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    NEW MATERIAL:A compound of formula I: [R is formula III (R1 is H or 1-5C alkyl group); Ar is 1,2,3,4-tetrahydro-8-quinolyl group which may be substituted by at least one 1-5C alkyl group], and its pharmacentically acceptable salts. EXAMPLE:1-[ N<2>-( 1, 2, 3, 4-Tetrahydro-8-quinolinesulfonyl)-L-arginyl ]-4-methyl-2-piperidinecarboxylic acid. USE:Antithrombins and blood platelet antiagglutinating agents, having a selective inhibitory action on thrombin with low toxicity, useful as a reagent for determination of blood thrombin, or a remedy and preventive for thrombosis. PROCESS:A compound of formula X (R2 is H, alkyl group, etc.; Q is 8-quinolyl group, etc.), obtained from a compound of formula II, is reduced, and, if necessary, subjected to hydrogenolysis or hydrolysis to give the compound of formula I.
    公开号:SU1042615A3
    申请号:SU792814248
    申请日:1979-08-30
    公开日:1983-09-15
    发明作者:Окамото Созуки；Кикумото Риодзи；Тамао Есикуни；Окубо Казуо；Тезука Тору；Тономура Синдзи；Хидзиката Акико
    申请人:Мицубиси Кемикал Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new N-arylsulfonyl-ab-argininamides, which have the opposite properties and low toxicity and can be used to treat thrombosis. and esters and amides of N -dansyl-c-arginine of the general formula C-1 n are known: - CH2 C-C-C-O-RI BH- $ 02 - Ci - Syu-alkyl, Ci-C "- cycloalkyl, allyl , mrno or dialkoxyalkyl, phenoxyalkyl radical, possessing anti-thrombotic properties 1, The disadvantage of these compounds is high toxicity. The purpose of the invention is the development of a process for the preparation of new N-arylsulfonyl-ob-arginine-amides, which have prutiomotromboznymi properties and low toxicity. This goal is achieved by the fact that according to the method of producing N-arylsulfonyl-oi-arginine amides of the general formula, m-C-IW-OTrCHf CHf SI-SOK (I) h Indicates a group; 0 - / 1 R is hydrogen or cj - C alkyl radical; Ar is an unsubstituted or substituted C 1 -C alkyl radical-1,2,3,4-tetrahydro-8-quinolyl radical based on the known quinoline hydrogenation reaction at SO-ISO C in the presence of a nickel catalyst 2j, a compound of the general formula COORj TC-II-CKf-CHf-CHf CR- where R has the indicated value Kg-hydrogen or lower alkyl radical) R, a nitr-group, or a tosyl-, or trityl-, or nitrobenzyloxycarbonyl-, or benzyloxycarbonyl radical; Q - an unmixed or substituted quinolyl radical with a C - C2-alkyl radical, reacting with water in the presence of a palladium radical or. tinic, or ruthenium catalysts in the environment of lower aliphatic alcohol-. The starting compound of formula IJ is taught according to the following scheme: t - W - CMj CMU CHg CH with UN-W - CH.CH.tJHj SNCOOH - I .. I HN k COOR, J.-N-CH CHf CHj, CHCON VR 1 If. -. 1 1 HN h -N-C C iM CHCOH -T, W I. - I W,. Jc-w-CHjCHjCHjCHCOrt, VR. 1 C-N-Wj i C 2 CHCOy H / VSO target product. In the above formulas, R, Ar, and Rf are as defined above} X halogen, protecting group for. about - amino groups, for example benzyloxycarbonyl or tert.-butoxycarbonyl}
    H and R are selected from the group consisting of hydrogen and protecting groups for guanidine, nitro, tosyl-trityl, oxycarbonyl groups / and at least one of R and R is a protecting group for guaniding group (Rj) hydrogen, lower C - C | d-alkyl, for example methyl- and ethyl-, or C-aralkyl, for example benzyl and phenethyl Q - 8-quinolyl, unsubstituted or substituted by at least one C-C-alkyl, which corresponds to Ar.
    The n -Arylsulfonyl-y-argivine target product is obtained by removing the N-substituent and, if R2, aralkyl, aralkyl; ny group, from the N -substituted-N-quinolinsulfonyl-OU-argininamide by means of hydrogenolysis and simultaneous hydrogenation of HINOLYL and HINOLILE. The 2,3,4-tetrahydroquinolyl part and, if P2 is alkyl, by means of hydrolysis of the ester group located in position 2 in the piperidine ring. Removal of the nitro and oxycarbonyl groups, for example, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, as protective groups for the guanidinium group, as well as the removal of the aralkyl group as the alcohol part of the ester group, is easily accomplished by hydrogenolysis.
    Hydrogenolysis and hydrogenation are carried out simultaneously in inert. for this reaction solvent, for example, in alcohols (methanol, ethano or in ethers, for example tetrahydrofuran, dioxane, in the presence of a hydrogen activating catalyst, for example Raney nickel, cobalt, or a noble metal catalyst, for example palladium, platinum, ruthenium, preferably in the presence of a noble metal catalyst, in an atmosphere of hydrogen at 0–200, preferably at 30–150 ° C. The duration of the reaction may vary depending on the catalyst, the hydrogen pressure and the reaction temperature, and usually 30 minutes g - 120 hours. The pressure of hydrogen is 1–200 kgf / cm, preferably 1–100 kgf / cm.
    Hydrogenolysis and hydrogenation are carried out until the stoichiometric amount of hydrogen is absorbed.
    The addition of an organic acid, for example acetic propionic, or inorganic acid, for example hydrochloric, is accelerated. An organic acid, for example acetic acid, can also be used as a solvent.
    The hydrolysis can be carried out before, during or after hydrogenolysis and hydrogenation. The hydrolysis of the ester group in which Rj is alkyl or aralkyl (only when hydrolysis is carried out on hydrogenolysis and hydrogenation) is carried out in the usual manner using, for example, mineral acid (hydrochloric, sulfuric} or base, for example, inorganic ( sodium hydroxide, kai hydroxide, barium potassium hydroxide).
    Alkaline hydrolysis is carried out o6fcj4Ho in water or an inert organic solvent containing WATER (for example, in alcohol, tetrahydrofuran, dioxane}, at 20-150 ° C, the reaction can last for 5 minutes - 20 hours.
    Acid hydrolysis is carried out in water or in an inert organic solvent, contains water (for example, in alcohols, tetrahydrofuran, dioxane), at 20-150 ° C for 30 minutes - 50 hours.
    1- (N-substituted-H-quinolinesulfonyl-oi-arginyl) -2-piperidinecarboxylic acid or 1g (H-substituted-K-quinolinesulfonyl -; /, - arginyl) -2-pipvindicarboxylate (f) is obtained by condensation of n -substituted-H -substituted-arginine (s) (typically, the N-substituent is a nitro group or acyl, and the N-substituent is a protective group for the amino group, for example, benzyloxycarbonyl, tert.-butoxycarbonyl) or its active derivative, for example, an acid halide, acid azide, an activated ester or a mixed carboxylic anhydride, with uyuschim amino acid derivative (s) or an active derivative thereof, for example mono- or disilylated and, if necessary, in the presence of a condensing agent such as carbodiimide, selectively removing only the substituent G1 N -substituted N-substituted by a ny-oi-argininamida (d) by catalytic. hydrogenolysis or acidolysis and subsequent condensation of the thus obtained n-substituted-ob-arginine amide (e) with a quinol isulfonyl halide (f), preferably chloride, in a solvent in the presence of a base (see diagram).
    From (2R, 4n) -4-alkyl-2-piperidinecarboxylic acids or their esters, they are obtained by the described methods (2R, 4E) -1 - (, 2,3,4-tetrahydro-8-quinolinsulfonyl-o-6-arginyl) -4 -alkyl-2-piperidinecarboxylic acids.
    Example."
    A. Egal-1-Hn -nitro-n- (tert.-butoxycarbonyl) -o6-arginyl g4-methyl-2-piperidinecarboxylate.
    To a stirred solution of 28.8 g of n-nitro-n-1-tert-butane carbonyl) -ot-arginine in 450 ml of anhydrous tetrahydrofuran, 9.0 g of triethylamine n 12.2 g of isobutyl chloroformate are added in turn at -20 s, ChereeE 10 min 15.2 g of ethyl 4-methyl-2-piperidinecarboxylate are added to this mixture and the mixture is stirred for 10 minutes at -20 ° C. Then the reaction mixture is warmed to room temperature, the solvent is distilled off the residue is dissolved in 400 ml of ethyl acetate, washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution is dried over anhydrous sodium sulfate. The solvent was distilled off, and 31.5 g (75%) of ethyl-1H-nitro (t-butoxycarbonyl; -ab-argyl-4-methyl-2-piperidinecarboxylate as syrup were obtained. IR spectrum (KBr): 3 300, 1 730, 1 680 hectares B. Chlorine fervently prenatal ethyl 1-N-nitroarginyl j-4-methyl-2-piperidinecarboxylate, To a stirred solution 30 g ethyl 1-p -nitro-M - ( tert-butoxycarbonyl) - "; i-arginyl-4-methyl-2-piperidinecarboxylate in 50 ml of ethyl acetate is added 80 ml of 10% anhydrous ethyl acetate hydrochloride at 3 hours. To this solution, 200 ml of ethyl ethyl acetate are added. Vogo ether. fifth product was filtered, washed with anhydrous ethyl ether to give the hydrochloride of ethyl. -1- {k -nitro-O6 -arginil) -4-methyl-2-piperidinecarboxylate as an amorphous solid. C. Ethyl-1-p -nitro-n - (3-methyl-8-quinolinesulfonyl) -o -argynyl-4-methyl-2-piperidinecarboxylate. To a stirred solution of 25 g of ethyl 1-(N-nitro-o6-arginyl) -4-methyl-2-piperidinecarboxylate hydrochloride in 200 ml of chloroform, 18.5 g of triethylamine and 14.7 g of Z-methyl-8 are added in turn. -quinolinesulfonyl chloride at 5 ° C and continue stirring for 3 hours at room temperature. Then the solution is washed twice with 50 ml of water. The chloroform solution is dried over anhydrous sodium sulfate. After distilling off the solvent, the residue is chromatographed on 50 g of silica gel in chloroform, washed with chloroform, and eluted with 3% methanol-chloroform. The fraction eluted from methanol-chloroform was distilled off, and 32.1 g (91%) ethyl-1-tfi -nitro-n (3-methyl-8-quinolin-sulfonyl) -ob-arginyl-4-methyl-2- was obtained. piperidicarboxylate in the form of an amorphous solid substance. IR spectrum (KVg): 3250, 1725, 1640. , D. 1-p -NITH-n- (3-methyl-8-xynolyslfonyl) -ot -arginyl-4-methyl-2-piperidinecarboxylic acid. Solution 30 j; ethyl-1-and -nitro-N - (3-methyl-8-quinolinsulfonyl) -01, -arginyl-4-methyl-2-piperidinecarboxylate in 100 ml of ethanol and 100 ml of 1N. The sodium hydroxide solution is stirred for 24 hours at room temperature. Then the solution is neutralized with 1N. hydrochloric acid solution and evaporated to 70 mp, adjusted to pH 11 by adding 1 n. sodium hydroxide solution, washed three times with 1.00 ml of ethyl acetate, acidified with 1N. hydrochloric acid solution and extracted thrice with 100 ml of chloroform. The combined chloroform solution is dried over anhydrous sodium sulfate, evaporated, and 28.0 g (97%) of 1-n-nitro-p - (3-methyl-8-quinolin-sulfonyl) -argynyl 3-4-methyl-2-piperidine hydroxy acid are obtained. in amorphous solid. IR spectrum (KVg): 3300, 1720, 1630 CM-V Calculated,%: C 50.26 / H.5, 69; N 17.84. C H K-yOjS Found,%: C 50.00; H 5.50; N 17.49. “E.1- and -3-Methyl-1, 2,3,4-tetra-hydro-8-quinolinsulfonyl) -p. α-arginyl-4-methyl-2-piperidinecarboxylic acid. To a solution of 3.00 g of 1-n-nitro-N - (3-methyl-8-quinolin-sulfonyl) -OC-arginyl-4-methyl-2-piperidinecarboxylic acid in 50 ml of ethanol, 0.5 g of palladium black are added. and then the mixture is shaken at a hydrogen pressure of 10 kgf / cm and for 8 hours, after which the ethanol solution is filtered to remove the catalyst, evaporated, and 2.50 g (90%) is obtained (3-methyl-1, 2.3 , 4-tetrahydro-8-quinolinesulfonyl) - ot-arginyl-4-methyl-2piperidinecarboxylic acid as an amorphous solid. IR spectrum (KBG) 3400, 1620, 1460, 1380 cm-. NMR spectrum of 100 MHz in the value of 5: 6.5 (triplet 1H); 7.1 (doublet 1H); 7.4 (doublet 1H). Calculated%: C 54.31, H 7.13; N 16.52 H, N60, jS Found:% C 54.01, H 6.98; K 16.61. Froze Preparation of til- (2R, 4H) -4-methyl-2-piperidinarboxylate.
    1), Separation of the trans and cis forms of ethyl 4-methyl-2-piperidinecarboxyl.
    The trans and cis forms of ethyl 4-methyl-2-piperidinecarboxylate are separated by distillation in vacuo. Trans-form: m.p. 83-85 ° C / 7 mm Hg; cis form: so pl. 107-108 ° С / 5 mm Hg. Art.
     2). Optical separation transform.
    Racemic ethyl 4-methyl-2-piperidinecarboxylate (the trans form is hydrolyzed by boiling with an excess of concentrated hydrochloric acid for 4 hours, after which 4-methyl-2-piperidinecarboxylic acid hydrochloride is obtained. The decomposition of the hydrochloride salt of the amino acid is carried out chromatography using an ion exchange resin of the type H {-Daiaion SK-112 manufactured by Mitsubishi Chemical Indastries) in the usual way and racemic 4-methyl-2-piperidinecarboxylic acid is obtained. To a solution of racemic amino acid (143.2 g) in boiling 95% ethyl alcohol (2900 ml) is added (L-tartaric acid (150 g). After cooling, the precipitated salt is separated by filtration. The crude crystals are recrystallized from 90% - of ethyl alcohol (1000 ml) and receive (2P, 4k-4-methyl-2-piperidinecarboxylic base acid, t. Pl. 183.9-185, +4.4 (in water).
    Calculated,%: C 45.05; H 6.53; , K 4.77.
    q, H ,,, NOa
    Found,%: C 45,12; H 6.48; N 4.70.
    The absolute configuration of the molecule is established by the method of X-ray diffraction of a crystal, which is a 1: 1 complex of the molecule with tartaric acid. The chromatose product is refined for 2000 ml of Diaion SK-112 ion-exchange emulsion in water, then washed with water and eluted with 3% hydroxide solution. Fractions. The aluminum from 4% ammonium hydroxide solution is evaporated to dryness to obtain (2R, 4E) -4-methyl-2-piperidinecarboxylic acid (63.0 g) as a powdery crystal. After recrystallization of the product from ethanol-water mixture, the corresponding amic acid is obtained, (2R, 4K) -4-methyl-2-piperidinecarboxylic, m.p. 275.0-277, 8 V; Wo -18.0, 2 N. HC1).
    Calculated,%: C 58.72; H 9.15; N 9.78.
    C-jH ,, N02
    Found,%: C 58.80; H 9.09; N9.71.
    3). Preparation of ethyl (2H, 4K) -4-methyl-2-piperidinecarboxylate.
    Thionyl chloride (128.6 g) is added dropwise to a stirred suspension (2R, 4K) -4-methyl-2-piperidinecarboic acid (51.6 g) in absolute methyl alcohol (690 ml) at a temperature below 30 ° C , continue stirring at room temperature for 1 hour, then for 1 hour at reflux temperature. After the solvent, the residue is dissolved in beneol (500 ml), washed with 5% potassium carbonate solution (100 ml), then with valuable sodium chloride solution (200 ml) and dried over anhydrous sodium sulfate. After distilling off the benzene, the residue was distilled in vacuo to obtain (2R, 4k) -4-methyl-2-piperidinecarboxylate (57.4 g), m.p. 83-85 ° С / 7 mm Hg, 24.0 (. In ethanol) -.
    Calculated,%: C 63.13; H 10.00; N 8.18.
    CpHrjNO
    Found,%: C 63.20; H 9.96; N 8.12.
     A. Ethyl- (2P, 4K) -1-K -NITrO-N - (tert-bugoxycarbonyl) -o6-arginyl-4-methyl-2-piperidine 91-carboxylate.
    To a stirred solution of 28.8 g of N-nitro-N- (tert-butoxycarbonyl) -oL-arginine in 450 ml of anhydrous tetrahydrofuran, 9.0 g of triethylamine and 12.2 g of isobutyl chloroformate are added in turn, while maintaining the temperature. After 10 minutes, 15.2 g of ethyl- (2R, 4k) -4-methyl-2-piperidinecarboxylate are added to this mixture, stirred for 10 minutes at, after which the reaction mixture is warmed to room temperature. The solvent is distilled off, the residue is dissolved in 400 ml of ethyl acetate, washed successively with 200 ml of water, 100 ml of a 5% aqueous solution of nitri bicarbonate, 100 ml of a 10% aqueous solution of citric acid and 200 ml of water. The ethyl acetate solution is dried over anhydrous sodium sulfate. The solution is evaporated and 31.3, g (74%) of ethyl- (2B, 4R) -nitro-N - (tert-by-boxycarybonyl) -OC-arginyl} -4-methyl-2-piperidinecarboxylate are obtained in the form of syrup.
    IR spectrum (KVg): 3300, 1730, 1680 cm.
    B. Ethyl hydrochloride- (2H, 4H -1- (N -HTPO-A-arginyl) -4-methyl-2-piperidinecarboxylate.
    To a stirred solution of 30 g of ethyl- (2R, 4R) -l-R -HHTpo-N- (TpeT.-butoxycarbonyl) -th -apginylJ-4-methyl-2-piperidinecarboxylate in 50 ml of ethyl acetate is added 80 ml of 10% - anhydrous hydrochloric ethyl acetate at. After 3 hours, 200 m of anhydrous ethyl ether is added to this solution to precipitate a viscous oily product. The resulting product is filtered off, washed with anhydrous ethyl ether to give ethyl hydrochloride {2B, 4E) -1- {N-nitro-l-arginyl) -4-methyl-2-piperidine capco Silat as an amorphous solid. ,, C. Ethyl- (2K, 4R) -1-n-nitro-H - (3-methyl-3-quinolinesulfonyl) -ab-arylJ-4-methyl-2-piperidinecarboxyl To a further fy solution of 25 g of ethyl hydrochloride - (2H, 4R) -1 - {N-nitro-ct-arginyl) -4-methyl-2-pyridinecarboxylate in 200 ml of chloroform is added in turn 18, g of triethylamine and 14.7 g of 3-methyl-8 -quinol sulfonyl chloride at, continue stirring for 3 hours at room temperature, and then the solution is washed twice with 50 ml of water. The chloroform solution is dried over anhydrous sodium sulfate. After distilling off the solvent, the residue is chromatographed on 50 g of silica gel in chloroform, washed with chloroform, and eluted with 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform is evaporated and 32.5 g (92.1%) of ethyl- (2n 4c) -1-M -HTPO-N - (3-methyl-8-quinol sulfonyl) -oi-argynyl 3-methyl-2-pi peridin carboxylate are obtained in as an amorphous solid. IR spectrum (KBG): 3250, 1725, 1640 CM-V D. (2R,. 4c) -1-N -HTPO-N - (3methyl-8-quinolin-sulfonyl-ob-arginyl-4-methyl-2-piperidinecarboxylic Acid. A solution of 30 g of ethyl- (2B, 4R) -1-n-nitro-to - (3-methyl-8-quinolinesulfonyl) -oC-arginyl} -4-methyl-2-piperidinecarboxylate in 100 ml of ethanol and 100 ml The 1N sodium hydroxide solution is stirred for 24 hours at room temperature, after which the mixture is neutralized with 1N hydrochloric acid solution and then evaporated to 70 ml. The resulting precipitate is filtered off, washed with 20 MP of water and 27 g (95 %) (2R, 4R) -I-N -nitro-n2- (3-methyl-8-quinolinsulfonyl) -oL-ap inil-4-methyl-2-piperidinecarboxylic acid, mp 211-213 ° C. IR spectrum (KBr): 3280, 1720, 1620. Calculated,%: C50.26; H5.69; N 17.84 ., Found,%: C 50, 05;; H, 5.45; N, 17.45. E. (2R, 4H) 3-Methyl-1,2,3,4 tetrahydro-B-quinolinesulfonyl) -arghenyl - 4-methyl-2-piperidinecarboxylic acid. To a solution of 3.00 g (2R, 4R) -1h- | P nitro-H - (3-methyl-8-quinol insulone) -et-agnyl-4-methyl-2-piperidinecarboxylic acid in 40 ml of ethanol and 10 ml acetic acid was added 0.3 g of 5% palladium black, after which the mixture was agitated under hydrogen pressure of 50 kgf / cm and 80 ° C for 4 hours, and then the solution was filtered to separate the catalyst and evaporated. The remaining viscous oil is shaken with a mixture of 30 ml of chloroform and 30 MP of the saturated sodium bicarbonate solution. The chloroform layer is washed with 30 ml of water and evaporated. The purified crystals formed are recrystallized. from ethanol and get 2.6 g (yield 94%) (2R, 4R) -1- (, 3-methyl-1, 2,3, 4-tetrahydro-8-hnnolinsulfonyl) - A-arginyl-4-methyl- 2-piperidinecarboxylic acid, so pl. 188-19lc. IR spectrum (KBr) j 3400, 1620, 1460, 1380 cm-. NMR spectrum of 100 MHz in CD30D, S values: 6.5 (1 H triplet), 7.1 (1 H doublet), 7.4 (1 H doublet). Calculated,%: C 54.31; H 7.13, N 16.52. - Cr "5b b05-h Found;%: C 54.05, H 6.94; N16.65. Froze (2R, 4H) (3-Methyl-1,2,3,4-tetrahydro-8-quinolin-sulfonyl-oC-arginyl-4-methyl-2-piperidinecarboxylic acid. From ethyl- (2R, 4R) -1-m - Nitro-N - (3-methyl-8-quinolinsulfonyl-flt-arginyl-4-methyl-2-piperidinecarboxylate, prepared in Example 2 (C), gives ethyl-; (2R, 4R) -1- (3-methyl- 1I2,3,4-tetrahydro-8-quinolin-sulfonyl) -ct-arginyl-4-methyl-2-piperidinecarboxylate according to the method described in Example 2 (E). 5 g of ethyl- (2B, 4R) - {3-methyl- 1,2,3,4-tetrahydro-8-quinolylsulfonyl), ot-arginyl-4-methyl-2-piperidinecarboxylate, 50 ml of ethanol and 50 ml of 1N aqueous sodium hydroxide solution for 24 h, the reaction mixture is neutralized with 1N aqueous hydrochloric acid solution and the ethanol is distilled off. The residual is reacted with 50 ml of chloroform and washed with water. After the solvent is distilled off, the resulting precipitate is filtered off and recrystallized from ethanol. , 6 g (33% yield) (2R, 4R) -I-CN - (3-methyl-1,2,3,4-tetrahydro-8-quinolin-sulfonyl) -OL-arginyl} -4-methyl-2-piperidinecarboxylic acids, so pl. 188-191c. Other N-arylsulfonyl-oh-arginine amines were synthesized in accordance with the procedure described in the examples given, the results of the tests are listed in the table.
    Example. (2R, 4R5-i-tN - - (Z-Methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) y-arginyl-4-methyl-2-piperidinecarboxylic acid.
    To a solution of 3.00 g of {2R, 4K) -nitro-n- (3-methyl-8-quinolin sulfonyl) -L-aprHHHnJ-4-methyl-2-piperidine carboxylic acid in 40 ml of ethanol and 10 ml of acetic acid are added 0.2 g of platinum dioxide, then the mixture is shaken under a hydrogen pressure of 50 kgf / cm at 80 ° C for 3 hours, after which the solution is filtered. To remove the catalyst and evaporated. The residual, viscous oil was shaken with a mixture of .30 ml of chloroform and 30 ml of a saturated sodium bicarbonate solution. The chloroform layer is washed with 30 ml of water and evaporated. The resulting crude crystals are recrystallized from ethanol to give 2.5 g (yield 90.3%) of (2R 4R) -I-N2- (3-methyl-l, 2,3,4-tetragilro-8-quinolin-sulfonyl) -E- arginyl-4-methyl-2-piperidinecarboxylic acid, so pl. 188-191 0.
    IR (kvg): 3400, 1720, 1460, 1380 cm
    NMR spectrum: 100 MHz V, S value: 6.5 (triplet, IH) 7.1 (doublet, 1H), 7.4 (doublet, 1H).
    Calculated% C 54.31; H 7.13; N 16.52.
    FeNfco s
    Found,%: C 54.21; H 6.98; N 16.34.
    Example B (2, 4) (3-Methyl-1, 2,3,4-tetrahydro-8-quinolinesulfonyl.) - b-arginyl} -4-methyl-2-piperidinecarboxylic acid.
    To a solution of 3.00 g of 2,4-l-N-nipo-N- (3-methyl-8-quinolin-sulfonyl-B-arginyl-4-methyl-2-piperidinecarboxylic ACID, 40 ml of ethanol and 10 ml of acetic acid are added 0.3 I 5% ruthenium on carbon, then the mixture is shaken under a hydrogen pressure of 50 kgf / cm at 80 ° C for 5 hours, after which the solution is filtered to remove the catalyst and evaporated.
    The residual viscous oil is shaken with a mixture of 30 ml of chloroform and 30 ml of saturated sodium bicarbonate solution. The chloroform layer is washed with 30 ml of water and evaporated. The resulting crude crystals were recrystallized from ethanol to give 2.45 g (yield 88.6%) of (2R, 4R) -1-n2- (3-methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) - l-arginyl-4-methyl-2-piperidinecarboxylic acid, t, pl. 188-191 ° C.
    IR spectrum (KVg): 3400, 1620, 1460 1380 cm.
    NMR spectrum :. 100 MHz in CDgOD, J s 6.5 (triplet, 1H), 7.1 (doublet, 1H), 7.4 (doublet, 1H).
    Calculated,%: C 54.31; H 7.13; N 16.52.
    C ,, H.N60, tS
    Found,%: C 54.13; H 6.91; N 16.59.
    The anti-thrombotic activity of n -ylsulfonyl-A-arginine amide is compared with the actuality of a known anti-thrombotic agent, methyl ester (p-tolylsulfonyl) - (; t-arginine 1) by determining the duration of fibrinogen coagulation.
    The measurement of the coagulation duration of fibrinogen is carried out as follows.
    A 0.8 ml aliquot of a fibrinogen solution prepared by dissolving 150 mg bovine fibrinogen (1 Cohn fraction) from Armor in 40 ml of buffered saline borate (, 4) is mixed with 0.1 ml of buffered saline boreate, 4 (control solution) or a solution of the sample in the same buffer and to these solutions in an ice bath was added a thrombin solution (5 units / ml) of the company Mochida Pharmaceutical.
    Immediately after mixing, the reaction mixture is transferred from the ice bath to a temperature bath.
    The duration of coagulation is defined as the length of time from the moment of transfer to the bath at a temperature of 25 ° C until the appearance of fibrin filaments. In cases where samples of the preparation are not added, the duration of coagulation is 50-55 seconds.
    The term concentration, necessary to double the duration of coagulation, means the concentration of active ingredient required to increase the normal duration of coagulation from 50-55 seconds to 100-110 seconds.
    The concentration required to double the coagulant duration is for the known antithrombotic agent methyl ester (p-tolylsulfonyl) - ob-arginine - 1100 ju and. The inhibitors presented in the table are designated as R and Ar in the formula (I) and the added part.
    When intravenously administered to an animal solution containing α-arylsulfonyl-og-arginineamide, high anti-thrombotic activity in circulating blood lasts for 1-3 hours.
    The half-life of circulating blood anti-thrombosis compounds was found to be approximately 60 minutes. The physiological condition of the animals (rats, rabbits, dogs and chimpanzees to which the compounds under study are administered remains good. Experimental decrease
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING T ^ -Aryl-Sulfonyl-ού-ARGININAMIDES of the general formula 1 xC-7I-CH.-CH, -CH, -CH-C0R (I) d
    1 'where R is Ri is hydrogen or C ( - cj-alkyl;
    Ar-unsubstituted or substituted by Cf-Cj-alkyl 1,2,3,4-tetrahydro-8-quinolyl radical, characterized in that the compound of general formula II
    RjOOC
    CHf-CH G CHf CH.- CO-ΒθΚ, ψα (II) where R {has the above meaning;
    Rg is hydrogen or a lower alkyl radical
    R, R is the nitro group or tosyl, or trityl, or nitrobenzyloxycarbonyl, or benzyloxycarbonyl radical / Q is the unsubstituted or substituted C <- Cg alkyl radical, the chenille radical is reacted with hydrogen in the presence of a palladium or platinum or ruthenium catalyst in the environment of lower aliphatic alcohol.
    SU., 1042615>
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA1131621A|1977-01-19|1982-09-14|Shosuke Okamoto|N.sup.2-arylsulfonyl-l-argininamides and thepharmaceutically acceptable salts thereof|
    NZ182812A|1975-12-09|1984-08-24|Mitsubishi Chem Ind|N2-arylsulphonyl-l-argininamides and pharmaceutical compositions|JPH0153256B2|1980-11-13|1989-11-13|Mitsubishi Kasei Kk|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/938,711|US4201863A|1974-11-08|1978-08-31|N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof|
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