SU1082321A3 - Process for preparing derivatives of 16-aminoprostaglandine or their salts - Google Patents

Abstract

1. A process for the preparation of 16-aminoprostaglandin derivatives of the general formula OH wherein the C-15 and C-16 atoms may be in the -S-or -R-configuration; Z is a hydrogen atom or a lower alkyl group, or their salts, of which it is equivalent to that of the derivative 9 ot, 1 1 o, 15-trioxn-16-, -p-nitrocarbobenzoximido-5-cis, 13-Trons-prostadiene acid total formulas where C-15 and C-16 atoms can be in -S-or -R-configurations; Z is a lower alkyl group, c is removed in any order from the P-nitrocarbobenzxsigruyu using zinc dust in acetic acid and, if desired, the ester group using an esterase enzyme or by alkaline hydrolysis and the resulting product is isolated in free form or as salt. 2. A method according to claim 1, wherein the alkaline hydrolysis is carried out in a mixture of methanol and water with lithium hydroxide. 3. The method according to claim 1, characterized in that Rhizopus Oryzal lipase is used as a esterase for knowledge of esterase.

Description

This invention relates to a process for the preparation of new derivatives of the prostate-tlandan row - namely, lfi-aminoprostaglandin of the general formula where C-15 and C-16 atoms can be found in the -S- or R-configuration; Z is a hydrogen atom or a lower alkyl group, or their salts with valuable pharmacological properties. Prostaglandins, which are substituted in the 15- or 16-position by the methyl group, are known, which possess valuable headlights; 1 - Cz. The purpose of the invention is to obtain new prostaglandin derivatives with improved properties compared with their closest structural analogues. The goal is achieved by the fact that, according to the proposed method, the derivative 9y, I loi, 15-trioxy-16-p-nitrocarbobenzoxamido-5-cis, 13-tro (ns-prostadiene acid of the general formula 5nogpcnf t where can be in -S or -K-configuration} Z - lower apical group, remove P-nitrocarbenzoxy group in any sequence using zinc dust and acetic acid and, if desired, complex-ester group using an enzyme of esterase, preferably Rhizopus Oryzal lipase, or using alkaline hydrolysis, preferably carried out in a mixture of lithium hydroxide with water and then the resulting product is dried in free form or as a salt. To complete the hydrolysis, it is desirable to carry out acid treatment of the product to its isoelectric point. Zinc in acetic acid is reduced at a temperature ranging from -5) C, especially desirable at a temperature of about 0 ° C. The ester group is hydrolyzed at 0-10 ° C, especially preferably at a temperature of about 5 ° C. The compounds of formula (II) used as starting materials are also new. It is expedient to obtain them by the following synthesis route: P-nitrocarbobenzoxy-norleucine of the formula (a symmetric carbon atom can be in the S- or R-configuration) (CH2) 3-CH-COOH HH-COOCHj-NOg is subjected to an exchange reaction with alkyl chloroformate. the resulting mixed anhydride of the formula Hj- (CH), - CH-CO-O-CO-OCHNg CHz Nff-COOCH is reacted with diaz by methane, as a result, a derivative of 1-diazo-2-oxo-3-p-Nitrocarbobenzoxamido- is formed heptane of the formula snz- (s; h2) w sn-s o-snc2 1W-COOCH This derivative is subjected to an exchange reaction with hydrochloric acid. The resulting 1-chloro-2-oxo-3-L.-nitrocarbobenzoxamido-heptane is reacted with trisubstituted phosphine according to the following scheme CH3- (CH2) c CO-CO-CHgCl (X) NH-COOCH24) -NOa where X is an alkyl or aryl group. This forms a phosphonium chloride derivative of the general formula VIII which undergoes an exchange reaction with alkali hydroxide to a phosphorane derivative of the general formula (IX) CH3- (OH2) HRH-CO-CH2-PCH3Cl-NH-OOOCH - IJIO CH3 ( CH2) h-CH-CO-CH P (X) h - l H-COOCHg-NOg A derivative of the phosphorane of formula VIII is subjected to an exchange reaction with 1o - (6-carbalkoxy-2-hexennl) -2 form mil-cyclopentane-3c 5o1 -diol-diacyl volume OOOY ITO where Y is a lower alkyl group or aryl group; Z is a lower alkyl group, up to an apkyl ester of 9ai, 1 loL-diacylox Si-15-OXO-6-p-nitrocarbenbenoxam DO-5-TsIS, 13-transprostadiene COOZ / p-srosn2-H Y of this ester C -atom 16 can be in the S- or R-configuration, Y and Z have the indicated values The ester of the general formula (XI) is reduced by an alkali metal borohydrate. The resulting alkyl ester 9ot 11 ut-diacyloxy-1 5 (5) -oxy- and 9 about, llci-diacyloxy-1 5 (R) -oxi-16-P-nitrocarbobenzoccamido-5-c, and 1 3-trans-prostadiene acids of the general formula (XII) are separated by C002 / -sHH-XX and are hydrolyzed in methanol medium using p-toluenesulfonic acid. Example 1. Methyl ester 9-6, PoC, 15 (1-trioxy-16 (8) -amino-3-Cys, 13-Tro (HC-prostadiene acid (1, & A)) 1.7 g methyl ester 9oi , Hoi, 1 5 (| I - trioxy 16 (5) -P-Nitro-5-i, is-1Z-trons-prostadiene acid (isomer A) is dissolved in 27 ml of acetic acid. To the cooled to O C solution 9 ml of water and 980 mg of zinc dust are added.The reaction mixture is stirred under nitrogen for 1 hour at 0 ° C. The pH value is then adjusted to 6-7 with cooling with 2 and sodium hydroxide solution. The solution is lyophilized. irate on a silica gel column (silica gel AO, Reanap, Budapest) using a chloroformethanol gradient with increasing methanol content. The product is washed out of the column with chloroform containing 12% methanol. 930 mg (80%) of methyl ester 9 vol., 11 oi- , 15 (1 -trioxy-16 (8) -amino-5-cis-TZ-trs ns-prostadiene acid (isomer L). IR spectrum (KBr) + OH 36003300, C O 1730 see Mass spectrum:; mole weight (m / z); 383. (m / z); 383, 352, 334, 86. Hydrochloride salt (hydrochloride): mp, 153-157 ° C. Chlorine content 8.3. Example 2. Methyl ester 9o (-, P ci, 1 5 () -trioxy-1 6 (2) -amino-3-CIS, 3-thrps-prostadiene acid (, Z CH.J, isomer B). 840 mg 9oC methyl ester, Po1,15 () -trioxy-1 6 (5) -p-nitrocarb6 benzoxamido-3-cis-13-1 wound-prostadiene acid (isomer B) is dissolved in 12 ml of acetic acid. To a solution cooled 4 ml of water and 980 mg of zinc dust are added while stirring. The reaction mixture is stirred for 1 hour under nitrogen at 0 ° C and then mixed with 10 m of dichloromethane. Then the zinc pit is filtered off and the filtrate is evaporated in vacuo to dryness. After evaporation, it is chromatographed on a column prepared from 80 g of silica gel using a dichloromethane-methanol gradient with increasing methanol content. The product is washed out of the column with 30% methanol / dichloromethane solution and 390 mg (68%) of methlol ether 9oi, II are obtained oi, 15ff) -trioxy-16 (8) -amino-5-cis (mS-prostadiene acid; IR spectrum (KBr); V NH h –OH 36003100, C O 1735 see Mass spectrum: molecular weight (t / g) 383. (ra / z) 383, 352, 334, 86. The starting materials for examples 1 | and 2 can be obtained as follows. . c) | -chloro-2-oxo-3 (8) -P-nitrocarbenzoxamidoheptane (VI). 1, 5 g of G7-nitrocarbenzoxy-8-norleucine is dissolved in 24 ml of tetrahydrofuran and O 54 ml of N-methylmorpholine and 0, 64 ml of isobutyl chloroformate are added to the solution. The solution is stirred at 30 minutes for 30 minutes, and then swept away with 25 ml of a 2% ethereal solution of diazomethane. The reaction mixture was further stirred for 3 hours at the same temperature. Thereafter, dry hydrogen chloride gas is passed through a solution containing the diazoketone for 1/2 hour. Reaction Mixture is vacuum evaporated. The oily residue after evaporation is crystallized by the addition of 20 MP of n-pentane, the resulting white crystalline substance is filtered and dried in vacuo. 1.57 g (95%) of 1-chloro-2-oxo-3 (8) -nitrocarbobenzoxamidoheptane were obtained. M.p. 72-75 0. The product is homogeneous according to thin-layer chromatography (adsorbent; silica gel G and silica gel 60 HF 254 + 366 per 8tahei Reanal, Budapest; means for transportation (Flic / 5mittel); ethyl acetate; n-heptane 30:70; Rr 0.41). IR spectrum (KVg); V NH 3300, J (ketone) 1730, fC 0 (am1) 1685 CM-J 5) Methyl ether 9oi, Ps - diacetoxy-15-oxo-1 6 (8) - -nitrocarbobenzoxamido-5i, is, 13-trans - prostadiene acid (XI, YZ CHE). 6.8 g of 1-chloro-2-oxo-3 (8) -P-nitrocarbenzoxamidoheptane are dissolved in 70 ml of dichloromethane. Dissolve and mix with 5.4 ml of tri-n-butylphosphine with stirring. The reaction mixture is kept at 60 ° C for 2 hours and evaporated to dryness in vacuo. 50 mp of water and unreacted tri-N-butyl 10 1 -phosphine are extracted with 2 x 30 ml of n-heptane to the residue after centrifugation. 20 ml of diethyl is added to the aqueous phase containing 2-oxo-3- (8) -P-nitrocarbobeneeoxamide-to-heptyl-I-butyl-phosphonium chloride. Then 10 ml of 2N sodium hydroxide solution are added dropwise with cooling (5 ° C) and the reaction mixture is stirred for 6 minutes. The organic phase is separated and the aqueous phase is extracted with 10 ml of diethyl ether. The combined ether extracts are dried over sodium sulfate and evaporated in vacuo to a volume of 10 ml. An ethereal solution containing 2-oxo-3 (8) -P-nitrocarbobeneoxamidoheptylidene-tri-H-buttrphosphorane with stirring under nitrogen atmosphere is added to a solution of 3.55 g of 1 ° C- (6-carbomethoxy-2-hexenyl) -2- formyl-cyclopentane; 5 ciL-diol-diacetate in 25 ml of tetrahydrofuran. After etching the ether, the reaction mixture was stirred at 20 ° C for 3 hours, then the solvent was removed in vacuo and the residue was chromatographed on a column prepared from 200 g of silica gel, using an H-hexane-ethyl acetate gradient with increasing Et-acetate content. The product is column by means of a 12% solution of ethyl acetate in N-hexane. Obtained 5.8 g (90%) of methyl ester, P c6 -diacetoxy-15-OXO-16 (8) -P-nitrocarbobenzoxamido-5-CISS, 13-Trax-prostadiene acid as an oil. IR spectrum (film) G VNH 34103340, A) C O 1730, V C C 1630 cm-1, Mass spectrum: mol. Weight (m / z); 664, (m / z); 644, 584, 524, 337, 319, 265, 259, 221. b) Methyl ester 9ci, lloL-diacetoxy-15 {e} 6 (I) -p-nitrocarbobenzoxamido-5-cis -1 3-tro (ns-prostadiene acid (isomer A) and 15 () -oxy-16 (8) -p-nitrocarbobenzoxamido-5-cis, 13-tro (ns-simple. Dienoic acid (isomer B), ( XII, YZ SC). 5.5 g of ethyl 9c ethyl ester, 11o (α-diacetoxyCi-15-oxo-16 (8) -n-nitrocarbenzoxamido-5-cis, 13-granc-prostadiene acid is dissolved in 100 ml of methanol and 323 mg of sodium borohydride is added to the solution while stirring at 5 ° C. The reaction mixture is stirred at 1 ° C. under nitrogen for 1 h, then poured into 500 g of O, 2 M p Astvora

primary acidic sodium phosphate. A mixture of extragerigones from 3.150 ml of ethyl acetate. The combined extracts are dried over anhydrous sodium sulphate and evaporated in vacuo. The product obtained crude in purity is purified by preparative thin layer chromatography (adsorbents: silica gel G and Bon 254 + 366 according to Stahl; manufacturer: Reanal, Budapest; transporting agent; n-hexane and ethyl acetate in a ratio of 1: 1). 3.2 g of methyl ester 9 aC, P ot-diacetoxy-15 () -oxy-16 (8) -p-nitro-carbobenzoxamido-5-cis, 13-trans-prostadiene acid are obtained (polar product, isomer A ) and 1.8 g of methyl ester 9oi. , 1 1O-diacetoxy-154) -oxy-16 (8) -P-nitrocarbenzoxyMido-5-Cys, 13-tro (ns-prostadiene acid (non-polar product, isomer B ;.

Methyl ester 9o, 1 I ot-diacetoxy-15- () -oxy-16- (I) -p-nitrocarbenzoxamido-3-cis, 13-trs ns-prostate enoic acid (oily product, isomer L).

IR spectrum (film): VNH 3440, 3360, l1 С About 1735 cmH

Mass spectrum; mole weight (m / z); 628, 615, 381, 265, 225.

Methyl ester 9o, 1 lot-diacetoxy-15 (f) -oxy-1 6 (5) -P nitrocarbobenzoxamido-5-Cys, 13-tr "is-prostadiene acid (oil, B, XII, Z" CHj).

Jk spectrum (film) -. V OH + NH 25003360, V С O 1740 CM- /

Mass spectrum: mol. Weight (m / zj; 628, 615, 381, 321, 265, 221.

tj Methyl ester 9c6, P oi, H 5 () -trioxy-16 (3) -p-nitrocarbobenoxam TO-5-CIS, 1 3-tro (ns-prostadiene acid (II, Z СН, isomer A).

3 g of methyl ester 9oL, lcii. diacetoxy-15 () -oxy-16- (5) - 1-nitro-carbobenzoxamido-5-CISS, GZ-Trchns-prostadiene acid (isomer A)

dissolved in 200 ml of anhydrous metagens

I

nola and add 7 g to the solution

p-toluenesulfonic acid monohydrate. The reaction mixture is stirred under nitrogen at room temperature for 24 hours and then drunk in 350 ml of a 1 M solution of sodium hydrogen phosphate (Na). The mixture is extracted with 3 x 80 ml of ethyl acetate. The combined extracts are evaporated in vacuo. The residue is purified by means of preparative thin-layer chromatography, using silica gel as the adsorbent (silica gel and silica gel 60 H 254 + 366 according to Stahl, manufacturer: Reanal, Budapest), and 95: 5 mixture of chloroform with ethanol. 2 g (76%) of chromatographically pure methyl ester of 9a6, 1 lot, 15 {) -trioxy-16 (8) -p-nitrocarbobenzoxamido-5-UiMc, 13-transprostadiene acid (isomer A) were obtained. M.p. 55-58 ° C.

Mass spectrum; mole weight (m / z): 544, 526, 513, 297, 265, 221.

2) Methyl ester 9d, 1 W, 15 () -trioxy-16 (S) -p-nitrocarbobenzoxamido-5-i, is, 13-trans-prostadiene acid (II; Z СH, isomer B).

1, 6 g of methyl ester 9 ° C 11 th -diacetoxy-15 {f) -oxy-16 (5) -n nitro-carbobenzoxamido-5-Cys, 13-tro (ns-prostadiene acid (isomer B) is dissolved in 90 ml of anhydrous methanol and 3.7 monogwd of p-toluic acid are added to the solution. The reaction mixture is stirred under nitrogen at room temperature for 24 hours. The product is isolated according to the method described in. 1.1 g (78%) of pure methyl ester 9o6 are obtained, lloi, 15 (1-trioxy-16 (5) -p-nitrocarbobenzoxamido-5-cis, 1Z-tritsc-prostadiene acid (isomer B).

IR spectrum (KVg): t) NH + OH 3400, 0 0 1720 cm-1.

Mass spectrum: mol. Weight (ra / z): 544, 526, 513, 297, 265, 221.

Example 3. 9-6, Po1, 15 (f -trioxy-16 (8) -ammy-5-cis-13-TpdHC-prostadiene acid (1; Z H, isomer A).

767 mg of methyl ester of 9cC, 1 lot of 15 () -trioxy-16 (8) -amino-5-tion of 13-trans-prostadiene acid (as in example 1) is dissolved in 36 ml of methanol. To the solution is added a solution of 720 ml of g of lithium oxide hydroxide in 12 ml of water. The reaction mixture is stirred under nitrogen at 8 h, then the pH value of the solution is adjusted to 6 with an 8% aqueous solution of pg.avielic acid. Methanol is evaporated under vacuum and the aqueous solution is lyophilized. The dry residue is chromatographed on a column prepared from 20 g of silica gel (silica gel 40, Reanal, Budapest) with a methanol / chloroform gradient characterized by an increasing methanol content. The products were washed out of the column with chloroform, containing 30% methanol. 665 mg (90%) chromatographically pure, 1 1c, 15 (|) -trioxy-16 (3) -amino-5-mi, msec, 13-Tro1IS-prostadiene acid (isomer A) were obtained. IR spectrum (KBr); - i) NH + OH 36002500, l) C O 1710 cm-. Mass spectrum: molecular weight (m / z): 369, (m / z): 369, 352, 334, 86. Example 4. 9oi. , 1 lct, l5 (|) -tp oxy-16 (S) - amino-5-J, c, 13-Tr ns-pro stadenoic acid (1; Z H, isomer B). 270 mg of methyl ester 9 (5, 15 (E) -trioxy-16 (8) -amino-5cis, 1 3-Trois-prostadiene acid (isomer in) is dissolved in 12 ml of methanol to the solution is added at O C 250 mg of lithium oxide hydrate in 4 ml of water. The reaction mixture is stirred in a nitrogen atmosphere at a pH of 10 hours and then isolated; the product is isolated according to the method described in Example 3. 230 mg of chromatographically pure 9 cL P oC, 1 5 (.) were obtained -trioxy-16 (8) -amino-5-Qi 13-TraNS-prostadiene acid (from measures B). Yield: 88%. IR spectrum (KVg.); i) NH + OH 36002500s C 1710 CMI Mass: Spectrum: mol. weight (m / z): 369. (m / z): 369, 352, 334, 86. Example 5. 9oi, 1 ° C, 15 {-trioxy-1 6 (S) -amino-5-cis, 13-trsx NA —gostogenic acid (1; ZH, isomer A). 350 mg of methyl ester 9d, 1 1 () -trioxy-16 (5) -P-nitrocarboben zoxamide-5-CIS, 13-tro (HC-prostadiene acid (isomer A)) are suspended in 20 ml of O, 1 M phosphate buffer () containing 60 mg of Rhyzopus Oryzal lipase, 350 mg of gum arabic and 15 mg of sodium taurocholate. The sauce is shaken at 28 ° C for 2 days on a shaking table, then diluted with 100 ml of water, acidified with citric acid and extracted three times. each time 20 ml of ethyl acetate. The combined extracts are evaporated in vacuo. The residue after parivat containing 9pt, 1 1 vol, 1 5 {-trioxy-16 (5) -p-nitrocarbenzene amido-5-csm, 1 3-trans-prostadiene acid (isomer A) is dissolved in 3 ml of a 70% aqueous solution of acetic acid. The solution is cooled to 0 ° C and stirred at this temperature with 350 mg of zinc oil in the atmosphere 1 hour. Then the reaction mixture is stirred with 20 ml of dichloromethane, the zinc dust is filtered and the filtrate is evaporated in a vacuum.The residue after evaporation is chromatographed on a column prepared from 5 g of silica gel, in the presence of a methanol-chloroform gradient characterized by an increasing methanol content. The product is extracted from the column with chloroform containing 70% methanol. Received: i05 mg (46%) 9o (., 1 lc /, 15 (f) -amino-5-cisG, 13-tro (ns-prostadiene acid (isomer A). Example 6. Methyl ester 9o, 1 1 oi , 1 5 () -trioxy-1 6 (R) -amino-5-CI s, 13-hrs (HC-prostadiene acid (, Z SI, isomer A). 560 mg of methyl ester 9oL, ci, 1 5 ( ) -trioxy-1 6- (PO-1 nitrocarbobenzoxamido-5-Cyc; 1 3-Tro (HC-prostadiene acid (isomer A)) is dissolved in 9 ml of acetic acid and added to the solution cooled to 0 ° C with stirring 3 ml of water and j30 mg of zinc dust. The reaction mixture is stirred at 0 ° C under nitrogen for 1 h, then the pH value is adjusted to 6-7 at cooling by adding 2N sodium hydroxide solution. The solution is lyophilized. The solid residue is chromatographed on a column prepared from 12 g of silica gel (silica gel 40, Reanal, Budapest) in the presence of a chloroform-methanol gradient characterized by an increasing methanol content. chloroform containing 12% methanol. 300 mg (79%) of 9cL methyl ester, 1 lot-, 15 (|) -trioxy-16 (K) -amino-5-CIS 13-trans-prostadiene acid (isomer A) was obtained, which melts at bz-bu C. Infrared spectrum (KBr); NH + OH 3350, С About 1740 cm. Mass spectrum: mol. Weight (m / z): 383. (m / z): 383, 352, 334, 86. P, p and m r 7. Methyl ether 9oi., 1-1 ° C, 15 C) -trioxy-1 6 (K) -amino-5-1LIS, I 3-transProstadienoic acid (I, Z СНз, isomer B). 1.4 g of methyl ester 9c, cL 15 {) -trioxy-1 6 (K) - (1-nitrocarboben11 zoxamido-3-cc, 13-tr "ns-prostadiene acid (isomer B) are dissolved in 21 ml of acetic acid and 7 ml of water and 820 mg of zinc dust were added to the solution cooled to fc. The reaction mixture was stirred under nitrogen at 0 ° C for 1 h and then the product was collected in the described manner as in Example 6. 710 mg (74%) of product were obtained. IR -spectrum (KBV): VNH + ОН 3560, 3350, -J С О 1730 cm. Mass spectrum: mol. weight (m / z): 383.. (m / z): 383, 352, 334, 86. The starting materials for examples 6 and 7 are 9oL methyl ester,} ci, i5 (/ -trioxy-1 6 (K) -p-nitrocarbenzoxy- amido-5-i, isp, 13-trins-prostadiene acid (isomer A) and methyl ester 9oL, 1 lot, 1 5 () - trioxy-16 (K) -p-nitrocarbobenzoxamido-5cis, 13-Tr "ms- prostadiene acid (isomer B) can be obtained according to the method described in connection with the starting materials in examples 1 and 2, but here it is derived from p-nitrocarbenzoxy-P.-norleucine. Physical data of the compounds obtained are: 0 (1 1-chloro -2-oxo-3 (K) - - nitro | carbobenzoxamido heptane (VI), m.p. 72-75 ° C. IR spectrum (KVg): A) NH 3300, t) C O (ketone) 1735, C O (amide) 1690 cm- .. 5) Methyl ether 9cL, 11 d - diathoxy-15-oxo-16 ( R) -p-nitrobenzoxamido-5-cis, 1Z-trans-prostadiene acid (oil) (X1; YZ CH). IR spectrum (film). V, N11 3350, O 1730, O 1630. Mass spectrum: molecular weight (m / z) ft 644. (m / z): 644, 584, 524, 337, 319, 265 259, 221. g) Methyl ether 9 o, 1 lot –diace toxi-15 (-oxy-16 (K) -p-nitro-carbobenzoxamido-5-i, is, 1 Ztra HC-prostadiene acid (oil) (XII, YZ CH2 isomer A), JK-spectrum (klenka);, NH 3400, 1} C O 1730 CM-f. Mass spectrum: mol. Weight (m / z): 628, 615, 381, 321, 265, 221. Methyl ether 9o, 1 1 ° C-diacetoxy-1 5 () -oxy -1 6- (K) -p-nitro-carboxybenzo-amido-5-cis, I 3 -trans-prostadiene acid (oil) (XII, YZ CHj, isomer B). IR spectrum (film): d NH + OH 3600-3200, V С O 1720 cm. 21 Mass spectrum: mol. Weight (m / z): 628, 615, 381, 265, 221.) Methyl ether 9 ot, 1 1 of, 1 5 (f J - trioxy-16 (R) -n-nitro rbobenzoxamido-5-yis, 13-.trans-prostadiene acid (II, Z CH3, isomer A). IR spectrum (film); V NH OH 3400, V С O 1720-1690 cm. Mass spectrum: mol. weight (m / z): 544, 526, 513, 297, 265, 221. d2) Methyl ether 9-1. ,, I 5 (/ -trioxy-1 6 (.R) -n -nitrocarbobenzoxamido-5-cis, 13-tro (ns-prostadiene acid (II, -CH, isomer B, mp 68-72 ° C) And the spectra (KBr); V, NH + OH 3380, O 1720 Mass spectrum: mol. Weight (m / z): 544, 526, 513, 297, 265, 221. Example 8. 9Ы, 1Ы, 15 (p-trioxy-1 6 (R) -amino-5-i, is, I 3- TpdHC. -Prostadiene acid (1, Z, isomer A). 250 mg of methyl ester 9 ° C, oL 1 5 C) -trioxy-16- (R) -amino-5-i, s, 13-tro-1H-prostadiene acid (isomer A) is dissolved in 12 ml of methanol. To the solution, at 0 ° C, 235 mg of lithium oxide hydrate in 4 ml of water. The reaction mixture is stirred under nitrogen at 10 h, then p The pH of the solution is adjusted at pH 6 with an 8% solution of oxalic acid in water. Methanol is evaporated under vacuum at 5 ° C and the remaining aqueous solution is lyophilized. The residue is chromatographed on a column prepared from 10 g of silica gel using an increasing chloroform methanol gradient. methanol content. The product is washed from the column with chloroform containing 30% methanol. 210 mg (877.) ,, 1 5 (t-trioxy-16 (I) -amino-5cis, 1 3-trans-prostadiene acid (isomer A) were obtained. IR spectrum (film), V NH OH 3300, - O C O 1720, C00 1570 (b) cm. Mass spectrum: mole weight (m / z): 369. (m / z): 369, 352, 334.86. Example 9. 9ot, 1 loi, 15 -trioxy-16 (R) -amino-5-Cys, 13-Trlns-prostadiene acid (1, Z H, isomer B). 574 g of methyl ester 9o, 11a, 15 (1 -trioxy-16 (R) -aMnHO -5-HMC, 13-trans-prostadiene acid (isomer 13 of measure B) was dissolved in 24 ml of methanol and added to the solution at 540 mg of hydroxide oxide in 8 ml of water. The mixture was stirred under nitrogen at 10 h, then the product was separated according to the method described Example 8. 500 mg (90%) of xpJpf are obtained at atographically pure 9ci, 11 ot, 1 AP of Tririoxy-16 (U-amino-5-Cyc, 13-Trstns-prostadiene acid (isomer B)), which melts at 88 C. IR spectrum (KBr) .vl) NH + OH 3300, C O 1720,: COO 1570 (b). Mass spectrum: mol. Weight (m / z): 369. (m / z): 369, 352, 334, B6. The biological properties of the compounds obtained by the proposed method were investigated using various tests to detect the effect of 9cC, 11c. , 15 (5). Trioxy-5-CISS, 13-trs ns-prostadiene acid (PGF2- /). For studies of organs containing smooth muscles, the bronchi of the guinea pig, small intestine and rat uterus were used. Organs were suspended in KrebsRinger's solution, and the effect was recorded on the basis of isotonic contractions. Using the CHRONO Loggregomera (A.VfR. Born), the suppressive effect exerted on the aggregation of human blood cells under the influence of 5 x 10 mol / l adenosine-5 -phosphate was determined. In addition, it was investigated according to the method of P. Tolnay, whether the target compounds are the substrate of the enzyme 15 | -oxy-prostaglandin dehydrogenase or not. New derivatives of 1B-aminoprostaglandin, obtained by the proposed method, by their intrinsic biological properties, deviate significantly from the PGF used as the zoi control of the preparation, as well as from its methyl ester, as evidenced by table. 1. Byggo found that the derivatives of 16-aminoprostaglandin are not the Substrate of the enzyme 15-hydroxy-prostaglandin dehydrogenase, i.e. This enzyme does not make compounds ineffective. As a result of the incorporation of the amino group at the C-atom 16, the inhibitory effect on the aggregation of blood cells changes only slightly. However, the effect of contraction of smooth muscles is substantially less than that exerted. It should be especially noted that this weakening of action is not the same for different organs. 16 (5) -amino-prostaglandin exerts a more selective effect on uterine muscles than PGF 2d-: Four new compounds listed in Table. I, were tested at a concentration of 1 X 10 mol / L by 15-hydroxy-prostaglandin dehydrogenase, they were not any sub-wastes for this enzyme. Table 1

PGFGG

PGF „-methyl ether

9 oL, 11 ot, 1 5 (E) -trioxy-1 6 (5) -amino-5 CMS-13-trans-prostadiene acid (isomer A)

9fit, 1 1s, 15 (| -trioxy-16 (E) -amino-5-CISS, 1 3-Trs ns-prostadiene acid. (Isomer L)

1.00

82 56 1.25

0.83

75 0.13

 9o (, 1 1 C5b, 1 51) -trioxy-16 (8) -amino-5-i, is, 1 3-trans-prostadiene methyl ether (isomer A)

9dL, d, 15 (1 trioxy-1 6 (R) -amino-5-CIS, 13-Trs (HC-prostadiene acid methyl ester (isomer L) Guinea pig; K rat The most favorable properties of the compounds of formula (I) about are in part of the action interrupting the pregnancy.In Betty mice, which were injected compounds subcutaneously on the 17th or 18th day of gestation, births that ended within 48 hours and the condition of the uterus removed subsequently were examined and under certain conditions the scars, the rest of the embryo (tl.JR nagt per), the groups, each of which consists of 5 w-tars, would La defined the relationship between dose and action for PGF "I, its methyl ester and also for the new derivative / 1; full 16-amino-rostaglandin. The proposed compounds turned out to be significantly more effective than methyl ester 9c, 11 oC, 1 5 () -trioxy-16 (8) -amino-5-i, m 13-trc1Hc-prostadiene acid (isomer A), the effect of which with respect to the indicator is given in Table 2 in comparison with the effect of PGP, and its methyl by ether. Table 2 EDjQ (mg / kg Compound body weight) subcutaneously PGF / methyl ester

Continued table.

0.17

0.99

52

0.05

0.02 Continued table. 2 Compound ED (mg / kg body weight) subcutaneously Methyl ester 9oi, 110, 1 5 (f} -trioxy-1 6 (3) -amino-5-i, is, 1Z-TroS-prostadiene acid isomer A Methyl ester 9 Of, 11 oi, 5 (b) -trioxy-1 6 (5) -amino-5-cis-1 3-trs (ns-prostadiene acid has, in addition to its extremely strongly abortive effect, a pharmacologically advantageous property. So , if PGF2o (. and its methyl ester 3 is used as a dosage necessary for ensuring an abortive effect, they also have a laxative effect. In the new derivative 16 (S) -amino-prostaglandin e administration 10-fold abortive dose no diarrhea was observed. Thus, using the inventive method were obtained new derivatives of 16-aminoprostaglandina having luchpshmn pharmacological properties compared to prior art.

Claims (3)

1. The method of obtaining derivatives 16-aminoprostaglandin of the general formula OH where C-15 and C-16 atoms can be in the -S- or -R configuration; Z - a hydrogen atom or a lower alkyl group, or salts thereof of the I lichayusch'iys t _e that derivative 9 d. , 1 1 cL, 15-trioxy-16-p-nitrocarbobenzoxamido-5-Cis, 13-Trans-prostadiene acid of the general formula where C-15 and C-16 atoms can be in the -S- or -R configuration; £ Z is a lower alkyl group, in any sequence, the p-nitrocarbobenzoxy group is removed with zinc dust in acetic acid and, if desired, the ester group with an esterase enzyme or SU <· η 1082321 2 I alkaline hydrolysis and the resulting target product is isolated in free form or in the form of salt. 2. The method of pop. 1, characterized in that alkaline hydrolysis is carried out in a mixture of methanol and water using lithium hydroxide. 3. The method of pop. 1, characterized in that lipase is used as an esterase enzyme