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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D209/58—[b]- or [c]-condensed
  • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
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  • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4

Definitions

• the present invention relates to novel heterocyclically substituted benzamides and their use in combating diseases.
• Calpains are intracellular, proteolytic enzymes from the group of so-called cysteine proteases and are found in many cells. Calpains are activated by increased calcium concentration, with a distinction being made between calpain I or ⁇ -calpain, which is activated by ⁇ -molar concentrations of calcium ions, and calpain II or m-calpain, which is activated by m-molar concentrations of calcium ions , distinguishes (P.Johnson, Int. J.Bioche. 1990, 22 (8), 811-22). Today, further calpain isoenzymes are postulated (K.Suzuki et al., Biol.Chem. Hoppe- Seyler, 1995, 376 (9), 523-9).
• calpains play an important role in various physiological processes. These include cleavages of regulatory proteins such as protein kinase C, cytoskeleton proteins such as MAP 2 and spectrin, muscle proteins, protein breakdown in rheumatoid arthritis, proteins when platelets are activated, neuropeptide metabolism, proteins in mitosis and others, the in. MJBarrett et al. , Life Be. 1991, 48, 1659-69 and K.K. Wang et al. , Trends in Pharmacol. Be . , 1994, 15, 412-9.
• Increased calpain levels were measured in various pathophysiological processes, for example: ischemia of the heart (e.g. heart attack), the kidney or the central nervous system (e.g. "stroke"), inflammation, muscular dystrophies, eye cataracts, injuries to the central nervous system (e.g. trauma), Alzheimer's disease, etc. (see KK Wang, above). It is suspected that these diseases are associated with increased and persistent intracellular calcium levels. As a result, calcium-dependent processes are overactivated and are no longer subject to physiological regulation. Accordingly, overactivation of calpains can also trigger pathophysiological processes.
• Irreversible inhibitors are generally alkylating substances and have the disadvantage that they react unselectively in the organism or are unstable. So show
• the irreversible inhibitors include, for example, the epoxides E 64 (E.B. McGowan et al., Biochem. Biophys. Res. Commun. 1989, 158, 432-5), ⁇ -haloketones (H. Angliker et al.,
• peptide aldehydes in particular dipeptide and tripepidic aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S.Mehdi, Tends in Biol. Sci. 1991, 16, 150-3) and the compounds from EP 520336.
• Peptide ketone derivatives have also been found as inhibitors of 5 cysteine proteases, especially calpain.
• ⁇ -leaving groups cause irreversible inhibition on the one hand and since a carboxylic acid derivative activates the keto group, effective inhibitors are found (see MRAngelastro et al., J.Med.Chem. 1990,33, 11-13; WO 92/11850; WO 92,12140; WO 94 / 00095 and WO 95/00535).
• peptide derivatives of these ketoamides and keto esters have so far been described as effective (Zhao Zhao Li et al., J.Med.Chem. 1993, 36, 3472-80; SLHarbenson et al., J.Med.Chem. 1994, 37, 2918-29 and see above MRAngelastro et al.).
• Ketobenzamides are already known in the literature.
• the ketoester PhCO-Abu-COOCH 2 CH 3 has been described in WO 91/09801, WO 94/00095 and 92/11850.
• the analog phenyl derivative Ph-CONH-CH (CH 2 Ph) -CO-COCOOCH 3 was described in MRAngelastro et al., J.Med.Chem. 1990, 33, 11-13 found as a weak calpain inhibitor. This derivative is also described in JP Burkhardt, Tetrahedron Lett., 1988, 3433-36.
• the importance of substituted benzamides has never been investigated.
• JP 8183759, JP 8183769, JP 8183771 and EP 520336 have described aldehydes derived from dipeptides, with saturated carbocyclic rings, for example cyclohexanes, or saturated heterocyclic rings, for example piperidines, being incorporated into these peptide inhibitors instead of an amino acid, which gave novel aldehydes as calpain inhibitors.
• the invention relates to heterocyclically substituted benzamides of the formula I.
• R 2 is hydrogen, -CC 6 alkyl, 0 -CC 6 alkyl,, OH, Cl, F, Br, J, CF 3 , NO 2 , NH 2 , CN, COOH, COO -CC 4 -Alkyl, -NHCO-C ⁇ -C 4 alkyl, -NHCO-phenyl, -CONHR 8 , NHS0 2 -C 1 -C 4 alkyl, -NHS0 2 -phenyl, -S0 2 -C ⁇ -C 4 alkyl or -S0 2 -phenyl or
• R 3 hydrogen, chlorine, bromine, fluorine, Ci - C 6 - alkyl, phenyl, NHCO-C ! -C 4 alkyl, N0 2 , or NH 2 ,
• R 4 Ci-C ⁇ -alkyl, which can also carry a phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylcycloheptyl, indolyl, pyridyl or naphthyl ring, which in turn contains one or two radicals R 7 is substituted, wherein R 7 is hydrogen, -CC 4 alkyl, -0-C !
• -C 4 -alkyl OH, Cl, F, Br, J, CF 3 , N0 2 , NH 2 , CN, COOH, COO-C ⁇ -C 4 -alkyl, -CONHR 8 , -NHCO-C ⁇ -C 4 - Alkyl, -NHCO-phenyl, -NHS0 2 -C ⁇ -C 4 alkyl, -NHS0 2 -phenyl, -S0 2 -C ⁇ -C 4 alkyl or -S0 2 -phenyl,
• R 6 is hydrogen, -CC 6 alkyl, -0 -CC 6 alkyl, OH, Cl, F, Br, J, CF 3 , N0 2 , NH 2 , CN, COOH, COO-C 1 -C 4 alkyl,
• R 8 is hydrogen or -CC 6 alkyl
• R 9 is hydrogen, C 1 -C 6 -alkyl, which still has a phenyl ring which can also carry a radical R 11 , and with
• R 12 is hydrogen or a co-alkyl chain which can be substituted by a phenyl ring which itself can also carry one or two R 11 radicals,
• n is the number 0, 1 or 2 and
• n is the number 0, 1, and 2.
• heterocyclically substituted benzamides of the formula I according to Claim 1 in which R 5 is hydrogen and R 1, R, R 3, R 4, X, m and n have the meaning given above.
• the compounds of formula I can be used as racemates or 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. On the other hand, the enantiomers Compounds can also be prepared by using commercially available compounds, for example optically active amino acids such as phenylalanine, tryptophan and tyrosine.
• the invention also relates to the compounds mesomeric and tautomeric to the compounds of the formula I, for example those in which the keto group of the formula I is present as an enol tautomer.
• the new compounds I can contain a basic or acidic group.
• the compounds I can be in the form of their physiologically tolerable salts, which can be obtained by reacting the compounds I with a suitable acid or base.
• Suitable acids for salt formation with compounds I according to the invention which contain a basic group can be, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid and sulfuric acid.
• Suitable bases are, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, ⁇ , ⁇ , ⁇ -tris (hydroxymethyl) methylamine and also other amines.
• ketobenzamides I according to the invention can be prepared in various ways, which were outlined in synthesis schemes 1, 2 and 3.
• the carboxylic acid esters II are converted into acids III with acids or bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an aqueous medium or in mixtures of water and organic solvents such as alcohols or tetrahydrofuran at room temperature or elevated temperatures, such as 25-100 ° C.
• acids or bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an aqueous medium or in mixtures of water and organic solvents such as alcohols or tetrahydrofuran at room temperature or elevated temperatures, such as 25-100 ° C.
• the acids III are linked to an ⁇ -amino acid derivative, using customary conditions which are described, for example, in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, chap. V, and C.R. Lrock, Comprehensive Organic Transformations, VCH Publisher, 1989, Ch.9.
• the carboxylic acids III are converted into "activated” acid derivatives R '-COOL, L representing a leaving group such as Cl, imidazole and N-hydroxybenzotriazole, and then by reaction with an amino acid derivative H 2 N-CH (R4) -COOR converted into the derivative IV.
• This reaction takes place in anhydrous, inert solvents such as methylene chloride, tetrahydrofuran and dirnethylformamide at temperatures from -20 to + 25 ° C.
• the derivatives IV which are generally esters, are converted into the ketocarboxylic acids V analogously to the hydrolysis described above.
• the keto esters I ' are prepared, using a method by Zhao Zhao Li et al. J.Med.Chem., 1993, 36, 3472-80.
• a carboxylic acid such as V is reacted with oxalic acid monoester chloride at elevated temperature (50-100 ° C) in solvents such as tetrahydrofuran and then the product thus obtained with bases such as sodium ethanolate in ethanol at temperatures of 25-80 ° C to the ketoester according to the invention I 'implemented.
• the keto esters I ' can be hydrolyzed to the ketocarboxylic acids according to the invention.
• the conversion to the ketobenzamides I ' is also carried out analogously to the method by Zhao Zhao Li et al. (see above).
• the keto group in I ' is protected at room temperature by adding 1, 2-ethanedithiol with Lewis acid catalysis, for example with boron trifluoride etherate, in inert solvents, such as methylene chloride, a dithiane being obtained.
• Lewis acid catalysis for example with boron trifluoride etherate
• inert solvents such as methylene chloride
• dithiane a dithiane
• Other esters or amides X are prepared by reaction with alcohols or amines under the coupling conditions already described.
• the alcohol derivative IX can also be oxidized to the ketocarboxylic acid derivatives I according to the invention.
• Benzoic acid derivatives III are combined with suitable amino alcohols X to give the corresponding benzamides XI.
• Common peptide coupling methods are used, which are described either in CRLarock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972f. or in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, Kap.V. It is preferred to work with "activated” acid derivatives of III, the acid group COOH being converted into a group COL.
• L represents a leaving group such as Cl, imidazole and N-hydroxybenzotriazole.
• This activated acid is then reacted with amines to form the iden XI.
• the reaction takes place in anhydrous, inert solvents such as methylene chloride, tetrahydrofuran and dirnethylformamide at temperatures from -20 to + 25 ° C.
• the alcohol derivatives XI can be oxidized to the aldehyde derivatives I according to the invention.
• Various customary oxidation reactions can be used for this (see CRLarock, Comrenhensive Organic Transformations, VCH Publisher, 1989, page 604 f.), Such as Swern- and Swern-analogous oxidations (TTTidwell, Synthesis 1990, 857-70), sodium hypochlorite / TEMPO (SLHarbenson et al., See above) or Dess-Martin (J.Org.Chem. 1983, 48, 4155).
• inert aprotic solvents such as dimethylformamide, tetrahydrofuran or methylene chloride with oxidizing agents such as DMSO / pyridine x SO 3 or DMSO / oxalyl chloride at temperatures from -50 to + 25 ° C.
• oxidizing agents such as DMSO / pyridine x SO 3 or DMSO / oxalyl chloride
• the same reaction procedure is used as for the representation of XI.
• the hydroxam derivatives XIII can also be obtained from the protected amino acids XII by conversion with hydroxylamine.
• the amide production processes already described are also used here.
• the protecting group Y 2 for example Boc, is cleaved off in a customary manner, for example using trifluoroacetic acid in methylene chloride.
• the benzamide-hydroxamic acids XIV 10 thus obtained can be converted into the aldehydes I according to the invention by reduction.
• lithium aluminum hydride is used as a reducing agent at temperatures from -60 to 0 ° C. in inert solvents such as tetrahydrofuran or ether.
• carboxylic acid esters II or carboxylic acids III have in some cases already been described or can be prepared in accordance with conventional chemical methods.
• precursors II of pyrimidiones I can be obtained from the corresponding isatoic anhydrides (see CK Reddy et al., Ind. J. Chem., 1987, 26B, 882) or directly from the 2-aminobenzoates. acid derivatives in sales of phenyl isocyanates (see: CM.
• ketobenzamides I according to the invention are inhibitors of cysteine proteases, in particular of cysteine proteases such as calpaine I and II and cathepsine B and L.
• Cathepsin B inhibition was determined analogously to a method by S.Hasnain et al., J.Biol.Chem. 1993, 268, 235-40.
• the inhibitory properties of calpain inhibitors are tested in buffer with 50 mM Tris-HCl, pH 7.5; 0.1 M NaCl;
• the cleavage of the substrate is linear for 60 min and the autocatalytic activity of calpain is low if the experiments are carried out at temperatures of 12 ° C. (see Chatterjee et al. 1996, Bioorg. & Med. Chem. Lett., Vol 6, 1619-1622).
• the inhibitors and the calpain substrate are added to the test batch as DMSO solutions, the final concentration of DMSO not exceeding 2%.
• Calpain is an intracellular cysteine protease. Calpain inhibitors must pass through the cell membrane to prevent the breakdown of intracellular proteins by calpain. Some known calpain inhibitors, such as E 64 and leupeptin, only poorly cross the cell membranes and accordingly, although they are good calpain inhibitors, show only poor activity on cells. The aim is to find connections with better membrane passage. We use human platelets as evidence of the membrane passage of calpain inhibitors.
• the platelet-rich plasma was pooled and diluted 1: 1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KC1, 0.5 mM MgCl 2 ⁇ 6 H 2 O, 0.24 mM NaH 2 PO 4 ⁇ H 2 0, 12 mM NaHC0 3 , 5.6 mM glucose, 1 mM EDTA, pH 7.4). After a centrifugation and washing step with platelet buffer, the platelets were adjusted to 10 7 cells / ml. The human platelets were isolated at RT. In the test mixture, isolated platelets (2 ⁇ 10 6 ) with different concentrations of inhibitors (dissolved in DMSO) were preincubated for 5 min at 37 ° C.
• platelet buffer platelet buffer: 68 mM NaCl, 2.7 mM KC1, 0.5 mM MgCl 2 ⁇ 6 H 2 O, 0.24 mM NaH 2 PO 4 ⁇ H 2 0, 12 mM NaHC0 3 ,
• the platelets were then activated with 1 ⁇ M Ionophore A23187 and 5 mM CaCl 2 . After 5 min incubation, the platelets were briefly centrifuged at 13000 rpm and the pellet was taken up in SDS sample buffer (SDS sample buffer: 20 mM Tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 5 ⁇ g / ml leupeptin, 10 ⁇ m pepstatin, 10% glycerin and 1% SDS). The proteins were separated in a 12% gel and pp60src and its 52-kDa and 47-kDa cleavage products were identified by Western blotting.
• the rabbit anti-Cys-src (pp60 c " src ) polyclonal antibody used had been purchased from Biomol Feinchemischen (Hamburg). This primary antibody was detected with an HRP-coupled second goat antibody (Boehringer Mannheim, FRG) Western blotting was carried out according to known methods.
• pp60src The cleavage of pp60src was quantified densitometrically, using controls which were not activated (control 1: no cleavage) and plates treated with ionophore and calcium (control 2: corresponds to 100% cleavage).
• the ED 50 value corresponds to the concentration of inhibitor at which the intensity of the color reaction of the 60 kDa band corresponds to the value intensity of control 1 plus control 2 divided by 2.
• calpain also plays a role in apoptotic cell death (M.K.T. Squier et al. J. Cell. Physiol. 1994, 159, 229-237; T. Patel et al. Faseb Journal 1996, 590, 587-597). Therefore, in another model, cell death was triggered with calcium in the presence of a calcium ionophore in a human cell line. Calpain inhibitors must enter the cell and inhibit calpain there to prevent cell death.
• cell death can be triggered by calcium in the presence of the ionophore A 23187.
• 10 5 cells / well are plated in microtiter plates 20 h before the experiment. After this period, the cells are incubated with various concentrations of inhibitors in the presence of 2.5 ⁇ M ionophore and 5 mM calcium. After 5 h, 0.05 ml of XTT (Cell Proliferation Kit II, Boehringer Mannnheim) are added to the reaction mixture. The optical density is determined approximately 17 hours later, in accordance with the manufacturer's instructions, in the EASY READER EAR 400 from SLT. The optical density at which half of the cells have died is calculated from the two measured values without Inhibitors incubated in the absence and presence of ionophore.
• a number of neurological diseases or mental disorders result in increased glutamate activity, which leads to states of overexcitation or toxic effects in the central nervous system (CNS).
• CNS central nervous system
• Glutamate antagonists including in particular NMDA antagonists or their modulators and the AMPA antagonists, are suitable for therapeutic use as agents against neurodegenerative diseases (Huntington's and Parkinson's diseases), neurotoxic disorders after hypoxia, anoxia or Ischemia, as it occurs after "Stroke”, or also as anti-epileptics, antidepressants and anxiolytics (cf. Medicinal Research 1990, 40, 511 - 514; TIPS, 1990, 11, 334 - 338 and Drugs of the Future 1989, 14 (11), 1059-1071).
• EAA Excitatory Amino Acids
• calpain inhibitors in cell cultures also have a protective action against cell death caused by EAA (H. Cauer et al., Brain Research 1993, 607, 354-356; Yu Cheg and AY Sun, Neurochem. Res 1994, 19, 1557-1564).
• EAA eg NMDA or AMPA
• the cortex halves are prepared from 15-day-old mouse embryos and the individual cells are obtained enzymatically (trypsin). These cells (glia and cortical neurons) are sown in 24 well plates. After three days (laminin coated plates) or seven days (ornithine coated plates) the mitosis treatment is carried out with FDU (5-fluoro-2-deoxyuridine). 15 days after cell preparation, cell death is triggered by adding glutamate (15 min). After the glutamate removal, the calpain inhibitors are added. 24 hours later, cell damage is determined by determining lactate dehydrogenase (LDH) in the cell culture supernatant.
• LDH lactate dehydrogenase
• the benzamides of the formula I are inhibitors of cysteine proteases such as in particular calpain I or II and cathepsin B or L and can thus be used to combat diseases which are associated with increased enzyme activity of the calpain enzymes or cathepsin enzymes , serve.
• neurodegenerative diseases which occur after ischemia, trauma, subarachnoidal bleeding and stroke and which include, in particular, stroke and head trauma, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease and Huntington's disease and also for treatment damage to the heart after cardiac ischemia, damage to the kidneys after renal ischemia, skeletal muscle damage, muscular dystrophies, damage caused by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes, restenosis of the bloodstream after angioplasty.
• the benzamides of formula I can be useful in chemotherapy of tumors and their metastases and for the treatment of diseases in which an increased level of interleukin-1 occurs, such as inflammation and rheumatic diseases.
• 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 ingredients are in an amount of 0.001 to 1% by weight, preferably 0.01 to 0.1
• the preparations are administered in single doses. 0.1 to 100 mg per kg body weight are given in a single dose.
• the preparations 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, in addition to the active ingredient, the customary carriers and diluents.
• pharmaceutical-technical auxiliaries such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated 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 administered in various modes of administration, for example orally, parenterally or 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.

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