HK1048999A1

HK1048999A1 - Azepinoindole derivatives, their preparation and use thereof

Info

Publication number: HK1048999A1
Application number: HK03101179.8A
Authority: HK
Inventors: W‧卢比施; W‧盧比施; M‧考克; T‧霍格; R‧格兰德尔; R‧穆勒; S‧舒尔特; R‧格蘭德爾; S‧舒爾特
Original assignee: 巴斯福股份公司
Priority date: 1999-09-28
Filing date: 2000-09-15
Publication date: 2003-04-25
Also published as: CZ20012373A3; BR0007174A; CA2352194A1; IL143349A0; BG105650A; NO20012567L; TR200101499T1; WO2001023390A3; HUP0104917A2; WO2001023390A2; KR20010087401A; SK8842001A3; NO20012567D0; HUP0104917A3; AU1271201A; EP1183259A2; JP2003510328A; PL347885A1; CN1374961A

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

Aza  indole derivatives, their preparation and use

The present invention relates to novel aza  indole (azepinoidolone) derivatives, their preparation and use as inhibitors of the enzyme polyadenylic acid ribose polymerase or PARP (EC 2.4.2.30) for the manufacture of medicaments.

Poly (adenosine diphosphate ribose) polymerase (PARP) [ alternatively, it is also known as "poly (adenosine diphosphate ribose) synthase" (PARS) ] is a regulatory enzyme found in the nucleus of the cell [ K.Ikai et al, J.Histochem.Cytochem ], 1983, 31, 1261-1264 ]. PARP is thought to play a role in the repair of DNA breaks [ m.s.satoh et al, Nature, 1992, 356, 356-358 ]. The DNA strand damage or break activates the enzyme PARP, which when activated, catalyzes the transfer of ADP ribose from NAD [ s. shaw, radiobiological evolution (adv. radiat. biol.) ], 1984, 11, 1-69 ]. During this process, nicotinamide is released from the NAD. The energy carrier ATP is applied to convert nicotinamide to NAD again by other enzymes. Therefore, excessive activation of PARP will result in a non-physiological high consumption of ATP and, in extreme cases, cell damage and cell death.

Free radicals (e.g., superoxide anion), NO, and hydrogen peroxide are known to cause DNA damage in cells, thus activating PARP. The formation of a large number of free radicals is observed in some pathophysiological conditions, and it is believed that this accumulation of free radicals causes or contributes to the observed cell or organ damage. This includes, for example, ischemic conditions of organs, such as in stroke, myocardial infarction [ C.Thiemermann et al, Proc. Natl.Acad.Sci.USA), 1997, 94, 679-683 ] or ischemia of the kidney, and also reperfusion injuries, such as those occurring after lysis of myocardial infarction (see above: C.Thiemermann et al). Thus, inhibition of the enzyme PARP should be a way to prevent or at least partially mitigate such damage. Therefore, PARP inhibitors would be a novel therapeutic principle for the treatment of several diseases.

The enzyme PARP affects the repair of DNA damage and therefore also plays a role in the treatment of cancer diseases, since a greater potential for action against tumor tissues is observed in combination with cytostatic active substances [ g.chen et al, cancer chemotherapy and pharmacology (cancer chemo. pharmacol.), 1988, 22, 303 ]. Non-limiting examples of tumors are: leukemia, glioblastoma, lymphoma, melanoma, breast cancer, and neck cancer.

In addition, PARP inhibitors have been found to exhibit immunosuppressive effects [ D.Weltin et al, J.Immunopharmacol, 1995, 17, 265-271 ].

PARP has also been found to be involved in immune disorders or diseases where the immune system plays an important role, such as rheumatoid arthritis and septic shock, and PARP inhibitors can show beneficial effects on the course of the disease [ h.kr * ger et al, Inflammation (Inflammation), 1996, 20, 203-215; ehrlich et al, rheumatology internationally (rheumatol. int.), 1995, 15, 171-172; szabo et al, proceedings of the national academy of sciences USA, 1998, 95, 3867-3872; s. cuzzocrea et al, european journal of pharmacology (eur.j. pharmacol.), 1998, 342, 67-76.

PARP in the meaning of the present invention is also to be understood as meaning isoenzymes of the above-mentioned PARP enzymes.

In addition, the PARP inhibitor 3-aminobenzamide showed protective effects in a model of circulatory shock [ S.Cuzzocrea et al, J.British Pharmacol, 1997, 121, 1065-1074 ].

Similar tests indicate that inhibitors of the enzyme PARP may be useful as agents for the treatment of diabetes [ V.Burkart et al, Nature Med. ], 1999, 5, 314-319 ].

WO00/42040 mentions aza  indoles which inhibit the PARP enzyme. This document describes that derivatives carrying a phenyl ring in the 2-position, which may additionally be substituted by simple substituents, are active.

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

The present invention describes novel aza  indole derivatives of formula I which are potent PARP inhibitors.

The invention relates to substituted aza  indole derivatives of general formula I,wherein A may be C₁～C₃Chains in which each carbon atom may additionally carry one or two of the following substituents: c₁～C₄Alkyl, OH, O-C₁～C₄Alkyl, COOH, COO-C₁～C₄Alkyl and phenyl, or one C atom may also carry an ═ O group, and X¹May be S, O or NH, and X²May be a carbon atom (which may additionally carry a C)₁～C₄Chain) and N, and X³May be N or C-R²Wherein, in the step (A),

R²c which may be hydrogen, branched or unbranched₁～C₆Alkyl radical, C₁～C₄Alkyl phenyl、

Phenyl, and

X²and X³Cannot be both N and R¹Can be hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C₁～C₆Alkyl, OH, nitro, CF₃、CN、NR¹¹R¹²、NH-CO-R¹³、O-C₁～C₄Alkyl radical, wherein R¹¹And R¹²Independently of one another, hydrogen or C₁～C₄Alkyl radical, R¹³Is hydrogen, C₁～C₄Alkyl radical, C₁～C₄Alkylphenyl or phenyl, and B can be unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic having up to 15 carbon atoms, unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic having up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, which are in each case additionally substituted by one R⁴And up to 3 different or identical radicals R⁵Substituted and may carry one or two carbon or sulfur atoms with one or two ═ O groups (e.g. keto, sulfone, or sulfoxide), R⁴Is- (D) p- (E) s- (F)¹)q-G¹-(F²)r-(G²)-G³Wherein G is¹、G²And G³Cannot be simultaneously hydrogen or a bond, and if p ═ s ═ 0 and q or r ═ 1 or p, q and r ═ 0, then G¹、G²And G³Cannot be both a bond or hydrogen, and D can be S, NR⁴³Or OE may be a phenyl group or a phenyl group,、-SO₂-、-SO₂NH-、-NHCO-、-CONH-、NHSO₂-、-NHCOCH₂X⁴and an

X⁴May be S, O or NH, and

F¹may be a linear or branched, saturated or unsaturated carbon chain of 1 to 8C atoms, and

F²not dependent on F¹To have F¹The same meaning of (a) is used,

G¹is a bond or may be unsaturated, saturated having up to 15 carbon atoms

Or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 14 carbon atoms and 0 &

Unsaturated, saturated with 5 nitrogen atoms, 0-2 oxygen atoms and 0-2 sulfur atoms

And or partially unsaturated monocyclic, bicyclic or tricyclic ring systems, which are in each case additionally substituted

Up to 3 different or identical radicals R⁵Substituted and may carry one or two carbons or sulfur

Atoms with one or two ═ O groups, and G²Is NR⁴¹R⁴²OrOr a bond, and G³Can be unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 15 carbon atoms, unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which are in each case additionally substituted by up to 3 different or identical radicals R⁵Substituted, and one or two carbon or sulfur atoms may also carry one or two ═ O groups, or hydrogen, and p may be 0 or 1, and s may be 0 or 1, and q may be 0 or 1, and R⁴¹May be hydrogen, C₁～C₆Alkyl (where each carbon atom may additionally carry up to two

Radical R⁶) Phenyl (which may additionally carry up to two radicals R)⁶) And (CH)₂) t-K, and R⁴²Can be hydrogen or C₁～C₆Alkyl, -CO-R⁸、CO₂-R⁸、SO₂NH₂、SO₂-R⁸、-(C＝N)-R⁸And- (C ═ N) -NHR⁸And R⁴³May be hydrogen or C₁～C₄Alkyl, and t may be 1, 2, 3 or 4, and K may be NR¹¹R¹²、NR¹¹-C₁～C₄Alkylphenyl, pyrrolidine, piperidine, 1, 2, 5, 6-

Tetrahydropyridine, morpholine, homopiperidine, piperazine, which may additionally be present

By alkyl radicals C₁～C₆Alkyl-substituted, and homopiperazines (homopiperazines), which may additionally be substituted

By alkyl radicals C₁～C₆Alkyl substitution, and R⁵Can be hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF₃、CN、NR¹¹R¹²、NH-CO-R¹³、C₁～C₄alkyl-CO-NH-R¹³、COR⁸、C₀～C₄alkyl-O-CO-R¹³、C₁～C₄Alkylphenyl, phenyl, CO₂-C₁～C₄Alkyl, and branched or unbranched C₁～C₆Alkyl, O-C₁～C₄Alkyl, S-C₁～C₄Alkyl, wherein each C atom of the alkyl chain may carry up to two radicals R⁶And the alkyl chain may also be unsaturated, and R⁶Can be hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C₁～C₆Alkyl, OH, nitro, CF₃、CN、NR¹¹R¹²、NH-CO-R¹³、O-C₁～C₄Alkyl radical R⁷May be hydrogen, C₁～C₆Alkyl, phenyl (wherein the ring may additionally be interrupted by up to two radicals R⁷¹Substituted), and one amine NR)¹¹R¹²Or cyclic saturated amines having 3 to 7 segments which may additionally be substituted by alkyl groups C₁～C₆Alkyl-substituted), and homopiperazines (which may additionally be substituted by alkyl groups C)₁～C₆Alkyl-substituted), and wherein, K, R⁵、R⁶And R⁷Radical R in (1)¹¹、R¹²And R¹³Independently of one another may take the form of¹The same meaning, and R⁷¹Can be OH or C₁～C₆Alkyl, O-C₁～C₄Alkyl, chloro, bromo, iodo, fluoro, CF₃Nitro, NH₂And R⁸May be C₁～C₆Alkyl, CF₃Phenyl, C₁～C₄Alkylphenyl, wherein the ring may additionally be substituted by up to two radicals R⁸¹Substituted, and R⁸¹Can be OH or C₁～C₆Alkyl, O-C₁～C₄Alkyl, chloro, bromo, iodo, fluoro, CF₃Nitro, NH₂And R⁹Can be hydrogen or C₁～C₆Alkyl radical, C₁～C₄Alkyl phenyl, CO₂-C₁～C₄Alkyl phenyl, CO₂-C₁～C₄Alkyl, SO₂-phenyl, COR⁸And phenyl, wherein the phenyl ring may additionally be substituted by up to two radicals R⁹¹Substituted, and R⁹¹Can be OH or C₁～C₆Alkyl, O-C₁～C₄Alkyl, chloro, bromo, iodo, fluoro, CF₃Nitro, NH₂As well as their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.

Preferred compounds of formula I are those: wherein A is optionally substituted C₂Chain, and X¹Is O, and R¹Is hydrogen.

Preferred compounds of formula I are those as shown above: wherein B may be an unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 15 carbon atoms, an unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which are in each case additionally substituted by one R⁴And up to 3 different or identical radicals R⁵Substituted, and may carry one or two carbon or sulfur atoms with one or two ═ O groups.

Particularly preferred radicals of B are the following: b is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which may additionally be substituted by one R⁴Or at most 2R⁵And (4) substitution.

Particularly preferred compounds of formula I are those: wherein R is⁴Is D-F¹ _0.1-G²-G³Wherein G is³Is hydrogen, and D is O or NR⁴³Wherein R is⁴³Is hydrogen or C₁～C₃Alkyl, and F¹Is C₂～C₄An alkyl group.

The compounds of formula I can be used as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are desired, they can be obtained by: for example, compounds of formula I or their intermediates are conventionally resolved using an appropriate optically active base or acid.

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

The invention also relates to such compounds: they are meso or tautomers of the compounds of formula I.

The invention further relates to physiologically tolerated salts of compound I, which are obtainable by conversion of compound I with a suitable acid or base. Suitable acids and bases are listed, for example, in Fortschritte der Arzneimitelforkung, 1966, Birkh die Verlag, Vol.10, pp.224-285. Such acids and bases 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.

By "prodrugs" is understood those compounds, i.e. which are metabolized in vivo to compounds of the general formula I. Typical prodrugs are phosphates, carbamates of amino acids, esters and others.

Aza  indole derivatives I of the present invention may be prepared by various methods, for example those described in WO 00/42040.

The substituted aza  indole derivatives I obtained in the present invention are inhibitors of enzymes like poly adenosine diphosphate ribose polymerase or PARP (EC 2.4.2.30).

The inhibition of substituted aza  indole derivatives I can be determined by enzyme assays known in the literature, the activity measure determined being K_iThe value is obtained. The inhibition of the enzyme polyadenylic acid diphosphate ribose polymerase or PARP (EC 2.4.2.30) by the aza  indole derivative I was determined in this way.

Substituted aza  indole derivatives of formula I are inhibitors of poly (adenosine diphosphate ribose) polymerase (PARP) [ alternatively, it is also known as "poly (adenosine diphosphate ribose) synthase" (PARS) ], and are therefore useful in the treatment and prevention of diseases associated with increased enzymatic activity of these enzymes.

The compounds of formula I can be used in the manufacture of medicaments for the treatment of post-ischemic injury and for the prevention of conditions in which ischemia of various organs is expected.

Therefore, substituted aza  indole derivatives of general formula I of the present invention can be used to treat and prevent neurodegenerative diseases of ischemia, trauma (craniocerebral trauma), major hemorrhage, subarachnoid hemorrhage and post-stroke episodes, as well as such neurodegenerative diseases: such as multiinfarct dementia, alzheimer's disease, huntington's disease and epilepsy, especially generalized epileptic seizures (e.g. epileptic seizures and tonic clonic seizures) and focal seizures (e.g. temporal lobe), as well as complex/focal seizures, and may furthermore be used for the treatment and prevention of damage to the heart after cardiac ischemia and damage to the kidney after renal ischemia, for example acute renal insufficiency caused by medical treatment (e.g. in the case of cyclosporin treatment), acute renal failure or damage during and after kidney transplantation. In addition, compounds of formula I may be used for the treatment of: acute myocardial infarction and acute myocardial infarction (for example using TPA, reteplase, streptokinase or laser or the rotor mechanical dissolution) during and after dissolution, and heart valve replacement and replacement after micro-infarction, aneurysm excision and heart transplantation. Likewise, the aza  indole derivatives I of the present invention can be used in the treatment of the following revascularization procedures: severely constricted coronary arteries (e.g., in PCTA and shunts), and severely constricted peripheral arteries (e.g., leg arteries). Furthermore, aza  indole derivatives I are also useful in the treatment of tumors and their metastases, and in the treatment of inflammation and rheumatic diseases (e.g. rheumatoid arthritis), and also in the treatment of diabetes, in the treatment of multiple organ failure (e.g. septic shock) and in the treatment of ARDS (acute respiratory distress syndrome, shocked lung).

The medicament of the invention comprises, in addition to conventional pharmaceutical excipients, a therapeutically active amount of compound I.

For topical application (e.g., as a powder, ointment or spray), the active compound may be present in conventional concentrations. In general, the active compound is present in an amount of 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.

For in vivo administration, the agent is administered in a single dose. In a single dose, 0.1-100 mg/kg body weight is given. The agent may be administered in one or more doses per day, depending on the nature and severity of the disease.

The medicaments of the invention contain, in addition to the active compound, customary carriers and diluents, corresponding to the desired mode of administration. For topical application, pharmaceutical excipients such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol stearate, ethoxylated fatty alcohol, liquid paraffin, petrolatum and lanolin may be used. For in vivo administration, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable.

Antioxidants (e.g., tocopherols and butylated hydroxyanisole and butylated hydroxytoluene), flavor modifying additives, stabilizers, emulsifiers and lubricants may also be present.

The substances contained in the formulations and the substances used for the production of the medicaments, with the exception of the active compounds, are toxicologically benign and compatible with the respective active compound. Medicaments are produced in a conventional manner, for example by mixing the active compounds with other conventional carriers and diluents.

The agents may be administered in a variety of modes of administration, for example, orally, parenterally, e.g., intravenously, by infusion, subcutaneously, intraperitoneally, and topically. Possible formulations are therefore, for example: tablets, emulsions, infusions and injections, pastes, ointments, gels, creams, lotions, powders and sprays.

Pharmacological examples:

inhibition of the enzyme poly (adenosine diphosphate ribose) polymerase or PARP (EC 2.4.2.30)

96-well microtiter plates (Flacon) were coated with histone (type II-AS; SIGMA H7755). For this purpose, the histones were dissolved in carbonate buffer (0.05M NaHCO)₃(ii) a pH 9.4) to give a concentration of 50. mu.g/ml. The wells of the microtiter plate were incubated overnight (each well contained 100. mu.l of the histone solution). The histone solution was then removed and each well was incubated with 200 μ l of 1% concentration BSA (bovine serum albumin) in carbonate buffer for 2 hours at room temperature. Next, the wells were washed three times with wash buffer (0.05% tween 10 in PBS). For the enzyme reaction, 50. mu.l of the enzyme reaction solution [ 5. mu.l of reaction buffer (1M tris HCl pH 8.0, 100mm MgCl.) was added to each well₂10mM DTT), 0.5 μ l PARP (c ═ 0.22 μ g/μ l), 4 μ l activated DNA (SIGMA D-4522, 1mg/ml in water), 40.5 μ l H₂O]Preincubation with 10. mu.l inhibitor solution for 10 min. By adding 40. mu.l substrate solution [ 4. mu.l reaction buffer (see above), 8. mu.l NAD solution (100. mu.M in H)₂O in), 28 μ l H₂O]The reaction is initiated. The reaction time was 20 minutes at room temperature. The reaction was stopped by washing three times with wash buffer (see above). Then keeping the temperature with a specific anti-poly-adenosine diphosphate ribose antibody at room temperatureAnd (4) hours. The antibody used was a monoclonal anti-polyadenylation antibody "10H" [ Kawamaitsu H et al, (1984), "different structures are recognized by monoclonal antibodies to polyadenylation". Biochemistry (Biochemistry)23, 3771-3777]. Polyclonal antibodies may also be used.

The antibody used was a 1: 5000 dilution diluted with antibody buffer (1% BSA in PBS; 0.05% Tween 20). After three washes with wash buffer, it was then incubated with the secondary antibody for one hour at room temperature. Here, for monoclonal antibodies, use was made of anti-rabbit IgG coupled to peroxidase (Boehringer Mannheim) and for rabbit antibodies, use was made of anti-rabbit IgG coupled to peroxidase (SIGMA A-6154), the antibodies used being diluted 1: 10000 in each case with antibody buffer. After three washes with wash buffer, the chromogenic reaction was performed, i.e., using 100. mu.l/well chromogenic reagent (SIGMA, TMB Ready mix, T8540) at room temperature for about 15 min. By adding 100. mu.l of 2M H₂SO₄The color reaction was stopped. The color was then measured immediately (450nm to 620 nm; ELISA "Easy Reader" EAR340AT plate Reader, SLT-Labinstraments, Austria). The IC50 value of the inhibitor to be measured is the inhibitor concentration at which half of the maximum color concentration change occurs.

The following compounds of the invention can be prepared by methods analogous to those described above: 1.2- [4- (4-n-propylpiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 2.2- (4-piperazin-1-ylphenyl) -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 3.2- [4- (4-isopropylpiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 4.2- [4- (4-benzylpiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 5.2- [4- (4-N-butylpiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 6.2- [4- (4-ethylpiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 7.2- [4- (2-N, N-dimethylaminoethyl-1-yloxy) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza  [5 ], 4, 3-c, d ] indol-6-one 8.2- [4- (2-pyrrolidinyl-1-yloxy) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 9.2- [4- (2-piperidin-1-ylethyl-1-yloxy) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 10.2- [4- (2-piperazin-1-ylethyl-1-yloxy) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza

 [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-l-en

-6H-aza  [5, 4, 3-c, d ] indol-6-one 12.2- {4- [2- (4-propylpiperazin-1-yl) eth-1-yloxy ] phenyl } -1, 3, 4, 5-tetrahydro-l

-6H-aza  [5, 4, 3-c, d ] indol-6-one 13.2- {4- [2- (4-ethylpiperazin-1-yl) eth-1-yloxy ] phenyl } -1, 3, 4, 5-tetrahydro-l

-6H-aza  [5, 4, 3-c, d ] indol-6-one 14.2- {4- [2- (4-benzylpiperazin-1-yl) eth-1-yloxy ] phenyl } -1, 3, 4, 5-tetrahydro-l

-6H-aza  [5, 4, 3-c, d ] indol-6-one 15.2- {4- [2- (4-acetamidopiperazin-1-yl) eth-1-yloxy ] phenyl } -1, 3, 4, 5-

tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 16.2- {4- [2- (4-benzoylaminopiperazin-1-yl) eth-1-yloxy ] benzene

Yl } -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 17.2- (4-homopiperazin-1-ylphenyl) -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ]

Indol-6-one 18.2- [4- (4-methylpiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 19.2- [4- (4-benzylhomopiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 20.2- [4- (4-n-butyl homopiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 21.2- [4- (4-ethylpiperazin-1-yl) phenyl ] -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 22.2-piperidin-4-yl-1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indol-6-one 23.2- (1-methylpiperidin-4-yl) -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indole

Do-6-one 24.2- (1-n-propylpiperidin-4-yl) -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ]

Indol-6-one 25.2- (1-benzylpiperidin-4-yl) -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ] indole

Do-6-one 26.2- (1-n-butylpiperidin-4-yl) -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ]

Indol-6-one 27.2- (1-isopropylpiperidin-4-yl) -1, 3, 4, 5-tetrahydro-6H-aza  [5, 4, 3-c, d ]

Indol-6-one 28.2- (2- (N, N-dimethylamino) eth-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-nitrogen

Hetero  [5, 4, 3-c, d ] indol-6-one 29.2- (2- (N, N-diethylamino) eth-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-nitrogen

Hetero  [5, 4, 3-c, d ] indol-6-one 30.2- (2-piperidin-1-ylethyl-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 31.2- (2-pyrrolidin-1-ylethyl-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 32.2- (3- (N, N-dimethylamino) propan-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-nitrogen

Hetero  [5, 4, 3-c, d ] indol-6-one 33.2- (3- (N, N-diethylamino) propan-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-nitrogen

Hetero  [5, 4, 3-c, d ] indol-6-one 34.2- (3-piperidin-1-yl-prop-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-aza 

[5, 4, 3-c, d ] indol-6-one 35.2- (3-pyrrolidin-1-yl-prop-1-ylamino) phenyl) -1, 3, 4, 5-tetrahydro-6H-aza

 [5, 4, 3-c, d ] indol-6-ones

Claims

1. A compound of the formula I,

wherein A may be C₁～C₃Chains in which each carbon atom may additionally carry one or two of the following substituents: c₁～C₄Alkyl, OH, O-C₁～C₄Alkyl, COOH, COO-C₁～C₄Alkyl and phenyl, or one C atom may also carry an ═ O group, and X¹May be S, O or NH, and X²It may be a carbon atom or a mixture thereof,it may additionally carry a C₁～C₄Chain, and N, and X³May be N or C-R²Wherein, in the step (A),

R²c which may be hydrogen, branched or unbranched₁～C₆Alkyl radical, C₁～C₄An alkyl phenyl group,

Phenyl, and

X²and X³Cannot be both N and R¹Can be hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C₁～C₆Alkyl, OH, nitro, CF₃、CN、NR¹¹R¹²、NH-CO-R¹³、O-C₁～C₄Alkyl radical, wherein R¹¹And R¹²Independently of one another, hydrogen or C₁～C₄Alkyl radical, and R¹³Is hydrogen, C₁～C₄Alkyl radical, C₁～C₄Alkylphenyl or phenyl, and B can be unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic having up to 15 carbon atoms, unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic having up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, which are in each case additionally substituted by one R⁴And up to 3 different or identical radicals R⁵Substituted and may carry one or two carbon or sulfur atoms and one or two ═ O groups, R⁴Is- (D) p- (E) s- (F)¹)q-G¹-(F²)r-(G²)-G³Wherein G is¹、G²And G³Cannot be simultaneously hydrogen or a bond, and if p ═ s ═ 0 and q or r ═ 1 or p, q and r ═ 0, then G¹、G²And G³Cannot be both a bond or hydrogen, and D can be S, NR⁴³Or OE may be a phenyl group or a phenyl group,-SO₂-、-SO₂NH-、-NHCO-、-CONH-、NHSO₂-、-NHCOCH₂X⁴and X⁴May be S, O or NH, and F¹Can be 1-8 original CLinear or branched, saturated or unsaturated carbon chains of subunits, and F²Not dependent on F¹To have F¹Same meaning of (A), G¹Is a bond or may be unsaturated, saturated having up to 15 carbon atoms

Atoms with one or two ═ O groups, and G²Is NR⁴¹R¹²OrOr a bond, and G³May be unsaturated, saturated or partially unsaturated having up to 15 carbon atoms

Having up to 14 carbon atoms and 0 to 5 nitrogen atoms,

Unsaturated, saturated or partially non-saturated with 0 to 2 oxygen atoms or 0 to 2 sulfur atoms

Saturated monocyclic, bicyclic or tricyclic ring, which in each case are additionally up to 3 different

Or the same radicals R⁵Substituted, and one or two carbon or sulfur atoms may also carry one or more

Two ═ O groups, or hydrogen, and p can be 0 or 1, and s can be 0 or 1, and q can be 0 or 1, and R⁴¹May be hydrogen, C₁～C₆Alkyl radicals in which each carbon atom may additionally bear up to two

Radical R⁶And, in addition, may carry up to two radicals R⁶Phenyl group of (a), (b) and (CH)₂) t-K, and R⁴²Can be hydrogen or C₁～C₆Alkyl, -CO-R⁸、CO₂-R⁸、SO₂NH₂、SO₂-R⁸、-(C＝N)-R⁸And- (C ═ N) -NHR⁸And R⁴³May be hydrogen or C₁～C₄Alkyl, and t may be 1, 2, 3 or 4, and K may be NR¹¹R¹²、NR¹¹-C₁～C₄Alkylphenyl, pyrrolidine, piperidine, 1, 2, 5, 6-

Tetrahydropyridines, morpholines, homopiperidines, piperazines, which may additionally be substituted by alkyl groups C₁～C₆Alkyl radical

Substituted, and homopiperazines, which may additionally be substituted by alkyl radicals C₁～C₆Alkyl substitution, and R⁵Can be hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF₃、CN、NR¹¹R¹²、NH-CO-R¹³、C₁～C₄alkyl-CO-NH-R¹³、COR⁸、C₀～C₄alkyl-O-CO-R¹³、C₁～C₄Alkylphenyl, phenyl, CO₂-C₁～C₄Alkyl, and branched or unbranched C₁～C₆Alkyl, O-C₁～C₄Alkyl, S-C₁～C₄Alkyl, wherein each C atom of the alkyl chain may carry up to two radicals R⁶And the alkyl chain may also be unsaturated, and R⁶Can be hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C₁～C₆Alkyl, OH, nitro, CF₃、CN、NR¹¹R¹²、NH-CO-R¹³、O-C₁～C₄Alkyl radical R⁷May be hydrogen, C₁～C₆Alkyl, phenyl, wherein the ring may additionally be substituted by up to two radicals R⁷¹Substituted, and one amine NR¹¹R¹²Or cyclic saturated amines having 3 to 7 segments which may additionally be substituted by alkyl groups C₁～C₆Alkyl-substituted, and homopiperazines, which may additionally be substituted by alkyl groups C₁～C₆Alkyl substitution, and wherein, K, R⁵、R⁶And R⁷Radical R in (1)¹¹、R¹²And R¹³Independently of one another may take the form of¹The same meaning is given to the same person,and R⁷¹Can be OH or C₁～C₆Alkyl, O-C₁～C₄Alkyl, chloro, bromo, iodo, fluoro, CF₃Nitro, NH₂And R⁸May be C₁～C₆Alkyl, CF₃Phenyl, C₁～C₄Alkylphenyl, wherein the ring may additionally be substituted by up to two radicals R⁸¹Substituted, and R⁸¹Can be OH or C₁～C₆Alkyl, O-C₁～C₄Alkyl, chloro, bromo, iodo, fluoro, CF₃Nitro, NH₂And R⁹Can be hydrogen or C₁～C₆Alkyl radical, C₁～C₄Alkyl phenyl, CO₂-C₁～C₄Alkyl phenyl, CO₂-C₁～C₄Alkyl, SO₂-phenyl, COR⁸And phenyl, wherein the phenyl ring may additionally be substituted by up to two radicals R⁹¹Substituted, and R⁹¹Can be OH or C₁～C₆Alkyl, O-C₁～C₄Alkyl, chloro, bromo, iodo, fluoro, CF₃Nitro, NH₂Or its tautomeric forms, possible enantiomeric and diastereomeric forms, and prodrugs thereof.

2. The compound of claim 1, wherein A is optionally substituted C₂Chain, and X¹Is O, and R¹Is hydrogen.

3. A compound of the formula I as claimed in either of claims 1 and 2, in which B may be unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 15 carbon atoms, unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms, which are in each case additionally substituted by one R⁴And up to 3 different or identical radicals R⁵Substituted, and may carry one or two carbon or sulfur atoms with one or two ═ O groups.

4. A compound of formula I according to claim 3, wherein B is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which may additionally be substituted by one R⁴Or at most 2R⁵And (4) substitution.

5. A compound of formula I in accordance with claim 4, wherein R⁴Is D-F¹ _0.1-G²-G³Wherein G is³Is hydrogen, and D is O or NR⁴³Wherein R is⁴³Is hydrogen or C₁～C₃Alkyl, and F¹Is C₂～C₄An alkyl group.

6. A medicament comprising a compound of formula I according to one of claims 1 to 5 in addition to conventional carriers and excipients.

7. Use of a compound of general formula I according to any one of claims 1 to 5 for the manufacture of a medicament having PARP inhibitory effect.

8. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of neurodegenerative diseases and neuronal damage.

9. The use according to claim 7 for the treatment of neurodegenerative diseases and neuronal damage caused by ischemia, trauma or major hemorrhage.

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

11. The use according to claim 7 for the treatment of alzheimer's disease, parkinson's disease and huntington's disease.

12. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment or prevention of ischemia-induced damage.

13. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of: epilepsy, especially generalized epileptic seizures, such as petit mal seizures and tonic/clonic seizures and partial seizures, such as temporal lobes, as well as complex/partial seizures.

14. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of: renal injury following renal ischemia, injury caused by medical therapy, such as in the case of cyclosporin therapy, and treatment during or after renal transplantation.

15. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of damage to the heart following cardiac ischemia.

16. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of: micro-infarctions, such as those produced during and after replacement of a heart valve, removal of aneurysms and heart transplantation.

17. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment in the following processes: revascularization of severely constricted coronary arteries, such as in PTCA and bypass, or of severely constricted peripheral arteries, especially the leg arteries.

18. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of: acute myocardial infarction and its medical dissolution or mechanical dissolution process or dissolution after injury.

19. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of tumors and their metastases.

20. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of: multiple organ failure sepsis, such as during septic shock, and acute respiratory distress syndrome.

21. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of: immunological disorders, such as inflammation, and rheumatic disorders, such as rheumatoid arthritis.

22. The use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of diabetes.