KR20010087401A - Azepinoindole Derivatives, the Production and Use Thereof - Google Patents

Abstract

The present invention relates to compounds of formula (I) and tautomers thereof, possible enantiomers and diastereomers and prodrugs thereof, their preparation and use.

<Formula I>

In the formula, the sign has the meaning given in the specification.

Description

Azpinoindole Derivatives, the Production and Use Thereof}

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

Poly (ADP-ribose) polymerase (PARP), also called poly (ADP-ribose) synthase (PARS), is a regulatory enzyme found in the cell nucleus (K. Ikai et al., J. Histochem. 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 disruption of the DNA strand is activated to activate the enzyme PARP, which catalyzes the transfer of ADP-ribose from the NAD (S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69). In this process, nicotinamide is released from the NAD. Nicotinamide is converted back to NAD by another enzyme using energy transfer ATP. Thus, overactivation of PARP will result in non-physiological consumption of large amounts of ATP, which in extreme cases leads to cell damage and cell death.

It is known that free radicals such as peroxide anions, NO and hydrogen peroxide can cause DNA damage in cells to activate PARP. The formation of large amounts of free radicals is observed in several pathophysiological symptoms, and the accumulation of these free radicals is believed to cause or contribute to the observed cell or organ damage. Such diseases include, for example, cardiac arrest, myocardial infarction (C. Thiemermann et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 679-683) or ischemic diseases of organs such as kidney ischemia, as well as myocardial myocardium. Reperfusion injury (see C. Thiemermann et al., Supra) that occurs after lysis of infarction. Thus, inhibition of the enzyme PARP may be a means of at least partially preventing or alleviating such damage. Thus, PARP inhibitors may be novel therapeutic applications for treating a variety of diseases.

Since the enzyme PARP affects the repair of DNA damage, it may also play a role in treating cancer diseases since higher action potentials on tumor tissues are observed with cytostatic agents. (G. Chen et al., Cancer Chemo Pharmacol. 1988, 22, 303). Non-limiting examples of tumors are leukemia, glioblastoma, lymphoma, melanoma, breast cancer and neck cancer.

It has also been found that PARP inhibitors can exhibit immunosuppressive action (D. Weltin et al., Int. J. Immunopharmacol. 1995, 17, 265-271).

Similarly, PARP has been associated with immunological diseases or diseases in which the immune system plays an important role, such as rheumatoid arthritis and septic shock, and it has been found that PARP inhibitors may have beneficial effects in the progression of the disease (H. Kroeger 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 the present invention should be understood to mean the isoenzyme of the above PARP enzyme.

PARP inhibitor 3-aminobenzamide also showed a protective effect in the model of circulatory shock (S. Cuzzocrea et al., Br. J. Pharmacol. 1997, 121, 1065-1074). It has also been experimentally shown that inhibitors of the enzyme PARP may be useful as a means for the treatment of diabetes mellitus (V. Burkart et al., Nature Med. 1999, 5, 314-319).

WO 00/42040 describes azepineindoles that inhibit PARP enzymes. Specifically, the document describes derivatives containing a phenyl ring at position 2, in which simple substituents may be further substituted, as active agents.

The compounds of formula (I) according to the invention are novel as they have not been described so far.

In the present invention, novel azepineindole derivatives of formula (I) which are potent PARP inhibitors are described.

The present invention relates to substituted azepineindole derivatives of formula (I) and tautomers thereof, possible enantiomers and diastereomers and prodrugs thereof.

Where

A may each additionally contain one or two C ₁ -C ₄ -alkyl, OH, OC ₁ -C ₄ -alkyl, COOH, COO-C ₁ -C ₄ -alkyl and phenyl or Carbon atoms may also be C ₁ -C ₃ chain, which may contain ═O group,

X ¹ may be S, O or NH,

X ² may be a carbon atom, which may further contain a C ₁ -C ₄ chain, and N,

X ³ may be N or CR ² , wherein R ² may be hydrogen, branched or unbranched C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkylphenyl, phenyl,

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

R ¹ is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C ₁ -C ₆ -alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are independent of each other Is hydrogen or C ₁ -C ₄ -alkyl, NH-CO-R ¹³ , wherein R ¹³ is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylphenyl or phenyl, OC ₁ May be -C ₄ -alkyl,

B is in each case further substituted with up to one R ⁴ and up to three different or identical radicals R ⁵ and comprises one or two carbon or sulfur atoms such as keto groups, sulfones or sulfoxides and also one or two Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings having up to 15 carbon atoms, containing up to 14 carbon atoms, up to 14 carbon atoms, and 0 to 5 nitrogen atoms May be an unsaturated, saturated or partially unsaturated mono-, non- or tricyclic ring having 0 to 2 and 0 to 2 sulfur atoms,

R ⁴ _is- (D) _p- (E) _s- (F ¹ ) _q -G ^1- (F ² ) _r- (G ² ) -G ³ ,

Wherein G ¹ , G ² and G ³ may not be hydrogen or a bond at the same time, and when p = s = 0 and q or r = 1 or p, q and r = 0, G ¹ , G ² and G ³ Two radicals cannot be bonded or hydrogen at the same time,

D may be S, NR ⁴³ (wherein R ⁴³ may be hydrogen or C ₁ -C ₄ -alkyl) or O,

E is phenyl, , -SO _2- , -SO ₂ NH-, -NHCO-, -CONH-, NHSO _2- , -NHCOCH ₂ X ⁴ , wherein X ⁴ may be S, O or NH,

F ¹ may be a straight or branched saturated or unsaturated carbon chain having 1 to 8 carbon atoms,

F ² is the F ¹ independently is as defined as F ^1,

G ¹ is a bond or, in each case, carbon, which may be further substituted with up to three different or identical radicals R ⁵ and may contain one or two carbon or sulfur atoms and one or two ═O groups Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings having up to 15 atoms, up to 14 carbon atoms, and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings,

G ² is NR ⁴¹ R ⁴² or Or a combination,

G ³ in each case is further substituted with up to 3 different or identical radicals R ⁵ and one or two carbon or sulfur atoms may also contain one or two ═O groups, 15 carbon atoms Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings, up to 14 carbon atoms, and 0-5 nitrogen atoms, 0-2 oxygen atoms, or 0-2 sulfur atoms, Saturated or partially unsaturated mono-, non- or tricyclic ring, or hydrogen;

p can be 0 or 1,

s can be 0 or 1,

q can be 0 or 1,

r can be 0 or 1,

R ⁴¹ is hydrogen, C ₁ -C ₆ which may contain in each carbon atom in the two or more radicals R ⁶ or less-phenyl which may further contain an alkyl, a radical R ⁶ of less than 2, and (CH ₂ ) _t -K

R ⁴² is 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 can be ⁸ ,

t can be 1, 2, 3 or 4,

K is NR ¹¹ R ¹² , NR ¹¹ -C ₁ -C ₄ -alkylphenyl, pyrrolidine, piperidine, 1,2,5,6 which may be further substituted with alkyl radicals C ₁ -C ₆ -alkyl Tetrahydropyridine, morpholine, homopiperidine, piperazine, and homopiperazine, which may be further substituted with alkyl radicals C ₁ -C ₆ -alkyl,

R ⁵ may contain hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , each carbon atom of the alkyl chain having up to two radicals R ⁶ . C ₁ -C ₄ -alkyl-CO-NH-R ¹³ , COR ⁸ , C ₀ -C ₄ -alkyl-O-CO-R ¹³ , C ₁ -C ₄ -alkyl, which may be unsaturated and the alkyl chain may also be unsaturated Phenyl, phenyl, CO ₂ -C ₁ -C ₄ -alkyl and branched or unbranched C ₁ -C ₆ -alkyl, OC ₁ -C ₄ -alkyl, SC ₁ -C ₄ -alkyl,

R ⁶ is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C ₁ -C ₆ -alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC _1- May be C ₄ -alkyl,

R ⁷ is hydrogen, C ₁ -C ₆ -alkyl, phenyl in which the ring may be further substituted with up to two radicals R ⁷¹ and one amine NR ¹¹ R ¹² , or an alkyl radical C ₁ -C ₆ -alkyl 3 to 7 membered cyclic saturated amines which may be further substituted, and homopiperazine which may be further substituted by alkyl radicals C ₁ -C ₆ -alkyl,

The radicals R ¹¹ , R ¹² and R ¹³ , R ⁵ , R ⁶ and R ⁷ in K may independently have the same meaning as R ¹ ,

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

R ⁸ may be C ₁ -C ₆ -alkyl, CF ₃ , phenyl in which the ring may be further substituted with up to two radicals R ⁸¹ , C ₁ -C ₄ -alkylphenyl,

R ⁸¹ can be OH, C ₁ -C ₆ -alkyl, OC ₁ -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ ,

R ⁹ is 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 phenyl ring may be further substituted with up to two radicals R ⁹¹ ,

R ⁹¹ may be OH, C ₁ -C ₆ -alkyl, OC ₁ -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ .

Preferred compounds of formula (I) are those in which A is a C ₂ chain which may be substituted, X ¹ is O and R ¹ is hydrogen.

Preferred compounds of formula (I) are those in which in each case B is further substituted with up to one R ⁴ and up to three different or identical radicals R ⁵ and one or two carbon or sulfur atoms and also one or two ═O Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings having up to 15 carbon atoms, up to 14 carbon atoms, and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms, which may contain groups Or a compound which may be an unsaturated, saturated or partially unsaturated mono-, non- or tricyclic ring of 0 to 2 sulfur atoms.

Particularly preferred radicals of B are phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole which may be further substituted with one R ⁴ or up to two R ⁵ , Naphthalene, piperazine, quinoline, pyrazine.

Very particularly preferred compounds of formula I are those wherein R ⁴ is DF ¹ _0,1- G ² -G ³ , wherein G ³ is hydrogen, and D is O or NR ⁴³ , where R ⁴³ is hydrogen or C _1- C ₃ -alkyl) and F ¹ is C ₂ -C ₄ -alkyl.

The compounds of formula (I) can be used as racemates, enantiomerically pure compounds or diastereomers. If enantiomerically pure compounds are desired, they can be obtained, for example, by separating the compound of formula (I) or its intermediate by conventional separation methods using a suitable optically active base or acid.

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

The invention also relates to compounds which are mesomers or tautomers of the compounds of formula (I).

The present invention also relates to the physiologically resistant salts of compound I which can be obtained by converting compound I with a suitable acid or base. Suitable acids and bases are described, for example, in Fortschritte der Arzneimittel forschung, 1966, Birkhaeuser Verlag, Vol. 10, pages 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 and the like, or sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.

Prodrugs are understood to mean those compounds that are metabolized in the body to a compound of formula (I). Typical prodrugs are phosphates, carbamate, esters and the like of amino acids.

Azepineindole derivatives I according to the invention can be prepared in a variety of ways as described in WO 00/42040.

The substituted azepineindole derivative I obtained in the present invention is an enzyme poly (ADP-ribose) polymerase or an inhibitor of PARP (EC 2.4.2.30).

The inhibitory action of substituted azepineindole derivatives I can be determined by activity assays that measure K _i levels using enzyme tests already known in the literature. Azepinoindole derivative I was measured in this manner for the inhibitory action of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30).

Substituted azepineindole derivatives of formula I are also inhibitors of poly (ADP-ribose) polymerase (PARP), also called poly (ADP-ribose) synthase (PARS), which are associated with increased enzyme activity of these enzymes. It can be used for the treatment and prevention of diseases.

The compounds of formula (I) can be used to prepare a medicament for the treatment of injury after ischemia and for the prevention of ischemia of various organs.

Thus, the azepineindole derivatives of formula (I) of the present invention are ischemic, traumatic (traumatic cranial and cerebral trauma), massive bleeding, neurodegenerative diseases that occur after subarachnoid hemorrhage and heart failure, and multiple infarct dementia, Alzheimer's disease, Huntington Neurodegenerative diseases such as diseases and epilepsy, in particular systemic interstitial seizures (eg small seizures and tonic hepatic seizures) and partial interstitial seizures (eg temporal lobes and complex / partial seizures) In addition, damage to the heart after cardiac ischemia and damage to the kidney after renal ischemia, for example, acute renal failure, acute renal failure, or damage occurring during or after renal transplantation caused by medical treatment, such as in the case of cyclosporine treatment It can be used for the treatment and prevention of. In addition, the compounds of formula (I) include acute myocardial infarction and injuries that occur during and after medical lysis (eg, TPA, reteplase, streptokinase, or mechanically using a laser or rotatable), and heart valves. It can be used to treat microinfarctions that occur during or after replacement, aneurysm resection and heart transplantation. The azepineindole derivative I of the invention can also be used for the treatment of very narrowed coronary artery regeneration, eg in the case of PCTA and bypass surgery, and in the case of very narrow peripheral artery, eg leg artery regeneration. . Moreover, azepineindole derivative I is used for the treatment of tumors and metastases thereof, for the treatment of rheumatic diseases and inflammation such as rheumatoid arthritis, and also for the treatment of diabetes mellitus, multi-organ failure, for example septic shock treatment and ARDS (acute respiratory disorder syndrome, Lung shock).

In addition to conventional pharmaceutical excipients, the pharmaceutical preparations according to the invention contain a therapeutically active amount of compound I.

In the case of topical topical preparations such as powders, ointments or sprays, the active compounds may be present in conventional concentrations. The active compound is usually present in an amount of 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.

For internal use, the formulation is administered in a single dose. In individual doses 0.1 to 100 mg per kg body weight is provided. The formulations may be administered one or more times daily, depending on the nature and severity of the disease.

Depending on the mode of administration desired, the pharmaceutical preparations according to the invention contain, in addition to the active compound, conventional vehicles and diluents. For 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, paraffin oil, petrolatum and wool can be used. . For internal use, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable.

Antioxidants such as tocopherol and butylated hydroxyanisole, and butylated hydroxytoluene, fragrance improvers, stabilizers, emulsifiers and lubricants may also be present.

In addition to the active compounds, the substances contained in the preparations and the materials used for preparing the pharmaceutical preparations are toxicologically harmless and compatible with each active compound. Pharmaceutical formulations are prepared in conventional manner, for example by mixing the active compound with other conventional vehicles and diluents.

Pharmaceutical formulations can be administered in a variety of modes of administration, for example oral, parenteral, such as intravenous infusion, subcutaneous, intraperitoneal and topical. Thus, formulations such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.

Pharmacological Example

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

96-well microtiter plates (Flacon) were coated with histone (type II-AS; SIGMA, H-7755). To this end, histones were dissolved at 50 μg / ml concentration in carbonate buffer (0.05 M NaHCO ₃ ; pH 9.4). Each well of the microtiter plate was incubated overnight with 100 μl of each of histone solution. The histone solution was then removed and each well incubated with 200 μl of a 1% concentration of BSA (serum albumin) solution in carbonate buffer for 2 hours at room temperature. The wells were then washed three times with wash buffer (0.05% Tween 10 in PBS). For enzyme reaction, 50 μl of enzyme reaction solution per well (5 μl of reaction buffer (1M Tris HCl pH 8.0, 100 mM MgCl ₂ , 10 mM DTT), 0.5 μl of PARP (c = 0.22 μg / μl), 4 μl Of activated DNA (Sigma D-4522, 1 mg / 1 ml of water), 40.5 μl of H ₂ O) was preincubated with 10 μl of inhibitor solution for 10 minutes. The enzyme reaction was initiated by adding 40 μl of substrate solution (4 μl of reaction buffer (see above), 8 μl of NAD solution (100 μM in H ₂ O), 28 μl of 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). It was then incubated with specific anti-poly-ADP-ribose antibody for 1 hour at room temperature. The antibody used was a monoclonal anti-poly- (ADP-ribose) antibody “10H” (Kawamaitsu H et al. (1984), monoclonal antibodies against poly (adenosine diphosphate ribose) recognize several structures, Biochemistry 23, 3771-3777). Polyclonal antibodies can also be used.

Antibodies were used diluted 1: 5,000 in antibody buffer (1% BSA in PBS; 0.05% Tween 20). After washing three times with wash buffer, it was incubated with secondary antibody for 1 hour at room temperature. Here, anti-mouse IgG coupled with peroxidase for monoclonal antibodies (Boehringer Mannheim) and anti-rabbit IgG coupled with peroxidase for rabbit antibodies (Sigma A-6154) ) Was used in an antibody buffer diluted 1: 10,000 each. After washing three times with wash buffer, the coloring reaction was performed using 100 μl / well of colorant (Sigma, TMB ready-to-use mix, T8540) at room temperature for about 15 minutes. 100 μl of 2M H ₂ SO ₄ was added to stop the coloring reaction. The color was then measured immediately (450 nm vs 620 nm; ELISA "Easy Reader" EAR340AT plate reader, SLT-Lab Instruments, Austria). The IC ₅₀ value of the inhibitor measured is the concentration of the inhibitor at which a half change in maximum color concentration occurs.

The following compounds according to the invention can be prepared analogously to the above process.

1. 2- (4- (4-n-propylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole -6-on

2. 2- (4-piperazin-1-ylphenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

3. 2- (4- (4-isopropylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole- 6-on

4. 2- (4- (4-benzylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole-6 -On

5. 2- (4- (4-n-butylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole -6-on

6. 2- (4- (4-ethylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole-6 -On

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

8. 2- (4- (2-pyrrolidinyleth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole -6-on

9. 2- (4- (2-piperidin-1-yleth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c ind-6-one

10. 2- (4- (2-piperazin-1-yleth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azino [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-azino [5,4 , 3-c, d] indole-6-one

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

13. 2- (4- (2- (4-ethyl-piperazin-1-yl) eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azino [5, 4,3-c, d] indole-6-one

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

15. 2- (4- (2- (4-acetamidopiperazin-1-yl) eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azino [5 , 4,3-c, d] indole-6-one

16. 2- (4- (2- (4-benzamidopiperazin-1-yl) eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azino [5 , 4,3-c, d] indole-6-one

17. 2- (4- Homopiperazin-1-yl-phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

18. 2- (4- (4-methylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole- 6-on

19. 2- (4- (4-benzylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole- 6-on

20. 2- (4- (4-n-butylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] Indole-6-on

21. 2- (4- (4-ethylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole- 6-on

22. 2-piperidin-4-yl-1,3,4,5-tetrahydro-6H-azinino [5,4,3-c, d] indol-6-one

23. 2- (1-Methylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

24. 2- (1-n-propylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

25. 2- (1-benzylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indole-6-one

26. 2- (1-n-butylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

27. 2- (1-Isopropylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

28. 2- (2- (N, N-dimethylamino) eth-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d Indole-6-on

29. 2- (2- (N, N-diethylamino) eth-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

30. 2- (2-piperidin-1-yleth-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] Indole-6-on

31. 2- (2-Pyrrolidin-1-yleth-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] Indole-6-on

32. 2- (3- (N, N-dimethylamino) prop-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

33. 2- (3- (N, N-diethylamino) prop-1-ylamino) phenyl-1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

34. 2- (3-piperidin-1-yl-prop-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azino [5,4,3-c, d] indol-6-one

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

Claims (22)

The compounds of formula (I) or tautomers, possible enantiomers and diastereomers thereof and prodrugs thereof. <Formula I> Where A may each additionally contain one or two C ₁ -C ₄ -alkyl, OH, OC ₁ -C ₄ -alkyl, COOH, COO-C ₁ -C ₄ -alkyl and phenyl or Carbon atoms may also be C ₁ -C ₃ chain, which may contain ═O group, X ¹ may be S, O or NH, X ² may be a carbon atom, which may further contain a C ₁ -C ₄ chain, and N, X ³ may be N or CR ² , wherein R ² may be hydrogen, branched or unbranched C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkylphenyl, phenyl, X ² and X ³ cannot be N at the same time, R ¹ is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C ₁ -C ₆ -alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are independent of each other Is hydrogen or C ₁ -C ₄ -alkyl, NH-CO-R ¹³ , wherein R ¹³ is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylphenyl or phenyl, OC ₁ May be -C ₄ -alkyl, B may in each case be further substituted with one R ⁴ and up to three different or identical radicals R ⁵ and may contain one or two carbon or sulfur atoms and also one or two ═O groups, Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings having up to 15 carbon atoms, up to 14 carbon atoms, and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to sulfur atoms May be a unsaturated, saturated or partially unsaturated mono-, non- or tricyclic ring of 2, R ⁴ _is- (D) _p- (E) _s- (F ¹ ) _q -G ^1- (F ² ) _r- (G ² ) -G ³ , Wherein G ¹ , G ² and G ³ may not be hydrogen or a bond at the same time, and when p = s = 0 and q or r = 1 or p, q and r = 0, G ¹ , G ² and G ³ Two radicals cannot be bonded or hydrogen at the same time, D may be S, NR ⁴³ (wherein R ⁴³ may be hydrogen or C ₁ -C ₄ -alkyl) or O, E is phenyl, , -SO _2- , -SO ₂ NH-, -NHCO-, -CONH-, NHSO _2- , -NHCOCH ₂ X ⁴ , wherein X ⁴ may be S, O or NH, F ¹ may be a straight or branched saturated or unsaturated carbon chain having 1 to 8 carbon atoms, F ² is the F ¹ independently is as defined as F ^1, G ¹ is a bond or, in each case, carbon, which may be further substituted with up to three different or identical radicals R ⁵ and may contain one or two carbon or sulfur atoms and one or two ═O groups Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings having up to 15 atoms, up to 14 carbon atoms, and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings, G ² is NR ⁴¹ R ⁴² or Or a combination, G ³ in each case is further substituted with up to 3 different or identical radicals R ⁵ and one or two carbon or sulfur atoms may also contain one or two ═O groups, 15 carbon atoms Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings, up to 14 carbon atoms, and 0-5 nitrogen atoms, 0-2 oxygen atoms, or 0-2 sulfur atoms, Saturated or partially unsaturated mono-, non- or tricyclic ring, or hydrogen; p can be 0 or 1, s can be 0 or 1, q can be 0 or 1, r can be 0 or 1, R ⁴¹ is hydrogen, C ₁ -C ₆ which may contain in each carbon atom in the two or more radicals R ⁶ or less-phenyl which may further contain an alkyl, a radical R ⁶ of less than 2, and (CH ₂ ) _t -K R ⁴² is 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 can be ⁸ , t can be 1, 2, 3 or 4, K is NR ¹¹ R ¹² , NR ¹¹ -C ₁ -C ₄ -alkylphenyl, pyrrolidine, piperidine, 1,2,5,6 which may be further substituted with alkyl radicals C ₁ -C ₆ -alkyl Tetrahydropyridine, morpholine, homopiperidine, piperazine, and homopiperazine, which may be further substituted with alkyl radicals C ₁ -C ₆ -alkyl, R ⁵ may contain hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , each carbon atom of the alkyl chain having up to two radicals R ⁶ . C ₁ -C ₄ -alkyl-CO-NH-R ¹³ , COR ⁸ , C ₀ -C ₄ -alkyl-O-CO-R ¹³ , C ₁ -C ₄ -alkyl, which may be unsaturated and the alkyl chain may also be unsaturated Phenyl, phenyl, CO ₂ -C ₁ -C ₄ -alkyl and branched or unbranched C ₁ -C ₆ -alkyl, OC ₁ -C ₄ -alkyl, SC ₁ -C ₄ -alkyl, R ⁶ is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C ₁ -C ₆ -alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC _1- May be C ₄ -alkyl, R ⁷ is hydrogen, C ₁ -C ₆ -alkyl, phenyl in which the ring may be further substituted with up to two radicals R ⁷¹ and one amine NR ¹¹ R ¹² , or an alkyl radical C ₁ -C ₆ -alkyl 3 to 7 membered cyclic saturated amines which may be further substituted, and homopiperazines which may be further substituted by alkyl radicals C ₁ -C ₆ -alkyl, The radicals R ¹¹ , R ¹² and R ¹³ , R ⁵ , R ⁶ and R ⁷ in K may independently have the same meaning as R ¹ , R ⁷¹ can be OH, C ₁ -C ₆ -alkyl, OC ₁ -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , R ⁸ may be C ₁ -C ₆ -alkyl, CF ₃ , phenyl in which the ring may be further substituted with up to two radicals R ⁸¹ , C ₁ -C ₄ -alkylphenyl, R ⁸¹ can be OH, C ₁ -C ₆ -alkyl, OC ₁ -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , R ⁹ is 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 phenyl ring may be further substituted with up to two radicals R ⁹¹ , R ⁹¹ may be OH, C ₁ -C ₆ -alkyl, OC ₁ -C ₄ -alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ . The method of claim 1, A is a C ₂ chain which may be substituted, X ¹ is O, A compound of formula I, wherein R ¹ is hydrogen. The process according to claim 1 or 2, wherein B in each case is further substituted with up to one R ⁴ and up to three different or identical radicals R ⁵ and comprises one or two carbon or sulfur atoms and also one or Unsaturated, saturated or partially unsaturated mono-, non- or tricyclic rings of up to 15 carbon atoms, containing up to 2 carbon atoms, up to 14 carbon atoms, and 0 to 5 nitrogen atoms, oxygen atoms A compound of formula (I) which may be an unsaturated, saturated or partially unsaturated mono-, non- or tricyclic ring of 0 to 2 or 0 to 2 sulfur atoms. 4. The compound of claim 3, wherein B is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, which may be further substituted with one R ⁴ or up to two R ⁵ The compound of formula (I) which is oxazole, naphthalene, piperazine, quinoline, pyrazine. The method of claim 4, wherein R ⁴ is DF ¹ _0,1 -G ² -G ³ , wherein G ³ is hydrogen, D is O or NR ⁴³ , wherein R ⁴³ is hydrogen or C ₁ -C ₃ -alkyl, A compound of formula I, wherein F ¹ is C ₂ -C ₄ -alkyl. In addition to the usual carriers and excipients, a medicament comprising the compound of formula (I) according to any one of claims 1 to 5. Use of a compound of formula (I) according to any one of claims 1 to 5 for the manufacture of a medicament having a PARP inhibitory action. Use according to claim 7 for the manufacture of a medicament for the treatment of neurodegenerative diseases and nerve damage. Use according to claim 7, for the treatment of neurodegenerative diseases and nerve damage caused by ischemia, trauma or massive bleeding. Use according to claim 7 for the treatment of heart failure and trauma of the cranial and cerebral bodies. Use according to claim 7, for the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease. Use according to claim 7 for the manufacture of a medicament for the treatment or prevention of injury due to ischemia. The method of claim 7, wherein the preparation of a medicament for the treatment of epilepsy, in particular systemic interstitial seizures (eg small seizures and tonic / clonic seizures) and partial interstitial seizures (eg, temporal lobes and complex / partial seizures) Use for. Use according to claim 7 for the preparation of a medicament for the treatment of renal injury following renal ischemia, for the treatment of damage caused by medicinal therapies such as during cyclosporine treatment, and for the treatment of and during renal transplantation. Use according to claim 7 for the manufacture of a medicament for the treatment of cardiac injury after cardiac ischemia. Use according to claim 7 for the manufacture of a medicament for the treatment of microinfarction, such as during and after heart valve replacement, aneurysm resection and heart transplantation. Use according to claim 7 for the manufacture of a medicament for treatment during angiogenesis of very narrowed coronary arteries such as PTCA and bypass surgery, or angiogenesis of very narrowed peripheral arteries, in particular the leg arteries. Use according to claim 7 for the manufacture of a medicament for the treatment of acute myocardial infarction and damage during and after medical or mechanical lysis. Use according to claim 7, for the manufacture of a medicament for the treatment of tumors and metastases thereof. Use according to claim 7 for the manufacture of a medicament for the treatment of multi-organ dyseptic sepsis, such as septic shock and acute respiratory disorder syndrome. Use according to claim 7 for the manufacture of a medicament for the treatment of rheumatic diseases such as rheumatoid arthritis and immunological diseases such as inflammation. Use according to claim 7 for the manufacture of a medicament for the treatment of diabetes mellitus.