Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • A61P25/28—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
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• isoenzymes and cathepsins for example B and L.
• Calpains are intracellular, proteolytic enzymes from the group of so-called cysteine proteases and are found in many cells.
• the enzyme calpain is 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 is activated, differentiates (P.Johnson, Int.J.Biochem. 1990, 22 (8), 811-22).
• Today, further Calpain isoenzies are postulated (K.Suzuki et al., Biol.Chem. Hoppe-Seyler, 1995, 376 (9), 523-9).
• calpaine 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 degradation in rheumatoid arthritis, proteins when platelets are activated, neuropeptide metabolism, proteins in mitosis and other tere, which in MJBarrett et al., Life Sei. 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, cataracts of the eyes, injuries to the central nervous system (e.g. trauma), Alzheimer's disease etc. (see KK Wang, above). It is believed that these diseases are related to 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. Therefore, it has been postulated that inhibitors of calpain enzymes can be useful in the treatment of these diseases. Various studies confirm this.
• Calpain inhibitors have already been described in the literature. However, these are predominantly either irreversible or peptide inhibitors. Irreversible inhibitors are generally alkylating substances and have the disadvantage that they react unselectively in the organism or are unstable. So these inhibitors often show undesirable side effects, such as toxicity, and are then restricted in use or unusable.
• the irreversible inhibitors include, for example, the epoxides E 64 (EBMcGowan et al., Biochem.Biophys .Res.Commun. 1989, 158, 432-5), ⁇ -haloketones (H. Angliker et al., J.Med Chem. 1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lat. 1990, 191-194).
• peptidic 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.
• peptidic aldehydes Under physiological conditions peptidic aldehydes have the disadvantage that they are often unstable due to the high reactivity, can be metabolized rapidly and tend to non-specific reactions which can be the cause of toxic effects (JAFehrentz and B. Castro, Synthesis 1983, 676-78).
• peptide aldehydes in the treatment of diseases is therefore only of limited or not useful. It is therefore not surprising that only a few aldehydes are used as active ingredients, especially when the aldehyde group is stabilized, for example by hemiacetal formation.
• a step forward is the discovery that certain peptidic ketone derivatives are also inhibitors of cysteine proteases and especially calpain.
• ketone derivatives are known as inhibitors in the case of serine proteases, the keto group being activated by an electron-withdrawing group such as CF 3 .
• CF 3 an electron-withdrawing group
• derivatives with ketones activated by CF 3 or similar groups are little or ineffective (MRAngelastro et al., J.Med.Chem. 1990, 33, 11-13).
• the present invention relates to piperidine-ketocarboxylic acid derivatives of the formula I.
• - C 4 alkyl and -S0Ph can mean;
• R3 represents -OR 6 and -NHR 6 ;
• rings such as phenyl, naphthalene, quinoxaline, quinoline, isoquinoline, pyridine, thiophene, benzothiophene, benzofuran, pyrimidine, thiazole, isothiazole, triazole, imidazole, cyclohexyl, cyclopentyl, fluorene, ind
• R 6 is hydrogen, a phenyl ring which can carry one or two radicals R s , Ci-C ⁇ -alkyl, branched or unbranched, which may contain a double bond or a triple bond, and a ring such as phenyl, naphthalene, pyridine, pyrimidine , Piperidine, pyrrolidine, morpholine, thiophene, quinoline and isoquinoline, where the aromatic rings can carry a maximum of two radicals -NR 7 R 8 or R 5 , where R 7 and R 8 independently of one another are hydrogen or Ci-Cg-alkyl, branched or unbranched, can mean.
• R 2 -C 6 -alkyl, branched and unbranched, -CH 2 -Ph and -CH 2 -pyridyl, R 3 mean -0R6 and -NHR6 and
• R4, R5 and R6 have the meaning according to the above claim.
• R 6 is hydrogen, -CC 4 alkyl, which may be substituted with a phenyl, pyridine or morpholine
• the compounds of the 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 classical resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid.
• the invention also relates to compounds of the formula I mesomeric or tautomeric compounds, for example those in which the keto group of the formula I is present as an enol tautomer.
• 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.
• piperidine-ketocarboxylic acid derivatives I according to the invention can be prepared in various ways, which have been outlined in schemes 1 and 2.
• derivative III is obtained by conversion under customary conditions with “activated” acid derivatives Rl-L, where L is a leaving group such as Cl, imidazole and N-hydroxybenzotriazole.
• L is a leaving group such as Cl, imidazole and N-hydroxybenzotriazole.
• This reaction takes place in anhydrous, inert solvents such as methylene chloride, Tetrahydrofuran and dimethylformamide at temperatures from -20 to + 25 ° C and is usually under the usual conditions as described in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, Chap. V, are summarized.
• the piperidine carboxylic acid esters III are converted into the acids IV 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 derivatives V which are generally esters, are converted into the ketocarboxylic acids VI analogously to the hydrolysis described above.
• the keto esters VII are prepared in a Dakin-West analog reaction, using a method by ZhaoZhao Li et al. J.Med.Chem., 1993, 36, 3472-80.
• a carboxylic acid such as V is reacted at elevated temperature (50-100 ° C) in solvents such as tetrahydrofuran with oxalic acid monoester chloride and then. the product thus obtained is reacted with bases such as sodium ethanolate in ethanol at temperatures of 25-80 ° C. to the ketoester I 'according to the invention.
• the Ketoester I ' can, as described above, be hydrolyzed, for example, to ketocarboxylic acids according to the invention.
• ketoamides I ' are also carried out analogously to the method by ZhaoZhao Li et al. (see above).
• the keto group in I ' is protected by adding 1,2-ethanedithiol with Lewis acid catalysis, such as, for example, boron trifluoride etherate, in inert solvents, such as methylene chloride, at room temperature, whereupon a dithiane is obtained.
• Lewis acid catalysis such as, for example, boron trifluoride etherate
• inert solvents such as methylene chloride
• esters O-alkyl
• these can be hydrolyzed to carboxylic acids IX, the procedure being analogous to the above methods, but preferably with lithium hydroxide in water / tetrahydrofuran mixtures at room temperature.
• Other esters or amides X are prepared by reaction with alcohols or amines under the coupling conditions already described. The alcohol derivative X can be oxidized again to ketocarboxylic acid derivatives I according to the invention.
• the ketone derivatives I contained in the present invention are inhibitors of cysteine proteases, in particular cysteine proteases such as calpains I and II and cathepsins B and L.
• the ketone derivatives I were measured in this way for the inhibitory effect of calpain I, calpain II and cathepsin B.
• Cathepsin B inhibition was determined analogously to a method by S.Hasnain et al., J.Biol.Chem. 1993, 268, 235-40.
• cathepsin B cathepsin B from human liver (Calbiochem)
• diluted to 5 units in 500 ⁇ M buffer 2 ⁇ L of an inhibitor solution made from inhibitor and DMSO (final concentrations: 100 ⁇ M to 0.01 ⁇ M).
• This mixture is preincubated for 60 minutes at room temperature (25 ° C.) and the reaction is then started by adding 10 ⁇ l 10 mm Z-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is monitored for 30 minutes at 405nM in a microtiter plate reader. The ICso's are then determined from the maximum gradients.
• calpain inhibitors The inhibitory properties of calpain inhibitors are tested in buffer with 50 mM Tris-HCl, pH 7.5; 0.1 M NaCl; 1 mM dithiotreithol: 0.11 mM CaCl 2 / using the fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 M dissolved in DMSO, Bachem / Switzerland) (Sasaki et al. J. Biol. Chem. 1984, Vol. 259, 12489-12494).
• Human ⁇ -calpain is made from erythrocytes to the methods of Croall and DeMartino (BBA 1984, Vol. 788, 348-355) and Graybill et al. (Bioorg. & Med. Lett.
• Ki values are calculated according to the usual equation for
• Calpain-mediated protein degradation in platelets was performed as described by Zhao ZhaoLi et al., J. Med. Chem., 1993, 36, 3472-3480 5. Human platelets were isolated from fresh sodium citrate blood from donors and adjusted to 10 7 cells / ml in buffer (5 mM Hepes, 140 mM NaCl and 1 mg / ml BSA, pH 7.3).
• 0 platelets 0.1 ml are preincubated for 5 minutes with 1 ⁇ l of various concentrations of inhibitors (dissolved in DMSO). This was followed by the addition of calcium ionophore A 23187 (1 ⁇ M in the test) and calcium (5 mM in the test) and a further incubation of 5 minutes at 37 ° C. After a centrifugation step, the 5 plates were taken up in SDS-Page sample buffer, 5 minutes Boiled at 95 ° C and the proteins separated in an 8% gel.
• ABSP actin binding protein
• the cortex halves were prepared from 15-day-old mouse embryos and the individual cells were 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), mitosis treatment is carried out with FDU (5-fluoro-2-deoxyuridine). 15 days after cell preparation, cell death is triggered by adding glutamate (15 minutes). 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
• 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 in a human cell line with calcium in the presence of a calcium ionophore. 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 were plated in microtiter plates 20 hours before the experiment. After this period, the cells were incubated with various concentrations of inhibitors in the presence of 2.5 ⁇ M ionophore and 5 mM calcium. After 5 hours, 0.05 ml of XTT (Cell Proliferation Kit II, Boehringer Mannheim) was added to the reaction mixture. The optical density is determined after about 17 hours, according to the manufacturer's instructions, in the Easy Reader EAR 400 from SLT.
• the optical density at which half of the cells died is calculated from the two controls with cells without inhibitors which were incubated in the absence and presence of ionophore.
• the ketone derivatives I are inhibitors of cysteine proteases such as calpain I or II and cathepsin B or L and can thus be used to combat diseases which are associated with an increased enzyme activity of the calpain enzyme or cathepsin enzymes .
• the present ketone derivatives I can then be used for the treatment of neurodegenerative diseases which occur after ischemia, trauma and mass bleeding, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease and Huntington's disease and also for the treatment of cardiac damage to the heart Ischemia, damage to the
• the ketone derivatives I can be useful in the chemotherapy of tumors and their metastasis and for the treatment of diseases in which an increased interleukin-1 level 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 substances are contained in an amount of 0.0001 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, in addition to the active ingredient, the customary pharmaceutical excipients and auxiliaries.
• pharmaceutical-technical auxiliaries such as ethanol, isopropanol, oxyethylated castor oil, oxyethylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycostearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat can be used.
• auxiliaries such as ethanol, isopropanol, oxyethylated castor oil, oxyethylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycostearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat can be used.
• the internal applications are, for example, milk sugar, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.
• 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 should be toxicologically safe and compatible with the respective active substance.
• the pharmaceutical preparations are produced in the 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 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.
• reaction mixture was stirred at room temperature for 16 h. Then 100 ml of water were carefully added and the mixture was stirred again for about 30 minutes. The approach was divided between water and ethyl acetate. The organic phase was washed several times with water, dried and concentrated in vacuo.
• the product was produced from intermediate 6a in accordance with the instruction lc.
• the product was prepared analogously to instruction 2b from example 6 and ethanolic ammonia solution.
• the product was prepared from intermediate la and methyl 2-amino-butyrate as described in lb.
• the product was produced from intermediate 10a in accordance with instruction lc.
• the product was produced from intermediate 10b in a manner analogous to instruction ld.
• the product was produced from product 10 and ethanolic ammonia solution in accordance with regulations 2a, b.
• the product was produced from intermediate 12b in accordance with instruction lc.
• the product was produced from intermediate 12c analogously to instruction ld.
• Example 12 The product was produced from Example 12 in accordance with the regulations 2a, b.
• the product was prepared from product 12 and 1- (3-amino-prop-1-yl) morpholine in accordance with instructions 2a, b.
• the product was prepared analogously to instructions 2a, b from example 12 and 2- (2-aminoethyl) pyridine.

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