Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/06—Peri-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
  • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to novel azepinoindole derivatives, their preparation and their use as inhibitors of the enzyme poly (ADP-ribose) poly erase or PARP (EC 2.4.2.30) for the production of medicaments.
• ADP-ribose enzyme poly
• PARP EC 2.4.2.30
• PARP Poly (ADP-ribose) polymerase
• PARS poly (ADP-ribose) synthase
• PARP is believed to play a role in repairing DNA breaks (M.S. Satoh et al., Nature 1992, 356, 356-358). Damage or breakage of the DNA strands activate the enzyme PARP, which, when activated, catalyzes the transfer of ADP-ribose from NAD (S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69).
• Nicotinamide is converted back into NAD by other enzymes using the energy source ATP. Overactivation of PARP would accordingly result in an unphysiologically high consumption of ATP and in extreme cases this leads to cell damage and cell death.
• radicals such as superoxide anion, NO and hydrogen peroxide can lead to DNA damage in cells and thus activate PARP.
• the formation of large amounts of radicals is observed in a number of pathophysiological conditions and it is assumed that this accumulation of radicals leads to or contribute to the observed damage to the cells or organs.
• ischemic conditions of organs such as in stroke, heart attack (C. Thiemermann et al., Proc. Natl. Acad. Sei. USA, 1997, 94, 679-683) or ischemia of the kidneys, but also reperfusion damage such as this for example, after lysis of a heart attack (see above: C. Thiemermann et al.).
• Inhibition of the PARP enzyme could therefore be a means to at least partially prevent or mitigate this damage.
• PARP inhibitors could thus represent a new therapeutic principle for the treatment of a number of diseases.
• the enzyme PARP influences the repair of DNA damage and could therefore also play a role in the therapy of cancer diseases, since in combination with cytostatically active substances a higher activity potential against tumor tissue was observed (G. Chen et al. Cancer Chemo. Pharmacol 1988, 22, 303).
• tumors are leukemia, glioblassomas, lymphomas, melanomas, mom and cervical cancers.
• PARP is involved in immunological diseases or diseases in which the immune system plays an important role, such as rheumatoid arthritis and septic shock, and that PARP inhibitors can have a favorable effect on the course of the disease (H Kroger et al. Infammation 1996, 20, 203-215; W. Ehrlich et al. Reumatol. Int. 1995, 15, 171-172; C. Szabo et al., Proc. Natl. Acad. Sei. USA 1998, 95, 3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol. 1998, 342, 67-76).
• PARP in the sense of this invention is also understood to mean isoenzymes of the PARP enzyme described above.
• WO 00/42040 lists azepinoindoles which inhibit the PARP enzyme.
• there derivatives are described as effective which carry a phenyl ring in the 2-position which can still be substituted with simple substituents.
• new azepinoindole derivatives of the general formula I are described, which are potent PARP inhibitors.
• the present invention relates to substituted azepinoindole derivatives of the general formula I.
• X 1 can be S, 0 and NH and
• X 2 is a carbon atom that can still carry a chain C 1 -C 4 , and N and
• X 3 can be N and CR 2 , where
• R 2 is hydrogen, branched and unbranched Ci-C ⁇ -alkyl, -C-C 4 alkylphenyl, phenyl and
• R 1 is hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C 1 -C 6 -alkyl, OH, nitro, CF 3 , CN, NR 1: 1 R 12 ,
• NH-CO-R 13 0-C ⁇ -C 4 alkyl, where R 11 and R 12 independently of one another are hydrogen or C 1 -C 4 -alkyl and R 13 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 - Alkyl-phenyl or phenyl mean, and
• X 4 can mean S, 0 or NH
• F 1 can be a straight-chain or branched saturated or unsaturated carbon chain of 1 to 8 carbon atoms and
• F 2 has the same meaning as F 1 independently of F 1 ,
• G 3 is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, an unsaturated, saturated or partially-unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms ,
• p can mean 0 and 1 and
• q can be 0 and 1 and
• r can be 0 and 1 and
• R 41 is hydrogen, Ci-Cg-alkyl, where each carbon atom can still carry up to two radicals R 6 , phenyl, which can still carry a maximum of two radicals R 6 , and (CH 2 ) t -K and
• R 43 is hydrogen and -C 4 alkyl
• R 5 hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF 3 , CN, NR ll R l2 , NH-CO-R 13 , C ⁇ -C-alkyl-CO-NH-R 13 , COR 8 , Co -C -alkyl-0-CO-R 13 , -C-C -alkyl-phenyl, phenyl,
• Ci-C ⁇ -alkyl C0 2 -C 4 -alkyl, and branched and unbranched Ci-C ⁇ -alkyl, 0-C ⁇ -C 4 alkyl, S-C ⁇ -C alkyl, each carbon atom of the alkyl chains having up to two radicals R 6 can wear and the alkyl chains can also be unsaturated, and R 6 hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched Ci-C ⁇ -alkyl, OH, nitro, CF 3 , CN, NR 1: L R 1 , NH-CO-R 13 , 0-C ⁇ -C - alkyl
• R 7 is hydrogen, Ci-Cg-alkyl, phenyl, where the ring can still be substituted with up to two radicals R 71 , and an amine NR ⁇ R 12 or a cyclic saturated amine with 3 to 7 members, still with an alkyl -Ri Ci-Cg-alkyl may be substituted, and homopiperazine, which may also be substituted with an alkyl radical Ci-C ß- alkyl, and
• R 11 , R 12 and R 13 in K, R 5 , R 6 and R 7 can independently assume the same meaning as R 1 , and
• R 7 ⁇ OH, C ! -C 6 alkyl, 0-C ⁇ -C 4 alkyl, chlorine, bromine, iodine, fluorine, CF 3 , nitro, NH 2 , and
• R 8 Ci-C ⁇ - alkyl, CF 3 , phenyl, -CC 4 -alkyl-phenyl, where the ring can be substituted with up to two radicals R 81 , and
• R 81 OH, Cx-Cg-alkyl, 0-C ⁇ -C 4 alkyl, chlorine, bromine, iodine, fluorine, CF 3 , nitro, NH 2 , and
• R 9 are hydrogen, C 6 alkyl, C 1 -C 4 alkyl, phenyl, C0 2 -C ⁇ -C alkyl, phenyl, C0 2 -C ⁇ -C 4 alkyl, S0 2 -phenyl, COR 8 and Phenyl, where the phenyl rings can also be substituted with up to two radicals R 91 , and
• R 91 can be OH, -C 6 alkyl, 0 -C 4 alkyl, chlorine, bromine, iodine, fluorine, CF 3 , nitro, NH 2 ,
• A is a C ⁇ -C 2 chain, which may be substituted
• X 1 represents 0
• R 1 is hydrogen.
• R 4 DF 1 o, ⁇ -G 2 -G 3 with G 3 is hydrogen and
• the compounds of the formula I can be used as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are desired, these can be obtained, for example, by carrying out a classic resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid.
• Alkyl chains can each be branched or unbranched. Unbranched alkyl chains are preferred.
• the invention also relates to compounds of the formula I which are mesomeric or tautomeric.
• the invention further relates to the physiologically tolerable salts of the compounds I, which can be obtained by reacting compounds I with a suitable acid or base.
• suitable acids and bases are listed, for example, in Progress in Pharmaceutical Research, 1966, Birkhäuser Verlag, Vol. 10, pp. 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid etc. or sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.
• Prodrugs are understood to mean those compounds which are metrabolized in vivo into compounds of the general formula I. Typical prodrugs are phosphates, carbamates of amino acids, esters and others.
• azepinoindole derivatives I according to the invention can be prepared in various ways, e.g. described in WO 00/42040.
• the substituted azepinoindole derivatives I contained in the present invention are inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30).
• the inhibitory effect of the substituted azepinoindole derivatives I can be determined using an enzyme test already known in the literature, a Ki value being determined as the yardstick.
• the azepinoindole derivatives I were measured in this way for the inhibitory effect of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.30).
• substituted azepinoindole derivatives of the general formulas I are inhibitors of poly (ADP-ribose) polymerase (PARP) or, as it is also called, poly (ADP-ribose) synthase (PARS), and can therefore be used for the treatment and prophylaxis of diseases, which are associated with an increased enzyme activity of these enzymes serve.
• PARP poly (ADP-ribose) polymerase
• PARS poly (ADP-ribose) synthase
• the compounds of the formulas I can be used for the production of medicaments for the treatment of damage after ischemia and for prophylaxis in the case of expected ischemia of various organs.
• the present azepinoindole derivatives of the general formula I can then be used for the treatment and prophylaxis of neurodegenerative diseases following ischemia, trauma (craniocerebral trauma), mass bleeding, subarachnoid bleeding and stroke occur, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease, Huntington's disease and epilepsy, in particular of generalized epileptic seizures such as petit mal and tonic-clonic seizures and partially epileptic seizures such as temporal lope and complex-partial Seizures, and further for the treatment and prophylaxis of damage to the heart after cardiac ischemia and damage to the kidneys after renal ischemia, for example acute renal insufficiency, caused by drug therapies such as cyclosporin treatment, the acute
• Kidney failure or damage that occurs during and after a kidney transplant can be used for the treatment of acute myocardial infarction and damage which occurs during and after its drug lysis (for example with TPA, reteplase, streptokinase or mechanically with a laser or rotablator) and of micro-infarcts during and after heart valve replacement, aneurysm resections and serve heart transplants.
• the present azepinoindole derivatives I can also be used to treat a revascularization of critically narrowed coronary arteries, for example in PCTA and bypass operations, and critically narrowed peripheral arteries, for example leg arteries.
• azepinoindole derivatives I can be useful for the treatment of tumors and their metastasis and for the treatment of inflammation and rheumatic diseases such as e.g. rheumatoid arthritis and also for the treatment of diabetes mellitus, for the treatment of multi-organ failure e.g. in septic shock and for the treatment of ARDS (acute respiratory distress syndrome shock lung).
• rheumatic diseases such as e.g. rheumatoid arthritis and also for the treatment of diabetes mellitus
• multi-organ failure e.g. in septic shock and for the treatment of ARDS (acute respiratory distress syndrome shock lung).
• the pharmaceutical preparations according to the invention contain a therapeutically effective amount of the compounds I.
• the active compounds can be present in the usual concentrations.
• the active substances are contained in an amount of 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.
• the preparations are administered in single doses. 0.1 to 100 mg per kg body weight are given in a single dose.
• the preparation can be administered daily in one or more doses depending on the type and severity of the diseases.
• the pharmaceutical preparations according to the invention contain the usual carriers and diluents in addition to the active ingredient.
• pharmaceutical-technical auxiliaries such as ethanol, isopropanol, oxyethylated castor oil, oxyethylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat can be used.
• Milk sugar, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable for internal use.
• Antioxidants such as tocopherol and butylated hydroxyanisole and butylated hydroxytoluene, taste-improving additives, stabilizers, emulsifiers and lubricants can also be present.
• the substances contained in the preparation in addition to the active substance and the substances used in the manufacture of the pharmaceutical preparations are toxicologically harmless and compatible with the respective active substance.
• the pharmaceutical preparations are produced in a customary manner, for example by mixing the active ingredient with other customary excipients and diluents.
• the pharmaceutical preparations can be in different
• Application modes are administered, for example, orally, parenterally and intravenously by infusion, subcutaneously, intraperitoneally and topically.
• Forms of preparation such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.
• a 96-well microtiter plate (flacon) is coated with histones (Type II-AS; SIGMA H7755).
• histones are dissolved in carbonate buffer (0.05 M NaHC0 3 ; pH 9.4) to a concentration of 50 ⁇ g / ml.
• the individual wells of the microtiter plates are incubated overnight with 100 ⁇ l of this histone solution.
• the histone solution is then removed and the individual wells are incubated with 200 ⁇ l of a 1% BSA (Bovine Serum Albumine) solution in carbonate buffer for 2 hours at room temperature. It is then washed three times with washing buffer (0.05% Tween10 in PBS).
• BSA Bovine Serum Albumine
• the enzyme reaction is started by adding 40 ⁇ l of a substrate solution (4 ⁇ l reaction buffer (see above), 8 ⁇ l NAD solution (100 ⁇ M in H 2 0), 28 ⁇ l H 2 0). Response time is 20 minutes at room temperature.
• the reaction is stopped by washing three times with washing buffer (see above). This is followed by a one-hour incubation at room temperature with a specific anti-poly-ADP-Ribose antibody.
• a monoclonal anti-poly (ADP-ribose) antibody "10H" (Kawamaitsu H et al. (1984) Monoclonal antibodies to poly (adenosine diphosphate ribose) recognize different structures. Biochemistry 23, 3771-3777) was used as the antibody. Polyclonal antibodies can also be used.
• the antibodies were used in a 1: 5000 dilution in antibody buffer (1% BSA in PBS; 0.05% Tween20). After washing three times with washing buffer, there is a one-hour incubation at room temperature with the secondary antibody.
• an anti-mouse IgG coupled with peroxidase Boehringer Mannheim
• an anti-rabbit IgG coupled with peroxidase SIGMA A-6154
• the color reaction is carried out using 100 ⁇ l / well color reagent (SIGMA, TMB ready mix, T8540) for approx. 15 min. at room temperature.
• the color reaction is stopped by adding 100 ul 2 M HS0 4 . Then the measurement is carried out immediately (450 nm against 620 nm; ELISA plate reader "Easy Reader” EAR340AT, SLT-Labinstruments, Austria).
• the IC50 value of an inhibitor to be measured lies at the inhibitor concentration, where a half-maximum change in color concentration occurs.

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