SK8842001A3 - Azepinoindole derivatives, the production and use thereof - Google Patents

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

Technical field

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 preparation of medicaments.

BACKGROUND OF THE INVENTION

Poly (ADP-ribose) polymerase (PARP) or, as it is also called, poly (ADPribose) synthase (PARS) is a regulatory enzyme found in beech nuclei (K. Ikai et al., J. Histochem. Cytochem. 31). , (1983), 1261-1264). PARP is believed to play a role in DNA repair repair (M. S. Satoh et al., Nature 356 (1992), 356-358). Damage or disruption of the DNA strands activates the enzyme PARP, which, if activated, catalyzes the transfer of ADP-ribose from NAD (S. Shaw, Adv. Radiat. Biol. 11 (1984), 1-69). In this process, nicotinamide is released from NAD. Nicotinamide is converted back to NAD by other enzymes, using the ATP energy carrier. Accordingly, overactivation of PARP could result in unphysiologically high ATP consumption, and in extreme cases this would lead to cell damage and cell death.

It is known that free radicals such as hyperoxide anion, NO, and hydrogen peroxide can lead to DNA damage in cells and thus to activation of PARP. The generation of large amounts of free radicals has been observed in a number of pathophysiological conditions and it is believed that this accumulation of free radicals results in or contributes to the observed damage to cells or organs. These include, for example, ischemic conditions of organs such as stroke, myocardial infarction (C. Thiemermann et al., Proc. Natl. Acad. Sci. USA 94 (1997), 679-683) or ischemia of the kidney, but also reperfusion injury such as occurs, for example, after lysing myocardial infarction (see above: C. Thiemermann et al.). Thus, inhibition of the PARP enzyme may be a means of preventing or reducing this damage, at least in part. Thus, PARP inhibitors could represent a new therapeutic principle in the treatment of a variety of diseases.

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The PARP enzyme affects DNA repair repair and could therefore also play a role in the treatment of cancer, since a higher effective potential against tumor tissues has been observed in combination with cytostatic agents (G. Chen et al. Cancer Chemo. Pharmacol. 22 (1988), 303 ). Non-limiting examples of tumors are leukemia, gliablastomas, lymphomas, melanomas, breast cancers and cervical cancers.

In addition, PARP inhibitors have been found to exert an immunosuppressive effect (D. Weltin et al. Int. J. Immunopharmacol. 17 (1995), 265-271).

PARP has also been implicated 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 may have a beneficial effect on disease progression (H. Krôger 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 meant to include the PARP enzyme isoenzymes described above.

The PARP inhibitor 3-aminobenzamide shows protective effects in a circulatory shock model (S. Cuzzocrea et al., Br. J. Pharmacol. 121 (1997), 1065 1074).

Similarly, there are experimental indications that inhibitors of the enzyme PARP could also be useful as agents for the treatment of diabetes mellitus (V. Burkhart et al., Nature Medicine (1999), 5314-519).

The compounds of the formula I according to the invention have not been described so far and are therefore novel.

International patent document WO 00/420040 discloses azepinoindoles that inhibit the PARP enzyme. In particular, derivatives which carry a phenyl ring at the 2-position, which may be additionally substituted by single substituents, are described as effective.

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9 9 9 9 9 9 9 9 99 ··· ··················

The present invention describes novel azepinoindole derivatives of formula I which are potent PARP inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to substituted azepinoindole derivatives of formula I

in which

A may be a C ₁ -C _3- chain, wherein each carbon atom may additionally carry one to two of the following substituents, such as: C 1 -C 4 -alkyl, OH, O-C 1 -C ₄ -alkyl, COOH, COO-C ₁ -C ₄ -alkyl a group and a phenyl group or a carbon atom may also carry a group = O, and

X ¹ can be S, O or NH, and

X ² can be a carbon atom which can additionally carry a CrC _4- chain, and N, and

X ³ can be N or CR ² where

R ² represents hydrogen may, branched or unbranched: Cr

C 6 -alkyl, C 1 -C ₄ -alkylphenyl, phenyl, and

X ² and X ³ cannot simultaneously denote N, and

R ¹ can be hydrogen, chloro, fluoro, bromo, iodo, branched or unbranched C 1 -C ₆ -alkyl, OH, nitro, CF ₃ , CN,

NR ¹¹ R ¹² , NH-CO-R ¹³ , O-C ₁ -C ₄ -alkyl, wherein R ¹¹ and R ¹² , independently of one another, are hydrogen or C 1 -C ₄ -alkyl, and R ¹³ is hydrogen, CrC _4- alkyl, C 1 -C ₄ -alkylphenyl or phenyl, and

R ⁴ may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing not more than 15 carbon atoms, unsaturated, saturated or partially unsaturated mono- or bicyclic ring containing not more than 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 one radical R ⁴ and at most 3 different or the same radicals R ⁵ , and may carry one or two carbon or sulfur atoms, and also one or two = 0, such as keto, sulfones or sulfoxides, is - (D) _p - ( E) _s - (F ¹ ) qG ¹ - (F ² ) r (G ² ) -G ³ , where G ¹ , G ² and G ³ cannot simultaneously represent hydrogen or a bond aakp = s = Oaq or r = 1 or p , qar = 0, then two residues G ¹ , G ² and G ³ cannot simultaneously represent a bond or hydrogen, and amenate S, NR ⁴³ or O can represent a phenyl group, = C = O, -SO ₂ -, -SO ₂ NH-, -NHCO-, -CONH-, -NHSO ₂ -, -NHCOCH ₂ X ⁴ , and

X ⁴ can be S, O or NH, and

F ¹ may be a linear chain or a branched saturated or unsaturated carbon chain of 1 to 8 carbon atoms, and

F ² , independently of F ¹ , has the same meaning as F ¹ ,

G ¹ represents a bond or may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi-5 or tricyclic ring containing up to 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 not more than 3 different or the same R ⁵ , and may carry one or two carbon or sulfur atoms and one or two groups = 0, and

G ² is NR ⁴¹ R ⁴² or

or a bond, and

G ³ may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 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 a maximum of 3 different or identical R ⁵ radicals, and may carry one or two carbon or sulfur atoms and may also carry one or two groups = 0, or hydrogen, and p can be 0 or 1 and s can be 0 or 1 and q can be 0 or 1 and can be 0 or 1 and

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R ⁴¹ may be hydrogen, C 1 -C ₆ -alkyl, wherein each carbon atom may optionally carry up to two R ⁶ radicals, phenyl which may optionally carry not more than two R ⁶ radicals and (CH ₂ ) _t -K, and

R ⁴² can be hydrogen, C 1 -C 6 -alkyl, -CO-R ⁸ , CO 2 -R ⁸ , SO ₂ NH ₂ , SO ₂ -R ⁸ , - (C = N) -R ^8, and - (C = N ) -NHR ⁸ , a

R ⁴³ can be hydrogen or C 1 -C ₄ -alkyl, whether it is 1, 2, 3 or 4; and

K may be NR ¹¹ R ¹² , NR ¹¹ -C 1 -C ₄ -alkylphenyl, pyrrolidine, piperidine,

1,2,5,6-tetrahydropiperidine, morpholine, homopiperidine, piperazine, which may be additionally substituted with a C 1 -C ₆ -alkyl group, and homopiperazine, which may be additionally substituted with a C 1 -C ₆ -alkyl group, and

R ⁵ can be hydrogen, chloro, fluoro, bromo, iodo, OH, nitro, CF 3, CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , C 1 -C 4 -alkyl-CO-NH-R ¹³ , COR ⁸ , C 0 -C 4 alkyl-OCO-R ^13, a C-C4-alkylphenyl, phenyl, CO2-C1-C4 alkyl group, a branched or unbranched Ci-C ₆ -alkyl, O-C-C ₄ alkyl group, S-C 1 -C ₄ -alkyl, wherein each carbon atom in the alkyl chains may carry up to two R ⁶ radicals and the alkyl chains may also be unsaturated, and

R ⁶ can be hydrogen, chloro, fluoro, bromo, iodo, branched or unbranched C 1 -C ₆ -alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , O-C 1 - C ₄ -alkyl, a

R ⁷ may be hydrogen, C 1 -C ₆ -alkyl, phenyl, wherein the ring may be additionally substituted with up to two R ⁷¹ radicals, and wherein one of the mines NR ¹¹ R ¹² or the cyclic saturated amine contains 3 to 7 members which may be additionally substituted with a C ₁ -C ₆ -alkyl group, and homopiperazine, which may be additionally substituted with a C 1 -C ₆ -alkyl group, and

-7 · ··· ······································ Where the residues R ¹¹ , R ¹² and R ¹³ in K, R ⁵ , R ⁶ and R ⁷ may, independently of each other, represent the same meaning as R ¹ , a

R ⁷¹ can be OH, C 1 -C ₆ -alkyl, O-C 1 -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and

R ⁸ can be C 1 -C 6 -alkyl, CF ₃ , phenyl, C 1 -C ₄ alkylphenyl, wherein the ring can be additionally substituted with up to two R ⁸¹ radicals, and

R ⁸¹ can be OH, C 1 -C ₆ -alkyl, OC-C 1-6 alkyl, chloro, bromo, iodo, fluoro, CF ₃ , nitro, NH ₂ , and

R ⁹ can be hydrogen, C 1 -C 6 -alkyl, C 1 -C ₄ -alkylphenyl, CO ₂ -C ₁ -C ₄ -alkylphenyl, CO ₂ -C ₁ -C ₄ -alkyl, SO ₂ -phenyl, COR ^8, and phenyl, wherein the the phenyl ring may be additionally substituted with up to two R ⁹¹ radicals, and

R ⁹¹ can be OH, C 1 -C ₆ -alkyl, O-C 1 -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF _{3 |} nitro, NH ₂ .

and tautomeric forms thereof, possible enantiomeric and diastereoisomeric forms, and prodrugs thereof.

Preferred compounds of formula I are those in which

A represents a C ₂ chain which may be substituted, and

X ¹ is O,

^R1 is hydrogen.

Preferred compounds of formula I are the above compounds in which

B may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 14 carbon atoms and 0 to 5

-8 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which in each case are additionally substituted by one radical R ⁴ and at most 3 different or the same radical R ⁵ , and may carry one or two atoms carbon or sulfur atoms as well as one or two groups = O.

Particularly preferred residues for B are the following residues

B represents phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which may additionally be substituted by one residue R ⁴ or at most two residues R ⁵ .

Particularly preferred compounds of formula I are those in which

R ⁴ represents ₀ DF ^1, IG ² -G ^3, wherein G ³ is hydrogen, and

D is O or NR ⁴³ wherein R ⁴³ is hydrogen or C 1 -C 6 alkyl,

F ¹ represents a C ₂ -C ₄ -alkyl group.

The compounds of formula I can be used in the form of racemates, enantiomerically pure compounds or diastereoisomers. If enantiomerically pure compounds are desired, these may be obtained, for example, by carrying out the classical resolution of the racemate with the compounds of formula I or intermediates thereof using a suitable optically active base or acid.

The alkyl chains may in each case be branched or unbranched. Unbranched alkyl chains are preferred.

The present invention also includes compounds that are mesomeric or tautomeric to the compounds of Formula I.

The present invention further relates to physiologically acceptable salts of a compound of formula I which can be obtained by converting compounds of formula I using a suitable acid or base. Suitable acids and bases are exemplified in U.S. Pat

Fortschritte der Arzneimittelforschung, 1966, Birkäuser Verlag, Vol. 10, p. 224 -9-

• ·· • ·· • « • · • ·· »· • • · · • ·· • · · • · • · • · • e · e • • • · • • · · • · ·· ·· ··· ·· • e · ·

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 and the like, and sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.

Prodrugs are those compounds that are metabolized in vivo to give compounds of Formula I. Typical prodrugs are phosphates, amino acid carbamates, esters, and others.

The azepinoindole derivatives of formula I of the present invention can be prepared by a variety of methods, as described in WO 00/42040.

The substituted azepinoindole derivatives of formula I included 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 of formula I can be determined using an enzyme assay already known in the literature, the activity measurement being determined as the Ki value. The azepinoindole derivatives of formula 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 formula 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 that are associated with increased activity of these enzymes.

The compounds of formula I may be used for the preparation of medicaments for the treatment of damage following ischemia and for prophylaxis where ischemia of various organs is expected.

Accordingly, the present azepinoindole derivatives of formula (I) may be used for the treatment and prophylaxis of neurodegenerative diseases that occur following ischemia, trauma (craniocerebral trauma), massive bleeding, subarachnoid haemorrhage and stroke, and neurodegenerative diseases, multiple infarction, Alzheimer's disease and

Huntington's disease and epilepsy, especially generalized epileptic

-10 seizures such as minor epileptic seizure and tonic / clonic seizures, and partial epileptic seizures such as epileptic seizures of the temporal lobe, and complex / partial seizures, and further for the treatment and prophylaxis of cardiac damage after myocardial ischemia and renal impairment after renal damage , for example, acute renal insufficiency, acute renal failure, damage caused by drug therapy, such as in the case of cyclosporine therapy, acute failure or damage that occurs during and after kidney transplantation. In addition, the compounds of formula I can be used to treat acute myocardial infarction and damage that occurs during and after its lysis in drug treatment (e.g., using TPA, reteplasia, streptokinase or mechanically with a laser or rotablator) and microinfarctions during and after cardiac replacement. valves, aneurysmal resection and heart transplantation. Similarly, the present azepinoindole derivatives of formula I may also be used to treat revascularization of critically narrowed coronary arteries, for example in PTCA and bypass operations, and critically narrowed peripheral arteries, for example leg arteries. In addition, the azepinoindole derivatives of formula I can be used in the treatment of tumors and their metastases and for the treatment of inflammation and rheumatic diseases such as rheumatoid arthritis as well as the treatment of diabetes mellitus, the treatment of multiorgan failure, for example during septic shock and ARDS (respiratory syndrome). adult deficiency, aduld respirators, distress syndrome, shock lungs).

In addition to the usual pharmaceutical excipients, the pharmaceutical compositions of the present invention contain a therapeutically effective amount of a compound of formula I.

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

In the case of internal use, the preparations are administered in single doses. A single dose of 0.1 to 100 mg per kg body weight is administered.

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The formulations may be administered daily in one or more doses, depending on the nature and severity of the disease.

Depending on the desired route of administration, the pharmaceutical compositions of the present invention contain, in addition to the active compound, conventional excipients and diluents. For topical topical use, 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, petrolatum and lanolin can be used. For internal use, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable.

In addition, antioxidants such as tocopherol and butylated hydroxyanisole as well as butylated hydroxytoluene, flavor enhancers, stabilizers, emulsifiers and lubricants may be present.

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

The pharmaceutical compositions can be administered by a variety of routes of administration, for example, orally, parenterally, such as intravenously by infusion, subcutaneously, intraperitoneally, and topically. Thus, formulations such as tablets, emulsions, infusions and injectable solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.

DETAILED DESCRIPTION OF THE INVENTION

Pharmacological examples

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

A 96 well microtiter plate (Flacon) was coated with histones (type II-AS; SIGMA H7755). For this purpose, the histones were dissolved in carbonate buffer (0.05 M

-12NaHCO ₃ ; pH 9.4) to give a concentration of 50 µg / ml. Individual wells of the microtiter plates were incubated overnight with 100 μΙ histone solution each. Then, the histone solution was removed and individual wells were incubated at room temperature with 200 μΙ of a 1% bovine serum albumin solution (BSA, bovine serum albumin) in carbonate buffer for 2 hours. The wells were then washed three times with wash buffer (0.05% Tween 10 in PBS). For the enzyme reaction, 50 μΙ enzyme reaction solution (5 μΙ reaction buffer (1 M TrisHCl pH 8.0, 100 mM MgCl ₂ , 10 mM DTT). 0.5 μΙ PARP (c = 0.22 pg / μΙ), 4 μΙ of activated DNA (SIGMA D-4522.1 mg / ml in water), 40.5 μΙ H ₂ O) was preincubated with 10 μΙ of inhibitor solution per well for 10 minutes. The enzyme reaction was started by adding 40 μΙ of substrate solution (4 μΙ of reaction buffer (see above), 8 μ N of NAD solution (100 µm in H ₂ O), 28 μ 28 H ₂ O). The reaction time was 20 minutes at room temperature. The reaction was stopped by washing three times with wash buffer (see above). This was followed by incubation for one hour at room temperature with specific anti-poly-ADP-ribose antibody. The antibodies used were anti-poly- (ADP-ribose) 10H monoclonal antibodies (Kawamaitsu).

H. et al. (1984) Monoclonal antibodies to poly (adenosine diphosphate ribose) recognize different structures, Biochem 23, 3771-3777). Monoclonal antibodies were also used.

Antibodies were used at a 1: 5,000 dilution in antibody buffer (1% BSA in PBS; 0.05% Tween 20). Washing three times with wash buffer was followed by incubation for one hour at room temperature with the secondary antibody. Here, anti-mouse-IgG coupled to peroxidase (Boehringer Mannheim) for monoclonal antibody was used and anti-rabbit-IgG coupled to peroxidase (SIGMA A-6154) was used for rabbit antibody, at a dilution of 1: 10,000 in antibody buffer. After washing three times with wash buffer, a color reaction was performed using 100 μΙ / well of color reagent (SIGMA, TMB ready mix, T8540) for approximately 15 minutes at room temperature. The color reaction was stopped with 100 μΙ 2 MH ₂ SO ₄ . The measurement was then performed immediately (450 vs 620 nm; Easy Reader EAR340AT ELISA plate reader, SLT-Lab Instruments, Austria). The IC ₅₀ to be measured,

- 13 means the concentration of inhibitor at which half the maximum change in color concentration occurs.

The following compounds of the present invention can be prepared in analogy to the above procedures:

2- (4- (4-n-propylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c] indol-6-one

2- 2- (4-Piperazin-1-yl-phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one

2- (4- (4-Isopropylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3c, d] indol-6-one

4. 2- (4- (4-Benzylpiperazin-1-yl) phenyl) -1,3 _L 4,5-tetrahydro-6H-azepino [5.4 _L 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-ethyl-piperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c _I, d] indole-6-όη

7. 2- (4- (2-N, N-dimethylaminoet-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indol-6 -one

8. 2- (4- (2-pyrrolidinylet-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, indol-6-one

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

10. 2- (4- (2-piperazin-1-ylet-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3c, d] indol-6-one

11. 2- (4- (2- (4-methylpiperazin-1-yl) et-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino- [5,4,3-c] , d] indol-6-one ··

12. 2- (4- (2- (4-propylpiperazin-1-yl) et-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino- [5,4,3-c] cd] indol-6-one

13. 2- (4- (2- (4-Ethylpiperazin-1-yl) et-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) et-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino- [5,4,3-c cd] indol-6-one

15. 2- (4- (2- (4-acetamidopiperazin-1-yl) et-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6Hazepino [5,4,3-c, d] indol-6-one

16. 2- (4- (2- (4-Benzamidopiperazin-1-yl) et-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6Hazepino [5,4,3-c, d] indol-6-one

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

19. 2- (4- (4-Benzylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3c, d] indol-6-one

20. 2- (4- (4-n-butylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3c, d] indol-6-one

21. 2- (4- (4-ethylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3c, 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-SAS-tetrahydro-1H-azepinol-5-yl-indol-e-one

24. 2- (1-n-Propyl-piperidin-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

27. 2- (1-Isopropyl-piperidin-4-yl) -1-SAS-tetrahydro-1H-azepinoISAS-c. Indol-e-one

28. 2- (2- (N, N-dimethylamino) et-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino- [5,4,3-c, d] indole- 6-one

29. 2- (2- (N, N-diethylamino) eth-1-ylamino) phenyl) -1 _I 3.4 _l 5-tetrahydro-6H-azepino [SAS-c.dJindol-e-one

30. 2- (2-Piperidin-1-ylet-1-ylamino) phenyl) -1-SAS-tetrahydro-1H-azepinofSAS-d-indol-6-one

31. 2- (2-Pyrrolidin-1-ylet-1-ylamino) phenyl) -1SAS-tetrahydro-1H-azepinofSAS- c, d] indol-6-one

32. 2- (3- (N, N-dimethylamino) prop-1-ylamino) phenyl) _-1,3,4-I, 5-tetrahydro-6H-azepino [5,4,3-cd] 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] indole- 6-one

34. 2- (3-Piperidin-1-yl-prop-1-ylamino) -phenyl) -1-SAS-tetrahydro-6H-azepinoISAS- c, d] indol-6-one

35. 2- (3-Pyrrolidin-1-yl-prop-1-ylamino) -phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one

Claims (22)

PATENT CLAIMS • · • · • ·· A compound of formula I wherein: A denotes a C-C ₃ A-chain, wherein each carbon atom can additionally carry one to two of the following substituents are: ClC ₄ alkyl, OH, O-Ci-C ₄ -alkyl, COOH, COO-C1 A C 4 alkyl group and a phenyl group or a carbon atom may also carry the group = O, and X ¹ can be S, O or NH, and X ² can be a carbon atom which can additionally carry a C 1 -C 4 chain, and N, and X ³ can be N or CR ² where R ² represents hydrogen may, branched or unbranched: C 1 -C 6 -alkyl, C 1 -C 4 -alkylphenyl, phenyl, and • X ² and X ³ cannot simultaneously denote N, and R ¹ can be hydrogen, chloro, fluoro, bromo, iodo, branched or unbranched C 1 -C 6 -alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ^12, NH-CO-R ^13, OC _r C ₄ alkyl group, wherein 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 • ·· • · · • ·· • · · · • ·· ·· · · • · · • · · · · · • · • · • · · · • · · ·· ·· • · e ··· ·· • · ·· · · B may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 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 radical R ⁴ and at most 3 different or the same radical R ⁵ , and may carry one or two carbon or sulfur atoms and also one or two groups = 0 R ⁴ represents - (D) p- (E) s- (F ¹ ) q G ¹ - (F ² ) _r - (G ² ) -G ³ , where G ¹ , G ² and G ³ cannot simultaneously represent hydrogen or a bond aakp = s = Oaq or r = 1 or p, qar = O, then two residues G ¹ , G ² and G ³ cannot simultaneously represent a bond or hydrogen, and D may be S, NR ⁴³ or O E can be a phenyl group, = C = O, -SO ₂ -, SO ₂ NH-, -NHCO-, -CONH-, -NHSO ₂ - -NHCOCH ₂ X ⁴ , and X ⁴ can be S, O or NH, and F ¹ may be a linear chain or a branched saturated or unsaturated carbon chain of 1 to 8 carbon atoms, and F ² , independently of F ¹ , has the same meaning as F ¹ , G ¹ represents a bond or may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 nitrogen atoms 2 sulfur atoms which in each case are additionally substituted by at most 3 different or the same -18 by the radicals R ⁵ , and may carry one or two carbon or sulfur atoms and one or two groups = 0, ar · » G ² is NR ⁴¹ R ⁴² or or a bond, and G ³ may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 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 a maximum of 3 different or identical R ⁵ radicals, and may carry one or two carbon or sulfur atoms and may also carry one or two groups = 0, or hydrogen, and p can be 0 or 1a s can be 0 or 1a q can be 0 or 1a r can be 0 or 1a R ⁴¹ may be hydrogen, C 1 -C ₆ -alkyl, wherein each carbon atom may optionally carry up to two R ⁶ radicals, phenyl which may optionally carry not more than two R ⁶ radicals and (CH ₂ ) _t -K, and -19R ⁴² may be hydrogen, C, -C6-alkyl, ^-CO-R8, CO2 ^R8, SO ₂ NH ₂ , SO ₂ -R ⁸ , - (C = N) -R ^8, and - (C = N) -NHR ⁸ , and R ⁴³ can be hydrogen or C 1 -C ₄ -alkyl, whether it is 1, 2, 3 or 4; and K may be NR ¹¹ R ¹² , NR ¹¹ -C ¹ -C ₄ -alkylphenyl, pyrrolidine, piperidine, 1,2,5,6-tetrahydropiperidine, morpholine, homopiperidine, piperazine, which may be additionally substituted with C 1 -C 6 -alkyl, and homopiperazine, which may be additionally substituted with C 1 -C ₆ -alkyl, and R ⁵ can be hydrogen, chloro, fluoro, bromo, iodo, OH, nitro, CF 3, CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , C 1 -C 6 -alkyl-CO-NH-R ¹³ , COR ⁸ , CO -C ₄ -alkylO-CO-R ¹³ , C 1 -C ₄ -alkylphenyl, phenyl, CO ₂ -C 1 -C ₄ alkyl, and branched or unbranched C 1 -C ₆ -alkyl, O-C ₁ -C ₄ -alkyl a group, S-C ₁ -C ₄ -alkyl, wherein each carbon atom in the alkyl chains may carry up to two R ⁶ radicals and the alkyl chains may also be unsaturated, and R ⁶ can be hydrogen, chloro, fluoro, bromo, iodo, branched or unbranched C 1 -C 6 -alkyl, OH, nitro, CF 3 CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , O-C 1 -C 4 -alkyl group, and R ⁷ may be hydrogen, C 1 -C 6 -alkyl, phenyl, wherein the ring may be additionally substituted with up to two R ⁷¹ radicals, and wherein one of the amines NR ¹¹ R ¹² or the cyclic saturated amine contains 3 to 7 members which may be additionally substituted a C 1 -C ₆ -alkyl radical, and homopiperazine, which may be additionally substituted by a C 1 -C ₆ -alkyl radical, and wherein the residues R ¹¹ , R ¹² and R ¹³ in K, R ⁵ , R ⁶ and R ⁷ may, independently of one another, have the same meaning as R ^1, and -20 • · R ⁷¹ R ⁸ r R ⁸¹ * * R ⁹ R ⁹¹ can be OH, C 1 -C 6 -alkyl, O-C ₁ -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and can be C 1 -C ₆ -alkyl, CF ₃ , phenyl C ₁ -C ₄ -alkylphenyl, wherein the ring may be additionally substituted with up to two R ⁸¹ radicals, and may be OH, C 1 -C ₆ -alkyl, O-C 1 -C ₄ -alkyl, chloro, bromo, iodo, fluoro , CF _3, nitro, NH _2, and may be hydrogen, _Cl-C6 alkyl group, a Ci-C ₄ -alkyl-radical, CO _{2 r} C, -C ₄ -alkyl-radical, CO ₂ -C ₁ -C ₄ - alkyl, SO ₂ -phenyl, COR ⁸ and phenyl, wherein the phenyl ring may be additionally substituted with up to two R ⁹¹ radicals, and may be OH, C 1 -C ₆ -alkyl, O-C ₁ -C ₄ -alkyl, chlorine , bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ . and tautomeric forms thereof, possible enantiomeric and diastereoisomeric forms, and prodrugs thereof. A compound of formula I according to claim 1, wherein A represents a C ₂ chain which may be substituted, and X ¹ is O, ^R1 is hydrogen. A compound of formula I according to either of claims 1 and 2, wherein B may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring containing up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms; -21 in each case are additionally substituted by one R ⁴ and at most 3 different or the same R ⁵ , and may carry one or two carbon or sulfur atoms as well as one or two = O groups. A compound of formula I according to claim 3, wherein B represents phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which may additionally be substituted by one residue R ⁴ or at most two residues R ⁵ . A compound of formula I according to claim 4, wherein R ⁴ represents ₀ DF ¹ .mu.g ² -C ^3, wherein G ³ is hydrogen, and D is O or NR ⁴³ wherein R ⁴³ is hydrogen or C 1 -C 3 alkyl, F ¹ represents a C ₂ -C ₄ -alkyl group. Pharmaceutical preparation, characterized in that it contains, in addition to the usual carriers and excipients, the compounds of the formula I according to any one of claims 1 to 6 5th Use of compounds of formula I according to any one of claims 1 to 5 for the preparation of pharmaceutical preparations having a PARP inhibitory effect. _; Use of compounds of formula I according to claim 7 for the preparation of pharmaceutical compositions for the treatment of neurodegenerative diseases and neuronal damage. The use according to claim 7, for the treatment of such neurodegenerative diseases and such neuronal damage that is / is caused by ischemia, trauma or massive bleeding. Use according to claim 7, for the treatment of stroke and craniocerebral trauma. -22 · · 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 ·· ··· ·· ·· · The use of claim 7, for the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease. Use of the compounds of formula I according to claim 7, for the preparation of pharmaceutical preparations for the treatment or prophylaxis of damage caused by ischemia. Use of compounds of formula I according to claim 7, for the preparation of pharmaceutical compositions , preparations for the treatment of epilepsy, in particular generalized epileptic seizures, such as minor epileptic seizure and tonic / clonic seizures, and partial epileptic seizures, such as epileptic temporal lobe seizures, and complex / partial seizures. Use of compounds of formula I according to claim 7, for the preparation of pharmaceutical compositions for the treatment of renal impairment after renal ischemia, damage caused by drug therapy, such as cyclosporine therapy, and for treatment during and after kidney transplantation. Use of compounds of formula I according to claim 7 for the preparation of pharmaceutical compositions for the treatment of cardiac damage following myocardial ischemia. Use of compounds of formula I according to claim 7, for the preparation of pharmaceutical preparations for the treatment of microinfarctions, such as during and after heart valve replacement, aneurysmal resection and heart transplantation. Use of the compounds of formula I according to claim 7, for the preparation of pharmaceutical preparations for treatment during revascularization of critically narrowed coronary arteries, such as in PTCA and bypass operations or critically narrowed ⁷ peripheral arteries, in particular leg arteries. and Use of compounds of formula I according to claim 7 for the preparation of pharmaceutical compositions for the treatment of acute myocardial infarction and injury during and after its medical or mechanical lysis. Use of the compounds of formula I according to claim 7, for the preparation of pharmaceutical preparations for the treatment of tumors and their metastases. -23 · · · 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 Use of compounds of formula I according to claim 7, for the preparation of pharmaceutical compositions for the treatment of multiorgan failure in sepsis, such as septic shock and adult acute respiratory distress syndrome. Use of the compounds of formula I according to claim 7 for the preparation of pharmaceutical compositions for the treatment of immunological diseases such as inflammation and rheumatic diseases such as rheumatoid arthritis. Use of compounds of formula I according to claim 7 for the preparation of pharmaceutical compositions for the treatment of diabetes mellitus.