15 caused by ischemia, trauma or mass bleeding.

10. Use according to claim 7 for the treatment of stroke and traumatic brain injury.

11. Use according to claim 7 for the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease.

12. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment or prophylaxis of damage caused by ischemia.

13. Use of compounds of the formula I according to claim 7 for the manufacture of medicaments for the treatment of epilepsy,

30 especially generalized epileptic seizures, such as petit mal and tonic-clonic seizures and partial epileptic seizures, such as temporal lope, and complex partial seizures.

35 14. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of kidney damage after renal ischemia, damage caused by drug therapy, such as during cyclosporia therapy, and for treatment during

40 and after kidney transplants.

15. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of damage to the heart after cardiac ischemia. 45

16. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of micro-infarcts such as, for example, during and after heart valve replacement, aneurysm resections and heart transplants.

17. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of a revasculariation of critical narrowed coronary arteries such as for example in PTCA and bypass operations or critically narrowed peripheral arteries, in particular leg arteries.

18. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of acute myocardial infarction and damage during and after its medicinal or mechanical lysis.

19. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of tumors and their metastasis.

20. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of sepsis of multi-organ failure such as, for example, during septic shock and the "acute respiratory distress synchrome".

21. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of immunological diseases such as inflammation and rheumatic diseases, such as rheumatoid arthritis.

22. Use of compounds of formula I according to claim 7 for the manufacture of medicaments for the treatment of diabetes mellitus.