Title of Invention

"ARYLGLYCINAMIDE DERIVATIVES"

Abstract

Arylglycinamide derivatives of general formula I or the pharmaceutically acceptable salts of inorganic acids selected from hydrochloric acid, sulphuric acid, phosphoric acid or sulphonic acid or organic acids selected from maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid or as salts with pharmaceutically acceptable bases selected from alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines selected from diethylamine, triethylamine or triethanolamine, wherein Ar denotes unsubstituted or mono- or di-substituced phenyl, or unsubstituted naphthyl, [in which the substituents of the phenyl independently of each other denote halogen (F, CI, Br, I), OH, methyl, methoxy, CF3, OCF3 or dimethylamine] or Ar is phenyl substituted by -OCH2O-, this group linking positions 2 and 3 or 3 and 4 of the phenyl; X denotes N(CH2)nR6 or CR7R8, wherein n is 0, 1 or 2, R4 denotes phenyl (C1-4) alkyl or naphthyl (C1-4) alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another are halogen (F, CI, Br, I), (C1-4)alkyl, O-(C1-4)alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of one another denote H, methyl or acetyl); and R5 denotes H, (C1-4)alkyl, (C3-6)cycloalkyl, CH2COOH, -CH2C(0)NH2, -OH or phenyl(C1-4)alkyl, with the proviso that 4-phenyl-l-(2-phenylacetic acid-N-benzylamide)-piperidine is excepted.

Full Text

The present invention relates to arylglycinamide derivatives. The invention relates to new arylglycinamide derivatives of general formula I (Formula Removed) and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists. The abbreviations used in the specification and claims are explained as follows: GDI = Carbonyldiimidazole DCCI = Dicyclohexylcarbodiimide HOBt = l-Hydroxybenzotriazole THF = Tetrahydrofuran DMF = Dimethyl formamide RT = Room temperature DMAP = 4-Dimethylaminopyridine TBTU = 0-Benzotriazolyl-tetramethyluronium- tetrafluoroborate In order to show the formulae, a simplified representation is used. In the representation of the compounds all CH3-substituents are represented by a single bond, and for example the following formula (Formula Removed) represents (Formula Removed) The invention relates to new arylglycinamide derivatives of general formula I (Formula Removed) or the pharmaceutically acceptable salts thereof, wherein Ar denotes unsubstituted or mono- to penta-substituted phenyl, or unsubstituted or mono- or di-substituted naphthyl, [in which the substituents of the phenyl and naphthyl independently of each other denote halogen (F, Cl, Br, I), OH, (C1-4)alkyl, 0-(C1-4) alkyl, CF3, OCF3 or NR9R10 (wherein R9 and R10 independently of each other denote H, methyl or acetyl)] or Ar is phenyl substituted by -OCH2O- or -0(CH2)20-; R1 and R2 together with the N to which they are bound form a ring of the formula (Formula Removed) wherein p is 2 or 3, X denotes oxygen, N(CH2)nR6 or CR7R8, wherein n is 0, 1 or 2, R6 is (C3-7)cycloalkyl, phenyl or naphthyl, wherein the phenyl may be mono- to tri-substituted by halogen (F, Cl, Br, I), (C1-4)alkyl, 0-(C1-4) alkyl, CF3, OCF3 or NR15R16 (wherein R15 and R16 independently of each other denote H, methyl or acetyl); R7 and R8 have one of the following meanings: a) R7 and R8 represent H if R3 is unsubstituted or substituted phenyl, b) R7 is phenyl, phenyl substituted by 1 to 3 substituents [wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, O-(C1-4)alkyl, CF3 or OCF3] , piperidinyl, 1-methylpiperidinyl, (Formula Removed) if R8 is H, -CONH2, -NHC(0)CH3, -N(CH3) C (O) CH3, CN (Formula Removed) or -C(0)N( (C1-3)alkyl)2 or c) R7 and R8 together form the group (Formula Removed) R3 denotes H, (C1-4)alkyl, unsubstituted or mono- to tri-substituted phenyl, wherein the substituents independently of one another represent halogen (F, Cl, Br, I), (C1-4)alkyl, O-(C1-4) alkyl, CF3, OCF3 or NR17R18 (wherein R17 and R18 independently of one another denote H, methyl or acetyl); R4 denotes phenyl (C1-4) alkyl or naphthyl (C1-4) alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another are halogen (F, CI, Br, I), (C1-4)alkyl, 0-(C1-4) alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of one another denote H, methyl or acetyl); and R5 denotes H, (C1-4) alkyl, (C3-6) cycloalkyl, CH2COOH, -CH2C(O)NH2, -OH or phenyl (C1-4) alkyl. The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P-antagonism and also neurokinin A- or neurokinin B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases. Compounds of general formula I may contain acid groups, chiefly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula I may therefore be obtained either as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid or sulphonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine or triethanolamine, etc. The compounds according to the invention may occur as racemates but may also be obtained as pure enantiomers, i.e. in (R)- or (S)-form. They may also occur as diastereoisomers or mixtures thereof. The preferred compounds of general formula I are those wherein R1 and R2 together with the N to which they are bound form a 6-membered ring of the formula (Formula Removed) wherein X denotes N(CH2)nR6 or CR7R8, wherein n, R6, R7 and R8 are defined as in claim 1. Particular mention should be made of compounds of formula I wherein X is N(CH2)nR6 wherein n is 0, 1 or 2 and R6 is (C3-7)cycloalkyl or phenyl, particularly those compounds wherein n is 0 and R6 is (C3-7) cycloalkyl, particularly those compounds wherein R6 is cyclobutyl or cyclohexyl. Mention should also be made of compounds of formula I wherein R7 and R8 have one of the following meanings: a) R7 and R8 denote H when R3 is unsubstituted or substituted phenyl, b) R7 is phenyl, piperidinyl (Formula Removed) if R8 is H, -CONH2, -NHC(0)CH3, -N(CH3) C (O) CH3 or CN, or c) R7 and R8 together form the group (Formula Removed) particularly those wherein R7 and R8 have one of the following meanings: a) R7and R8 denote H when R3 is unsubstituted or substituted phenyl, b) R7 is phenyl, (Formula Removed) when R8 is H, -CONH2 or CN, or c) R7 and R8 together form the group (Formula Removed) The preferred compounds are those wherein R7 denotes phenyl, (Formula Removed) and R8 is H or CN, particularly those wherein R7 is pyridine and R8 is H. Of the compounds defined above, the preferred ones are those wherein Ar denotes unsubstituted or mono- or di-substituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br, I), OH, methyl, methoxy, CF3, OCF3 or dimethyl amine] or Ar is phenyl substituted by -OCH2O-, this group connecting positions 2 and 3 or 3 and 4 of the phenyl, particularly those wherein Ar denotes unsubstituted or mono- or di-substituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br), methoxy or CF3] or Ar is phenyl substituted by -OCH2O-, this group connecting positions 2 and 3 or 3 and 4 of the phenyl. The preferred compounds are those wherein Ar is phenyl, 3 , 4-dichlorophenyl, 3,4-dimethoxyphenyl or 3,4-methylenedioxyphenyl. Of the compounds defined above, particular mention should be made of those wherein R3 is phenyl or preferably H. Of the compounds defined above, mention should also be made of those wherein R4 denotes phenyl (C1-3)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, the substituents independently of one another being halogen (F, C1, Br, I), methyl, methoxy, CF3 or OCF3 ; and R5 denotes H, (C1-3)alkyl, CH2COOH, -CH2C(O)NH2 or phenethyl, particularly those compounds wherein (Formula Removed) and R5 denotes H or CH3. The following compounds are preferred: (Formula Removed) and (Formula Removed) The term naphthyl used above includes both 1-naphthyl and 2-naphthyl. The present invention relates to Arylglycinamide derivatives of general formula I (Formula Removed) or the pharmaceutically acceptable salts of inorganic acids selected from hydrochloric acid, sulphuric acid, phosphoric acid or sulphonic acid or organic acids selected from maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid or as salts with pharmaceutically acceptable bases selected from alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines selected from diethylatnine, triethylamine or triethanolamine, wherein AR denotes unsubstituted or mono- or di-substituced phenyl, or unsubstituted naphthyl, [in which the substituents of the phenyl independently of each other denote halogen (F, CI, Br, I), OH, methyl, methoxy, CF3, OCF3 or dimethylamine] or Ar is phenyl substituted by -OCH2O-, this group linking positions 2 and 3 or 3 and 4 of the phenyl; p is 2 or 3, X denotes N(CH2)nR6 or CR7R8, wherein n is 0, 1 or 2, R6 is {C3-7)cycloalkyl or phenyl, R7 and R8 have one of the following meanings: a) R7 is phenyl, piperidinyl. (Formula Removed) and R8 is H, -CONH2, -NHC(0)CH3, -N(CH3)C(O)CH3, CN or c) R7 and R8 together form the group (Formula Removed) R4 denotes phenyl (C1-4) alkyl or naphthyl (C1-4) alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another are halogen (F, CI, Br, I), (C1-4)alkyl, 0-(C1- 4)alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of one another denote H, methyl or acetyl); and R5 denotes H, {C1-4)alkyl, (C3-6)cycloalkyl, CH2COOH, -CH2C(O)NH2, -OH or phenyl(C1-4) alkyl, with the proviso that 4-phenyl-l-{2-phenylacetic acid-N-benzylamide)-piperidine is excepted. Test results for compounds according to the invention: The receptor affinity for the NK1-receptor (substance P-receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK1-receptors, measuring the displacement of 125I-labelled substance P. The Ki-values thus obtained demonstrate the efficacy of the compounds: Compound of Example 3: 1.4 nM Compound of Example 4: 1.0 nM Compound of Example 5: 1.3 nM Compound of Example 33: 1.3 nM Compound of Example 45: 1.6 nM Compound of Example 46: 1.4 nM Compound of Example 52: 1.1 nM Compound of Example 53: 2.3 nM Compound of Example 58: 6.4 nM Compound of Example 59: 4.2 nM Compound of Example 65: 9.2 nM Compound of Example 66: 1.4 nM Compound of Example 68: 1.5 nM Compound of Example 70: 2.8 nM Compound of Example 71: 2 .1 nM Compound of Example 72: 6 . 8 nM Compound of Example 73: 1.7 nM Compound of Example 74: 11.8 nM Compound of Example 75: 18 0 nM Compound of Example 76: 7.0 nM The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have, in particular, NK1-antagonism, but also NK2- and NK3-antagonistic properties. The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P-antagonism and also neurokinin A- or neurokinin B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases: treatment and prevention of inflammatory and allergic diseases of the respiratory tract, such as asthma, chronic bronchitis, emphysema, rhinitis or coughs, eye diseases such as conjunctivitis and iritis, skin diseases such as dermatitis in contact eczema, urticaria, psoriasis, sunburn, insect bites and stings, neurodermitis, itching and postherpetic pain, diseases of the gastrointestinal tract such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel, Hirschsprung's disease; diseases of the joints such as rheumatoid arthritis, reactive arthritis and Reiter syndrome; for treating diseases of the central nervous system such as dementia, Alzheimer's disease, schizophrenia, psychosis, depression, headaches (e.g. migraine or tension headaches) and epilepsy; for the treatment of tumours, collagenosis, dysfunction of the urinary tract, haemorrhoids, nausea and vomiting, triggered for example by radiation or cytostatic therapy or motion and pain of all kinds. The invention therefore also relates to the use of the compounds according to the invention as remedies and pharmaceutical preparations which contain these compounds. They are preferably for use in humans. The compounds according to the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route or by inhalation, by transdermal route, if desired with the aid of iontophoresis or enhancers known from the literature, and by oral route. For parenteral administration, the compounds of formula I or the physiologically acceptable salts thereof, optionally with conventional substances such as solubilisers, emulsifiers or other adjuvants, may be made into solutions, suspensions or emulsions. Suitable solvents include, for example, water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of various solvents. In addition, the compounds may be administered by means of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or by mesins of intranasal preparations. The oral effectiveness of compounds of general formula I can be demonstrated using the following standard test: Inhibition of the lowering of blood pressure caused by NK1 in anaesthetised guinea pigs. Guinea pigs weighing 300-500 grams were anaesthetised with pentobarbital (50 mg/kg i.p.), intubated and mechanically ventilated with 10 ml of ambient air per kg of body weight at a rate of 60 breaths per minute. The blood pressure was measured in the blood flow through the carotid artery. In order to introduce substances intravenously, the jugular vein was cannulated. By the intravenous administration of the NK1-agonist [ßAla4, Sar9, Met(O2)11] SP(4-11) (0.2 µmol/kg) a brief lowering of the blood pressure was triggered which was repeated at 10 minute intervals by repeatedly giving the NK1-agonist. (Formula Removed) The neurokinin-antagonist was then administered by intraduodenal route and at 10 minute intervals a lowering of blood pressure was induced by means of the NK1-agonist. The inhibition of the lowering of blood pressure caused by the above-mentioned NK1-agonist was measured before and after treatment with the neurokinin-antagonist. The compound of Example 5 yielded an ID50 of 1.4 mg/kg. (ID50 is the dose which inhibits the lowering of blood pressure caused by the NK1-agonist by 50%.) The compounds according to the invention may be prepared by generally known methods. The compounds may be prepared in various ways. The two commonest methods are shown in the following scheme: (Formula Removed) Method A. The carboxylic acid may be linked to the amine HN(R5)R4 in various ways. The usual methods are coupling methods such as those used in peptide chemistry. A coupling reagent such as TBTU, DCCI/HOBt, GDI, etc., is added to the coupling partners in an approximately equivalent amount. Suitable solvents are DMF, THF, CH2Cl2, CHCl3, acetonitrile or other inert solvents or mixtures thereof. The appropriate temperature range is between -50°C and +120°C, preferably between 0°C and 40°C. The carboxylic acid may also initially be converted by means of SOCI2, SO2Cl2, PCI3, PCI5 or PBrs or mixtures thereof, by known methods, into the corresponding acid halide which is subsequently reacted with the amine HN(R5).R4 in an inert solvent such as CH2Cl2, THF or dioxane at temperatures between -50°C and +100°C, typically between 0°C and 20°C. Another alternative is to convert the carboxylic acid initially into the alkylester, usually the methylester, by known methods and then to react this ester with the amine HN(R5)R4 in an inert solvent such as DMF, dioxane or THF. The reaction temperatures are between 20°C and 150°C, typically between 50°C and 120°C. The reaction may also be carried out in a pressurised container. Process B. In this, the α-halo-arylacetamide derivative obtained according to known procedures is reacted with the amine R1(R2)NH, thereby generating hydrogen halide. In order to mop up the cleaved (or excess) hydrogen halide, inorganic bases are used such as K2CO3, NaHCO3 or CaCO3, or organic bases may be used such as triethylamine, Hiinig base, pyridine or DMAP, or an excess of the amine R1(R2)NH may be used. DMF, THF, dioxane or other inert solvents are used. The temperature range for the reaction is from 0 to lO0°C, typically from 10 to 80°C. Process C. The compounds according to the invention in which R5 is not H may also be prepared as follows: first of all, the corresponding compound in which R5 is H is synthesised according to process A or B. Then N-alkylation is carried out as follows in order to introduce alkyl, cycloalkyl or CH2COOH. The compound according to the invention wherein R5 is H is deprotonated with an equivalent quantity of NaH, NaNH2, KOH, NaOCH3 or some other strong base. Anhydrous inert solvents such as THF, dioxane or diethylether are used. Then the corresponding alkylating agent is added slowly in the form of the corresponding halide, tosylate or mesylate. The reaction is carried out in the temperature range from -50°C to +100°C, typically between 0°C and +50°C. The method is described in detail in Example 33. Example 1: (Formula Removed) 1st Step: 2.2 g of 1-cyclohexylpiperazine were dissolved in 150 ml of anhydrous DMF, mixed with 2 g of K2CO3, stirred at room temperature for 2 0 minutes and then cooled to 5°C. 2.7 g of methyl (R, S)-α-bromophenylacetic acid were added and the suspension was stirred overnight at RT. The precipitate was filtered off and the filtrate was evaporated down. The residue was taken up in ethyl acetate, extracted twice with 10% KHCO3 solution and once with saturated NaCl solution. The organic phase was dried over Na2S04, filtered and evaporated down, and 3.7 g of (R, S) -l-cyclohexyl-4- (methyl 2-phenylacetate)-piperazine were obtained in the form of a yellow oil. Yield: about 100%. 2nd Step: 2.3 g of the product of the first step were dissolved in 10 ml of methanol, mixed with 14 ml of IN NaOH and the resulting emulsion was stirred overnight at room temperature. The clear reaction solution was neutralised by the addition of 14 ml of 1N HCl, evaporated to dryness, the residue was treated with isopropanol and the solid matter was collected by suction filtration. The filtrate was evaporated down and the residue was triturated again with isopropanol, the solid matter was suction filtered and combined with the solid obtained earlier. In this way, 1.6 g of (R,S)-1-cyclohexyl-4-(2-phenylacetic acid)-piperazine were obtained as a white solid. Yield: 75%. 3rd Step: 0.6 g of the product of the second step, 0.48 g of 3 , 5-bis-(trifluoromethyl)-benzylamine and 0.32 g of HOBT were suspended in 60 ml of THF/CH2CI2 (1:1) and adjusted to pH 8.5 by the addition of about 0.7 ml of Hiinig base. 0.77 g of TBTU were added and the mixture was stirred overnight at room temperature. The clear reaction solution was evaporated down in vacuo, the residue was taken up in CH2Cl2 and extracted twice with 10% KHSO4 solution, once with saturated NaCl solution, twice with 10% KHCO3 solution and once more with saturated NaCl solution. The organic phase was dried over Na2S04, filtered and evaporated down, whereupon crystallisation took place. 0.685 g of (R,S)-l-cyclohexyl-piperazinyl-4-[2 -phenylacetic acid-N-(3,5-bis- trif luoromethylbenzyl) amide] were obtained as a yellowish solid. Yield 64%. Mp: 124 - 129°C. FAB-MS : (M+H)+ = 528.2. Example 2 (Formula Removed) 1st step: 0.49 g of 3,5-bis-(trifluoromethyl)-benzylamine were dissolved in 30 ml of anhydrous CH2Cl2, 0.3 ml of triethylamine were added, the mixture was cooled in an ice bath and over 2 0 minutes a solution of 0.46 g of (R,S)-α-bromophenylacetyl chloride in 10 ml of CH2Cl2 was added dropwise. After the mixture had stood at room temperature over a weekend, the solvent was eliminated and the solid residue was triturated with diethylether, suction filtered and the filtrate was evaporated down. 0.6 g of α-bromophenylacetic acid N- (bis-trifluoromethyl-benzyl)-amide were obtained as a light beige solid. Yield: 43.5%. 2nd Step: 0.21 g of 4-propionylamino-piperidine hydrochloride were dissolved in 3 0 ml of anhydrous DMF, 0.33 g of K2CO3 were added and the mixture was stirred for 30 minutes at room temperature. Over 20 minutes a solution of 0.68 g of the product of the first step in 10 ml of DMF were added dropwise to this mixture, which was then stirred overnight at room temperature. The suspension was filtered, the filtrate was evaporated down, the oily residue obtained was taken up in ethyl acetate, extracted twice with 10% KHCO3 solution and once with saturated NaCl solution. The organic phase was dried over Na2S04, filtered, the filtrate was evaporated down and the semi-solid residue obtained was triturated with diethylether and suction filtered. 0.33 g of (R,S)-4-propionylamino-l- [2-phenylacetic acid-N(3,5-bis-trifluoromethyl-benzyl) -amide] -piperidine were obtained as a white solid. Yield: 64%. Mp: 189 - 191°C FAB-MS: (M+H) "" = 516.4. Example 33: (Formula Removed) Mp: >240°C; FAB-MS: (M+H)+ = 556.4 0.3 g of the compound according to Example 25 were converted into the corresponding base by treatment with KHCO3 and dried. The resulting product was dissolved in 5 ml of anhydrous THF, 34 mg of NaH (60% in oil) were added and the mixture was stirred for 1.5 hours at room temperature. Then 0.1 g of methyliodide were added and the mixture was stirred overnight. The reaction mixture was mixed with 2 ml of THF/water (1:1) then with 25 ml of water and extracted 3 times with ether. The combined ether extracts were dried over Na2S04 and evaporated down in vacuo, thereby obtained 170 mg of the desired compound in the form of a free base (oil) . This was converted into the dihydrochloride by the addition of an excess of ethereal HCl, the dihydrochloride being obtained in the form of yellow crystals. Yield: 113 mg (36%) . The other compounds of the invention may be prepared analogously, e.g. as follows: Example 3 (Formula Removed) Mp: 235 - 238°C. FAB-MS: (M+H) ^ = 542.2 Example 4 (Formula Removed) Mp: >240°C (Decomp.). FAB-MS: (M+H)+ = 542.3 Example 5 (Formula Removed) Mp: 158 - 164°C; FAB-MS: (M+H)+= 556.4 Example 6 (Formula Removed) Mp: 97 - 99°C; FAB-MS: (M+H)+ = 556.3 Example 7 (Formula Removed) Mp: >240° (Decomp.); FAB-MS: (M+H)+ = 528.4. Example 8: (Formula Removed) Mp: 102 - 105°C; FAB-MS: (M+H)+ = 640.3 Example 9: (Formula Removed) Mp: 141 - 149°C; FAB-MS: (M+H)+ = 579.2. Example 10 (Formula Removed) Mp: 218-223°C; FAB-MS: (M+H)+ = 579.3 ^- Example 11: (Formula Removed) Mp: >220° (Decomp.); FAB-MS (M+H)+ = 571.3 Example 12: (Formula Removed) Mp: 205-210°C; FAB-MS: (M+H)+ = 591.3 Example 13 (Formula Removed) Mp: 87 - 95°C,- FAB-MS: (M+H)+ = 571.2 Example 14 (Formula Removed) Mp: 164-166°C; FAB-MS: (M+H)+ = 537.3. Example 15 (Formula Removed) Mp: 208 - 210'C; FAB-MS: (M+H)+ = 578.3. Example 16: (Formula Removed) Mp: 110-115°C; FAB-MS: (M+H)+ = 542.3 Example 17 (Formula Removed) Mp: 118 - 123°C; FAB-MS: (M+H)+ = 556.3 Example 18: (Formula Removed) Mp: 134 - 136°C; FAB-MS: (M+H)+ = 514.3 Example 19: (Formula Removed) Mp: >240° (Decomp.): FAB-MS: (M+H)+ = 564 Example 20 (Formula Removed) Mp: 180 - 185°C; FAB-MS: (M+H)+ = 564.3 Example 21 (Formula Removed) Mp: 228 - 232°C; FAB-MS: (M+H)+ = 606/608 Example 2 2 (Formula Removed) Mp: 70 - 73°C; FAB-MS: (M+H)+ = 586 Example 23 (Formula Removed) Mp: 248 - 254°C; FAB-MS: (M+H)+ = 596/598/600 Example 24 (Formula Removed) Mp: 210°C; FAB-MS: (M+H)+= 664.1 Example 25 (Formula Removed) Mp: 192 - 199°C; FAB-MS : (M+H)+ = 542.3 Example 26 (Formula Removed) Mp: 112 - IIS-C; FAB-MS: (M+H)"" = 562/564 Example 27 (Formula Removed) Mp: 124 - 127°C; FAB-MS: (M+H)+ = 606/608 Example 28 (Formula Removed) Mp: 118 - 120°C; FAB-MS: (M+H)+ = 606/608 Example 29 (Formula Removed) Mp: 120 - 122°C; FAB-MS: (M+H)+ = 562/564 Example 3 0 (Formula Removed) Mp: >240°C; FAB-MS: (M+H)+ = 562/564 Example 31 (Formula Removed) Mp: >24 0°C; FAB-MS: (M+H)+ = 546.3 - Sh^ Example 32 (Formula Removed) Mp: 125-130°C (Decomp. ) ; FAB-MS: (M+H)+ = 610.4 Example 33 (Formula Removed) Mp: >240'C; FAB-MS: (M+H)"" = 556.4 Example 34 (Formula Removed) Mp: 145 - 151°C; FAB-MS: (M+H) + = 641.3 Example 35 (Formula Removed) Example 36 (Formula Removed) Mp: 175 - 176.5°C Example 37 (Formula Removed) Mp: 157 - 158° Example 38 (Formula Removed) Mp: 155 - 172°C FAB-MS: (M + H) + = 592.2 Example 40 Example 39(Formula Removed) Example 40 (Formula Removed) Example 41 (Formula Removed) Example 42 (Formula Removed) Mp: 142 - 150°C FAB-MS: (M + H) + = 558.2 Example 43 (Formula Removed) Example 44 (Formula Removed) Mp: 107 - 111°C; FAB-MS: (M+H)+ = 575.6 Example 45 (Formula Removed) M.p: >230°C Example 46 (Formula Removed) M.p: >230°C Example 4 7 (Formula Removed) M.p: 127-137°C FAB-MS: (M+H) + = 592 Example 48 (Formula Removed) Example 49 (Formula Removed) Example 50 (Formula Removed) M.p. 106-110°C FAB-MS: (M+H)+ = 549.4 Example 51 (Formula Removed) Example 52 (Formula Removed) Mp: 133 -143 °C FAB-MS: (M+H)+ = 542.3 Example 53 (Formula Removed) M.p. 110-120ºC FAB-MS: (M+H)+ = 570.4 Example 54 (Formula Removed) Example 55(Formula Removed) Example 5 6 (Formula Removed) Example 5 7 (Formula Removed) Example 5 8 (Formula Removed) Mp: 212 - 216°C (Decomp.) FAB-MS: (M+H)+ = 624.3/626.3/628.3 Example 5 9 (Formula Removed) Mp: 244 - 246ºC (Decomp.) FAB-MS: (M + H) + = 624.1/626.2/628 Example 6 0 (Formula Removed) Mp: 113 - 123°C FAB-MS: (M+H)+ = 550.3 Example 61 (Formula Removed) Mp: 195 - 205°C Example 62(Formula Removed) Mp: 210 - 218ºC FAB-MS: (M + H) + = 620/622 Example 63 (Formula Removed) Mp: 215 - 224°C FAB-MS: (M + H)+ = 576/578 Example 64 (Formula Removed) Mp: 85 - 92°C FAB-MS: (M + H)+ = 572.5 Example 65(Formula Removed) Mp: 148 - 156°C FAB-MS: (M + H)+= 578.4 Example 66 (Formula Removed) Mp: 113 - 117°C (decomp.) FAB-MS: (M + H)+ = 528.5 Example 67 (Formula Removed) Mp: 265 - 268ºC (decomp.) FAB-MS: (M + H)+ = 619.3 Example 68 (Formula Removed) Mp: 236 - 238°C (decomp.) FAB-MS: (M + H) + = 528.3 Example 69 (Formula Removed) Mp: 177 - 187°C FAB-MS: (M + H)+ = 605.3 Example 7 0 (Formula Removed) Mp: 123 - 133ºC (decomp.) FAB-MS: (M + H) + = 616.3 Example 71 (Formula Removed) Mp: 87 - 97°C FAB-MS: (M + H)+ = 600.2 Example 72 Mp: >230°C Example 73 (Formula Removed) Mp: >230ºC Example 74 (Formula Removed) Mp: >230°C Example 75 (Formula Removed) Mp: 91 - 98°C. FAB-MS: (M + H)+ = 574.4 Example 76 (Formula Removed) Mp: 234 - 236°C Example 77 (Formula Removed) Mp: 195 - 198ºC Example 78 (Formula Removed) Pharmaceutical Preparations: In-iectable solution 200 mg of active substance* 1.2 mg of monopotassium dihydrogen phospate = KH2PO4 ) 0.2 mg of disodium hydrogen phosphate = ) (buffer) NaH2P04. 2H2O ) 94 mg of sodium chloride ) or ) (isotonic) 520 mg of glucose ) 4 mg of albumin (protease protection) q.s. sodium hydroxide solution ) q.s. hydrochloric acid ) to adjust the pH to pH 6 sufficient water to make a 10 ml solution for injection Injectible solution 200 mg of active substance* 94 mg of sodium chloride or 520 mg of glucose 4 mg of albumin q.s. sodium hydroxide solution ) q.s. hydrochloric acid ) to adjust the pH to pH 9 sufficient water to make a 10 ml solution for injections Lyophilisate 200 mg of active substance* 520 mg of mannitol (isotonic/structural component) 4 mg of albumin Solvent 1 for lyophilisate 10 ml of water for injections Solvent 2 for lyophilisate 20 mg of Polysorbate®80 = Tween®80 (surfactant) 10 ml of water for injections * Active substance: compound according to the invention, e.g. that of Examples 1 to 78. Dosage for humans weighing 67 kg: 1 to 500 mg We Claim: 1. Arylglycinamide derivatives of general formula I (Formula Removed) or the pharmaceutically acceptable salts of inorganic acids selected from hydrochloric acid, sulphuric acid, phosphoric acid or sulphonic acid or organic acids selected from maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid or as salts with pharmaceutically acceptable bases selected from alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines selected from diethylamine, triethylamine or triethanolamine, wherein Ar denotes unsubstituted or mono- or di-substituced phenyl, or unsubstituted naphthyl, [in which the substituents of the phenyl independently of each other denote halogen (F, CI, Br, I), OH, methyl, methoxy, CF3, OCF3 or dimethylamine] or Ar is phenyl substituted by -OCH2O-, this group linking positions 2 and 3 or 3 and 4 of the phenyl; p is 2 or 3, X denotes N(CH2}nR6 or CR7R8, wherein n is 0, 1 or 2, R6 is (C3-7)cycloalkyl or phenyl,- R7 and R8 have one of the following meanings: a) R7 is phenyl, piperidinyl, (Formula Removed) and R8 is H, -CONH2, -NHC(0)CH3. -N(CH3)C(0)CH3, CN or c) R7 and R8 together form the group (Formula Removed) R4 denotes phenyl (C1-4) alkyl or naphthyl (C1-4) alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another are halogen (F, CI, Br, I), (C1-4)alkyl, O-(C1-4)alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of one another denote H, methyl or acetyl); and R5 denotes H, (C1-4)alkyl, (C3-6)cycloalkyl, CH2COOH, -CH2C(0)NH2, OH or phenyl(C1-4)alkyl, with the proviso that 4-phenyl-l-(2-phenylacetic acid-N-benzylamide)-piperidine is excepted. 2. Compound as claimed in claim 1, wherein X denotes N(CH2)nR6, wherein n and R6 are defined as in claim 1. 3. Compound as claimed in claim 2, wherein n is 0 and R6 is (C3-7) cycloalkyl. 4. Compound as claimed in claim 3, wherein R6 is cyclobutyl or cyclohexyl. 5. Compounds as claimed in claim 1, wherein R7 and R8 have one of the following meanings: a) R7 is phenyl, (Formula Removed) and R8 is H, -CONH2 or CN, or c) R7 and R8 together form the group (Formula Removed) 6. Compound as claimed in claim 5, wherein R7 is phenyl, (Formula Removed) or and R8 is H or CN. 7. Compound as claimed in claim 6, wherein R7 is piperidino and R8 is H. 8. Compound as claimed in claim 1, wherein Ar denotes unsubstituted or mono- or di-substituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, CI, Br), methoxy or CF3] or Ar is phenyl substituted by -OCH2O-, this group connecting positions 2 and 3 or 3 and 4 of the phenyl. 9. Compound as claimed in claim 8, wherein Ar is phenyl, 3,4-dichlorophenyl, 3,4-methylen-edioxyphenyl. 10. Compound as claimed in one of claims 1 to 9, wherein R4 denotes phenyl(C1-3)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, the substituents independently of one another being halogen (F, CI, Br, 1), methyl, methoxy, CF3 or OCF3; R5 denotes H, (C1-3)alkyl, CH2COOH, -CH2C(0)NH2 or phenethyl. 11. Compound as claimed in claim 10, wherein R4 is (Formula Removed) and R5 is H or CH3. 12. Compound as claimed in claim 1 which is (Formula Removed) 13. Arylglycinamide derivatives of general formula I as defined in claim 1 substantially as herein described with reference to the foregoing examples.

Documents:

754-DEL-1996-Abstract-(05-08-2008).pdf

754-DEL-1996-Abstract-(10-10-2008).pdf

754-DEL-1996-Abstract-(17-09-2008).pdf

754-DEL-1996-Abstract.pdf

754-DEL-1996-Claims-(05-08-2008).pdf

754-DEL-1996-Claims-(10-10-2008).pdf

754-DEL-1996-Claims-(17-09-2008).pdf

754-DEL-1996-Claims.pdf

754-del-1996-complete specification (granded).pdf

754-DEL-1996-Correspondence-Others-(02-07-2010).pdf

754-DEL-1996-Correspondence-Others-(05-08-2008).pdf

754-DEL-1996-Correspondence-Others-(17-09-2008).pdf

754-DEL-1996-Correspondence-Others.pdf

754-del-1996-correspondence-po.pdf

754-DEL-1996-Description (Complete)-(10-10-2008).pdf

754-DEL-1996-Description (Complete)-(17-09-2008).pdf

754-DEL-1996-Description (Complete)-05-08-2008.pdf

754-DEL-1996-Description (Complete).pdf

754-DEL-1996-Form-1-(05-08-2008).pdf

754-DEL-1996-Form-1-(17-09-2008).pdf

754-DEL-1996-Form-1.pdf

754-del-1996-form-13-(05-08-2008).pdf

754-DEL-1996-Form-18.pdf

754-DEL-1996-Form-2-(05-08-2008).pdf

754-DEL-1996-Form-2-(17-09-2008).pdf

754-DEL-1996-Form-2.pdf

754-DEL-1996-Form-3-(05-08-2008).pdf

754-DEL-1996-Form-4.pdf

754-DEL-1996-Form-6.pdf

754-DEL-1996-GPA-(02-07-2010).pdf

754-DEL-1996-PA-(05-08-2008).pdf

754-DEL-1996-Petition-137-(05-08-2008).pdf

754-DEL-1996-Petition-138-(05-08-2008).pdf

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