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  • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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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. 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 activated, differentiates (P.Johnson, Int. J.Biochem. 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 degradation in rheumatoid arthritis, proteins in the activation of platelets, neuropeptide metabolism, proteins in mitosis and others that occur in MJ Barrett et al. , Life Be. 1991, 48, 1659-69 and K.K. ang et al., Trends in Pharmacol. Be . , 1994, 15, 412-9.
• regulatory proteins such as protein kinase C, cytoskeleton proteins such as MAP 2 and spectrin
• muscle proteins protein degradation in rheumatoid arthritis
• proteins in the activation of platelets proteins in mitosis and others that occur in MJ Barrett et al. , Life Be. 1991, 48, 1659-69 and K.K. ang et al., Trends in Pharmacol. Be . , 1994
• Elevated 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 ang, above). It is believed 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.
• calpain inhibitors show cytotoxic effects on tumor cells (E.Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25th-28th Sept., Int.J.Oncol. 5 (Suppl.), 1994, 381).
• Calpain inhibitors have already been described in the literature, but mostly these are either irreversible or peptide inhibitors.
• Irreversible inhibitors are usually alkali substances and have the disadvantage that they are irr. Organism react unselectively 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), halogen ketones (H. Angliker et al., J.Med. Cherr. 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 i Biol. Sci. 1991, 16, 150 -3).
• MDL 28170 Z-Val-Phe-H
• peptidic aldehydes have the disadvantage that they are often instable due to the high reactivity 3 bil are, can be metabolized quickly and tend to non-specific reactions that can be the cause of toxic effects (JA Fehrentz and B. Castro, Synthesis 1983, 676-78.
• Peptide ketone derivatives are also inhibitors of cysteine proteases, especially calpains.
• 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).
• Ketobenz ⁇ r.ide 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 (C-: 2 Ph) -CO-COCOOCH 3 was in MRAngelastro et al. , J.Med.Chem .. 1990,33, 11-13 as a weak calpain inhibitor, however. This derivative is also described in JP Burkhardt, Tetra-hedron Lett., 1988, 3433-36. However, the importance of substituted benzamides has never been investigated.
• the active ingredients are administered intravenously, for example as an infusion solution.
• calpain inhibitors which have sufficient water solubility so that an infusion solution can be prepared.
• many of the calpain inhibitors described have the disadvantage that they show little or no water solubility and are therefore not suitable for intravenous administration.
• Such active substances can only be applied with auxiliary substances which are intended to impart water solubility (cf. RT Bartus et al. 4
• substituted non-peptidic aldehydes, ketocarboxylic acid esters and ketoamide derivatives have been described. These compounds are new and surprisingly show the possibility of incorporating rigid structural fragments into potent non-peptide inhibitors of cysteine proteases, e.g. Calpain. Furthermore, salt bonds with acids are possible with the present compounds of the general formula I, which all carry at least one aliphatic amine radical. A large number of these substances show water solubility as a 0.5% solution at pH 0 4-5 and thus they show the desired profile for intravenous application, as is required, for example, in stroke therapy.
• the present invention relates to amides of the general formula I
• R 1 can denote hydrogen, Ci-Cg-alkyl, branched and unbranched, phenyl, naphthyl, quinolinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinazolyl, quinoxalyl, thienyl, benzothienyl, benzofuranyl, furanyl, and indolyl, the rings also having can be substituted up to 3 radicals R 6 , and
• R 2 is hydrogen, Ci-C ⁇ alkyl, branched or unbranched, O-Ci-Cg-alkyl, branched or unbranched, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C-C 6 alkyl- Phenyl, C 2 -C 6 alkenyl phenyl, C 2 -C 6 alkynyl phenyl, OH, Cl, F, Br, J, CF 3 , N0 2 , NH 2 , CN, COOH, COO-C ⁇ -C 4 -alkyl, NHCO-C 4 alkyl, NHCO-phenyl, CONHR 9 , NHS0 2 -C-C 4 alkyl, NHS0 2 -phenyl, S0 2 -C-C 4 alkyl and S0 2 -phenyl mean and
• R 3 can represent NR 7 R 8 or a ring like - NN Rs -N - B '-N ⁇ - ⁇ > - - ⁇ ⁇ N - R »
• R 4 -Ci-C ⁇ -alkyl branched or unbranched, which can also carry a phenyl, pyridyl or naphthyl ring, which in turn is substituted with a maximum of two R 6 radicals, and
• R 5 is hydrogen, COOR 11 and CO-Z, wherein Z is NR 12 R 13 and
• R 6 is hydrogen, C ⁇ -C-alkyl, branched or unbranched
• -OC 1 -C 4 - alkyl OH, Cl, F, Br, J, CF 3 , N0 2 , NH 2 , CN, COOH, COO -CC 4 -alkyl, -NHCO -CC 4 -alkyl , -NHCO-phenyl, -NHS0 2 -C ⁇ -C 4 alkyl, -NHS0 -phenyl, -S0 2 -C ⁇ -C 4 alkyl and -S0_Phenyl means and
• R 7 is hydrogen, C ⁇ -C 6 alkyl, linear or branched, and that can be substituted with a phenyl ring, which itself can be substituted with one or two radicals R 10 , and
• R 8 is hydrogen, Ci-C ⁇ - alkyl, linear or branched, and that can be substituted with a phenyl ring, which itself can also be substituted with one or two radicals R 10 , and
• R 9 is hydrogen, Ci-C ⁇ -alkyl, branched or unbranched, which can also carry a substituent R 16 , phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, naphthyl, quinolinyl, imidazolyl, which also have one or two substituents R 14 can, and
• R 10 hydrogen f, -CC 4 alkyl, branched or unbranched
• R 11 is hydrogen, Ci-Cg-alkyl, linear or branched, and that can be substituted with a phenyl ring, which itself can also be substituted with one or two radicals R 10 , and
• R 12 is hydrogen, Ci-Cg-alkyl, branched and unbranched, means, and
• R 13 is hydrogen, Ci-Cg-alkyl, branched or unbranched, that with a phenyl ring, which can still carry a radical R 10 , and with
• R 14 is hydrogen, C ⁇ -Cg-alkyl, branched or unbranched
• 0-C ⁇ -Cg-alkyl branched or unbranched, OH, Cl, F, Br, J, CF 3 , N0 2 , NH 2 , CN, COOH, COO-C ⁇ -C 4 alkyl means or two radicals R 14 one Can represent bridge OC (R 15 ) 2 0 and
• R 15 is hydrogen, Ci-Cg-alkyl, branched and unbranched, means and
• R 16 is phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl,
• 7 B means phenyl, pyridine, pyrimidine, pyrazine, imidazole and thiazole and
• n a number 0, 1 or 2
• n independently of one another means a number 0, 1, 2, 3 or 4.
• 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 classical resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid. On the other hand, the enantiomeric compounds can also be prepared by using commercially available compounds, for example optically active amino acids such as phenylalanine, tryprophan and tyrosine.
• the invention also relates to compounds of the formula I which are mesomeric or tautomeric, for example those in which the aldehyde or 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.
• 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.
• the amides I according to the invention can be prepared in various ways, which have been outlined in the synthesis scheme.
• Heterocyclic carboxylic acids II are combined with suitable amino alcohols III to give the corresponding amides IV.
• Common peptide coupling methods are used, which are described in either CRLarock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972f. or in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, Kap.V.
• L represents a leaving group such as Cl, imidazole and N-hydroxybenzotriazole.
• This activated acid is then reacted with amines to give the amides IV.
• the reaction takes place in anhydrous, inert solvents such as methylene chloride, tetrahydrofuran and dimethylformamide at temperatures from -20 to + 25 ° C.
• These alcohol derivatives IV can be oxidized to the aldehyde derivatives I according to the invention.
• Various customary oxidation reactions can be used for this (see CRLarock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 f.) Such as Swern- and Swern-analogous oxidations (TTTidwell, Synthesis 1990, 857-70), sodium hypochlorite / TEMPO (S .L.Harbenson 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 / py x S0 3 or DMSO / oxalyl chloride at temperatures from -50 to + 25 ° C., depending on the method (see above literature) .
• the carboxylic acid II can be reacted with aminohydroxamic acid derivatives VI to give benzamides VII.
• the same reaction procedure is used as for the preparation of IV.
• the hydroxam derivatives VI can be obtained from the protected amino acids V by conversion with a hydroxylamine.
• An amide production process already described is also used here.
• the protective group X for example Boc, is split off in the customary manner, for example using trifluoroacetic acid.
• the amide hydroxamic acids VII 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.
• the heterocyclically substituted amides I bearing a ketoamide or ketoester group according to the invention can be prepared in various ways, which were outlined in synthesis schemes 2 and 3. If appropriate, the carboxylic acid esters Ha are converted into acids II 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.
• This reaction takes place in anhydrous, inert solvents such as methylene chloride, tetrahydrofuran and dimethylformamide at temperatures from -20 to + 25 ° C.
• the derivatives XI which are generally esters, are converted into the ketocarboxylic acids XII analogously to the hydrolysis described above.
• the keto esters I ' are prepared in a Dakin-West analog reaction, using a method by ZhaoZhao Li et 10 al. J.Med.Chem., 1993, 36, 3472-80.
• a carboxylic acid such as XII 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 for example, be hydrolyzed to ketocarboxylic acids according to the invention.
• ketobenzamides I ' is 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
• keto-carboxylic acids II are derived from aminohydroxycarboxylic acid derivatives XIII (preparation of XIII see S.L. Harenson et al., J.Med.Chem. 1994, 37,2918-29 or JP Burkhardt et al. Tetrahedron Let. 11
• Swern- and Swern-analogous oxidations preferably dimethyl sulfoxide / pyridine-sulfur trioxide complex in solvents such as methylene chloride or tetrahydrofuran, optionally with the addition of dimethyl sulfoxide, at room temperature or temperatures from -50 to 25 ° C, (TTTidwell, Synthesis 1990, 857-70) or sodium hypochlorite / TEMPO (SLHarbenson et al., see above).
• Other esters or amides XVI are prepared by reaction with alcohols or amines under the coupling conditions already described. The alcohol derivative XVI can be oxidized again to ketocarboxylic acid derivatives I according to the invention.
• Ether-bridged derivatives are prepared by alkylation of the corresponding alcohols or phenols with halides.
• the sulfoxides and sulfones are accessible by oxidation of the corresponding thioethers. 12
• Alkene-bridged and alkyne-bridged compounds are prepared, for example, by Heck reaction from aromatic halides and corresponding alkenes and alkynes (cf. I.Sakamoto et al., Chem.Pharm.Bull., 1986, 34, 2754-59).
• the chalcones are formed by condensation from acetophenones with aldehydes and can optionally be converted into the analog alkyl derivatives by hydrogenation.
• Amides and sulfonamides are prepared analogously to the methods described above from the amines and acid derivatives.
• dialkylaminoalkyl substituents are obtained by reductive amination of the aldehyde derivatives with the corresponding amines in the presence of borohydrides, such as BH 3 -pyridine complex or or NaBH 3 CN (A: F: Abdel-Magid, C: A: Maryanoff, KG Carson, Tetrahedron Lett 10990, 31, 5595; AE: Moormann, Synth. Commun. 1993, 23, 789).
• borohydrides such as BH 3 -pyridine complex or or NaBH 3 CN
• heterocyclically substituted amides 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 amides I were measured in this way for the inhibitory action 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.
• an inhibitor solution prepared from inhibitor and DMSO (final concentrations: 100 ⁇ M to 0.01 ⁇ M), are added to 88 ⁇ L cathepsin B (cathepsin B from human liver (Calbiochem), diluted to 5 units in 500 ⁇ M buffer). This mixture is preincubated for 60 minutes at room temperature (25 ° C.) and then the reaction is 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 microplate reader. The ICso's are then determined from the maximum gradients. 13
• calpain inhibitors The inhibitory properties of calpain inhibitors are tested in buffer with 50 mM Tris-HCl, pH 7.5; 0.1 M NaCl; 1mM dithiotreithol; 0.11 mM Ca Cl 2 , the fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachern / Switzerland) being used.
• Human ⁇ -calpain is isolated from erythrocytes and after several chromatographic steps (DEAE-Sepharose, Phenyl-Sepharose, Superdex 200 and Blue-Sepharose), enzyme with a purity> 95% is obtained, assessed according to SDS-PAGE, Western Blot Analysis and N -terminal sequencing.
• the cleavage of the substrate is linear and the autocatalytic activity of calpain is low if the tests are carried out at temperatures of 12 ° C.
• the inhibitors and the calpain substrate are added to the test batch as DMSO solutions, the final concentration of DMSO not exceeding 2%.
• Ki values are determined using the classic equation for reversible inhibition:
• 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 create connections with better membrane 14 common to find. We use human platelets as evidence of the passage of calpain inhibitors into the membrane.
• pp60src After platelet activation, the tyrosine kinase pp60src is cleaved by calpain. This was done by Oda et al. in J. Biol. Chem., 1993, Vol 268, 12603-12608. It was shown that the cleavage of pp60src can be prevented by calpeptin, an inhibitor for calpain. Based on this publication, the cellular effectiveness of our substances was tested. Fresh human blood with citrate was mixed for 15 min. centrifuged at 200g.
• the platelet-rich plasma was pooled and diluted 1: 1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KCl, 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.
• test mixture isolated platelets (2 x 10 6 ) with different concentrations of inhibitors (dissolved in DMSO) for 5 min. pre-incubated at 37 ° C. The platelets were then activated with 1 ⁇ M Ionophore A23187 and 5 mM CaCl. After 5 min.
• 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 ⁇ g / ml 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 polyclonal rabbit antibody Anti-Cys-src (pp60 c-src ) used was purchased from Biomol Feinchemischen (Hamburg). This primary antibody was detected using 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).
• control 1 no cleavage
• control 2 corresponds to 100% cleavage
• the ED 5 o value corresponds to the concentration of inhibitor at which the intensity of the color reaction is reduced by 50%.
• 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 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 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 Mannnheim) was added to the reaction mixture. The optical density is determined approximately 17 hours later, 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.
• 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). Glutamate mediates its effects via various receptors. Two of these receptors are classified according to the specific agonists NMDA receptor and AMPA receptor. Antagonists against these glutamate mediated effects 16 can thus be used to treat these diseases, in particular for therapeutic use against neurodegenerative diseases such as Huntington's chorea and Parkinson's disease, neurotoxic disorders after hypoxia, anoxia, ischemia and after lesions such as those occurring after stroke and trauma, or also as antiepileptics (see Pharmaceutical Research 1990, 40, 511-514; TIPS, 1990, 11, 334-338; Drugs of the Future 1989, 14, 1059-1071). De
• EAA Extracerebral application of excitatory amino acids
• EAA antagonists central active ingredients
• An ED 50 value was determined as a measure of the effectiveness of the substances, in which 50% of the animals become symptom-free by a fixed dose of either NMDA or AMPA by the previous ip administration of the measuring substance.
• heterocyclically substituted amides I are inhibitors of cysteine derivatives 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 enzymes or cathepsin enzymes.
• the present amides I can thereafter be used for the treatment of neurodegenerative diseases which occur after ischemia, trauma, subarachnoid bleeding and stroke, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease, Huntington's disease and epilepsy and furthermore for the treatment of damage to the Heart after cardiac ischemia, kidney damage after renal ischemia, skeletal muscle damage, muscular dystrophy, damage caused by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes, restenosis of the bloodstream after angioplasty.
• the amides I can be useful in the chemotherapy of doors and their metastasis and for the treatment of diseases in which an increased level of interleukin-1 is 17 occurs, as with inflammation and rheumatic diseases.
• the pharmaceutical preparations according to the invention contain a therapeutically effective amount of the compounds I.
• the active ingredients can be contained 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, 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 and intravenously by infusion, subcutaneously, intraperitoneally and topically.
• Examples 8-28 were prepared analogously to Example 7.

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