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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07D215/16—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 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
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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
  • C07D239/96—Two oxygen atoms

Definitions

• isoenzymes and cathepsins for example B and L represent.
• 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 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 , (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 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. 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 when platelets are activated proteins when platelets are activated
• neuropeptide metabolism proteins in mitosis and others
• 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. rauma), Alzheimer's disease, etc. (see KK ang, 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.
• calpain inhibitors show cytotoxic effects on tumor cells (0 E. Shhiba et al. 20th Meeting Int. Ass. Ereast Cancer Res., Sendai Jp, 1994, September 25-28, Int. J. Oncol 5 (Suppl.), 1994, 381).
• Calpain inhibitors have already been described in the literature. However, these are predominantly either irreversible or peptide inhibitors. Irreversible inhibitors are usually alkylating substances and have the disadvantage that they are in the
• the irreversible inhibitors include, for example, the epoxides E 64 (E.B. McGowan et al., Bio formerly Biophys. Res. Commun.
• peptidic aldehydes in particular dipeptide and tripepidic aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S.Mehdi, Trends in Biol. Sei. 1991, 16, 150-3).
• peptidic aldehydes Under physiological conditions, peptidic aldehydes have the disadvantage that they are often unstable due to their high reactivity, can be metabolized quickly and lead to unspecific 3 see reactions that can be the cause of toxic effects (JA-Fehrentz and B. Castro, Synthesis 1983, 676-78.
• JP 08183771 (CA 1996, 605307) and EP 520336 have described aldehydes which are derived from 4-piperidinoylamides and 1-carbonyl-piperidino-4-yl amides as calpain inhibitors.
• the aldehydes claimed here which are derived from heteroaromatically substituted amides of the general structure I, have so far been described.
• Other aldehyde derivatives are in Chatterjee ez al. Bioorganic & Medicinal Chemistry Letters 1997, 7, 287-290, Bioorganic & Medicinal Chemistry Letters 1996, 6, 1619-1622, WO 97/10231 and WO 97/21690.
• Peptidic ketone derivatives are also inhibitors of cysteine proteases, especially calpains.
• cysteine proteases especially calpains.
• ketone derivatives are known as inhibitors, the keto group being activated by an electron-withdrawing group such as CF3.
• CF3 electron-withdrawing group
• cysteine proteases derivatives with ketones activated by CF3 or similar groups have little or no activity (MRAngelas ro et al., J.Med. Chem. 1990, 33, 11-13).
• a xanthene derivative of a ketobenzamide has been described as a cal pain inhibitor.
• 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 analogous phenyl derivative Ph-CONH-CH (CH 2 Ph) -CO-COCOOCH 3 was described in MRAngelastro et al. , J. Med. Chem. 1990, 33, 11-13 as a weak calpain inhibitor, however. This derivative is also in JPBurkhardt, Tetra - hedron Let t. , 1988, 3433-36.
• substituted benzamides has never been investigated.
• the active ingredients are administered intravenously as a solution for infusion.
• calpain inhibitors which have sufficient water solubility so that an infusion solution can be prepared.
• calpain inhibitors have the disadvantage that they wrestle only ge ⁇ or show water solubility and thus is ineligible for intravenous application in question.
• Such active substances can only be applied with auxiliaries which are intended to impart water solubility (cf. RT Bartus et al. J Cereb. Blood Flow Metab. 1994, 14, 537-544).
• auxiliaries which are intended to impart water solubility
• these additives for example polyethylene glycol
• a non-peptide calpain inhibitor which is therefore water-soluble without auxiliaries and therefore probably more tolerable, can be used to great advantage.
• Well-effective non-peptide calpain inhibitors with sufficient water solubility have not been described so far and would therefore be new.
• Non-peptidic aldehydes, ketocarboxylic acid esters and ketoamide derivatives have been described in the present invention. These compounds are novel and surprisingly show the possible ⁇ ness on, by incorporation of rigid structural fragments po ⁇ tent non-peptide inhibitors of cysteine proteases such as calpain to. Furthermore, salt bonds with acids are possible in the present compounds of the general formula I, which all carry at least one aliphatic amine radical. This leads to an improved solubility in water and thus the compounds show the desired profile for intravenous application, as is required, for example, in stroke therapy.
• the present invention relates to substituted amides of the general formula I
• Rl can be -C 6 alkyl, phenyl, naphthyl, quinolyl, pyridyl, pyrimidyl, pyridazyl, quinazolyl and quinoxalyl, where the rings can also be substituted with up to 2 radicals R4, and
• R3 means hydrogen and CO-NR6R7
• R4 is hydrogen, Cl-C4-alkyl, branched or unbranched and 0-Cl-C4-alkyl;
• R5 is hydrogen, C1-C4-alkyl, branched or unbranched and - 0-C1-C4-alkyl;
• R6 is hydrogen, -CC 6 alkyl, branched and unbranched, means, and
• R7 is hydrogen, Ci-C ⁇ -Al yl, branched or unbranched, means, and
• n means a number 0, 1 or 2.
• 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 produced by using commercially available compounds, for example optically active amino acids such as phenylalanine, tryptophan 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.
• amides I according to the invention which carry an aldehyde group can be prepared in various ways, which was outlined in synthesis scheme 1.
• Carboxylic acids II are linked with suitable amino alcohols III to give the corresponding amides IV.
• Common peptide coupling methods are used, either in CRLarock, 7
• 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 + 250C, depending on the method (see literature above).
• 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 Abspal ⁇ processing of the protecting group P, for example Boc takes place in a customary manner, for example with 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 00C in inert solvents such as tetrahydrofuran or ether. 8th
• the substituted amides I according to the invention, a Ketoamid- or keto group carry, can on Various - done 0 nen paths that in the synthesis scheme 2 WUR outlined ⁇ .
• the carboxylic acids II are mixed with aminohydroxycarboxylic acid derivatives X (preparation of XI see SLHarbenson et al., J.Med. Chem. 1994, 37, 2918-29 or JP Burkhardt et al. Tetrahedron Let t. 40 1988, 29, 3433- 3436) under customary peptide coupling methods (see above, Houben-Weyl), whereby amides XIII are obtained.
• the derivatives XIII obtained can be oxidized to the ketocarboxylic acid derivatives I 'according to the invention.
• Various customary oxidation reactions see CRLarock, Comprehensive Organi c Transformations, VCH Publisher, 1989, page 604 f.
• 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 (S. L. Harbenson et al., See above) , to use.
• these can be hydrolyzed to carboxylic acids XII, the procedure being analogous to the above methods, but preferably with lithium hydroxide in water / tetrahydrofuran mixtures at room temperature, but note that that in this case a radical is selected for the protective group R ', for example tert-butyl-O, which allows the selective cleavage of one of the two ester groups.
• R ' for example tert-butyl-O
• Other amides XIII are prepared by reaction with amines under coupling conditions already described. The alcohol derivative XIII can be oxidized again to ketocarboxylic acid derivatives I 'according to the invention.
• 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). 10
• Amides and sulfonamides are prepared analogously to the methods described above from the amines and acid derivatives.
• compounds of general formula I can also be synthesized by changing or swapping the reaction sequences listed in Schemes 1 and 2.
• the further reaction to I takes place, as shown in the scheme, by ester hydrolysis and oxidation.
• 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 carried out 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 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 microplate reader. The IC50's are then determined from the maximum gradients. 11
• 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, the fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachem / 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 find compounds with better membrane compatibility. We use human platelets as evidence of the passage of calpain inhibitors into the membrane. 12
• the platelet-rich plasma was pooled and diluted 1: 1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KC1, 0.5 M 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 107 cells / ml. The human platelets were isolated at RT.
• test mixture isolated platelets (2 x 106) 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 2 . After 5 min. Incubation, the platelets were yaws briefly at 13,000 rpm zentrifu ⁇ and the pellet in SDS sample buffer was added (SDS sample buffer: 20 mM Tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.
• 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 (pp60src) used was purchased from Biomol Fein-Chemicals (Hamburg). This primary antibody was detected using an HRP-coupled second goat antibody (Boehringer Mannheim, FRG). The Western blotting was carried out according to known methods.
• pp60src The cleavage of pp60src was quantified densitometrically, using non-activated controls (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 50 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 5 seven days (ornithine coated plates) with FDU
• LDH lactate dehydrogenase
• cell death can be triggered by calcium in the presence of the ionophore A 23187.
• 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 have died is calculated from the two controls with cells without inhibitors that are absent and
• 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 40 lead system
• neurodegenerative diseases such as Huntington's and Parkinson's disease, neurotoxic disorders after hypoxia, anoxia, ischemia and 14 after lesions as they occur after stroke and trauma, or also as anti-epileptics (see Medicinal Research 1990, 40, 511-514; TIPS, 1990, 11, 334-338; Drugs of the Fu ture 1989, 14-, 1059-1071).
• EAA Extracerebral application of excitatory amino acids
• EAA antagonists centrally active substances
• 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, damage by reperfusion after vascular occlusion, 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, damage to the kidneys after renal ischemia, skeletal muscle damage, muscular dystrophies, damage caused by proliferation of the smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes, re-stenosis of the bloodstream Serve angioplasty.
• the amides I can be useful in the chemotherapy of tumors and their metastasis and for the treatment of diseases in which an increased level of interleukin-1 occurs, such as inflammation and rheumatic diseases. 15
• 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, in addition to the active ingredient, the customary excipients and diluents.
• pharmaceutical-technical auxiliaries such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycolostearate, ethoxylated fatty alcohols, paraffin oil, vase ⁇ line 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.
• 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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  • 1999-04-19 EP EP99917996A patent/EP1073631A1/de not_active Withdrawn
  • 1999-04-19 CA CA002328435A patent/CA2328435A1/en not_active Abandoned
  • 1999-04-19 SK SK1394-2000A patent/SK13942000A3/sk unknown
  • 1999-04-19 US US09/647,677 patent/US6448254B1/en not_active Expired - Fee Related
• 2000
  • 2000-10-13 BG BG104855A patent/BG104855A/xx unknown
  • 2000-10-19 NO NO20005266A patent/NO20005266D0/no not_active Application Discontinuation
  • 2000-11-15 HR HR20000776A patent/HRP20000776A2/hr not_active Application Discontinuation
  • 2000-11-17 ZA ZA200006711A patent/ZA200006711B/en unknown

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