Derivatives of glycine or a physiologically acceptable salt, having the ability to inhibit the binding of fibrinogen in fibrinogenic receptor of platelets

 

(57) Abstract:

Purpose: in biochemistry and medicinal chemistry due to their ability to inhibit the binding fibrinogenic receptor. The essence of the invention: derivatives of glycine General formula 1: R-CONH-CH2CONHCH(R)CH2COOH , where R is a group of the formula-CH(othera)-(CH2)1-6NH-Rb(R - 1) (T)m-C6H4CH2NH2(R - 2) (T)m-C6H4(NH)nC(NH)-L (R - 3) or n = 0 or Ra-hydrogen, -COOC1-C4-alkyl, Z-COC5H4N3, -SO2-naphthyl or-COCH2H(Y)CH2CH2NH-Y, y is hydrogen, BOC, or Z, Rbgroup of the formula-C(NH)(CH2)0-3CH3or alternatively, if Ragroup of the formula-COC6H4N3, -SO2-naphthyl or-COCH2N(Y)CH2CH2NHY , Rb-amino group, where n is the number 1 or 0, the L-amino group or, if n is 1, L is -(CH2)0-3-CH3T is a group of formula-CH2-(O)nn = 1 or, -CH(Rd)-CH2or-CH2CO- , and one is contained in the T-group of the carbonyl groups can exist in the form of Catala Rd-hydrogen or otheraor R=H or COR0, R0- -NH0C1-4alkyl-NH(CH2)1-4-C0H4Hal, -NHC0H4COOH or a radical, Enya the above General formula with a protected amino group: Phe, Ala - t-butyloxycarbonyl, Asp, Val - ot-butilkoi, Arg-benzyloxycarbonyloxy, Ala-benzyl. Reagent 2: deblocare. The compounds have low toxicity and have a high ability to inhibit the binding of fibrinogen. table 1.

The invention relates to the derivatives of glycine or their physiologically acceptable salts, a new biologically active compounds possessing the ability to inhibit the binding of fibrinogen in fibrinogenic receptor of platelets.

Close structural analogues are glycinamide derivatives of 4-amidinopropane.

However, the known compounds are inhibitors of serine proteases and not have the ability to inhibit the binding of proteins, such as fibrinogen, to the corresponding receptors on the cell surface.

The purpose of the invention - the search for new compounds in the series of derivatives of glycine, having the ability to inhibit the binding of fibrinogen in fibrinogenic receptor blood cells.

Goal is achieved by the described derivatives of glycine General formula I:

R-CONH-CH2-CONH-CH(R')-CH2COOH where R is a group of the formula

-CH(NH-Ra)-(CH2)1-6-NH-Rb(R - 1)

-(T)m-C6H4ahydrogen, -COO-C1-4-alkyl, Z-COC6H4N3-SO2-naphthyl or-COCH2N(Y)CH2CH2NHY Y = hydrogen, BOC, or Z Rcgroup of the formula - C(NH) (CH2)0-3CH3or

or, if Ragroup of the formula: -COC6H4N3, -SO2-naphthyl, -COCH2N(Y)CH2CH2NHY, Rb- amidinopropane n = 1 or 0 L = amino group or, if n = 1, then L -(CH2)0-3CH3T = group of formula -(CH2) (OH)nn = 1 or 0-CH(Rd)CH2- or-CH2CO-, and one is contained in the T-group of the carbonyl groups can exist in the form of ketala

Rd- hydrogen or othera< / BR>
R1is hydrogen or CORo< / BR>
Ro- -NH C1-4-alkyl,

-NH(CH2)1-4C2H4Hal, -NH (C6H4COOH or a radical linked through the amino group

-aminocarbonyl acids or their physiologically acceptable salts, having the ability to inhibit the binding of fibrinogen in fibrinogenic receptor of platelets.

The following examples describe the formation of compounds of formula I.

P R I m e R 1. A) a Solution of 55 mg (3-(p-AMINOPHENYL)-L-alanyl)-Gly-Asp (OtBu)Ser (tBu)OtBu - hydroiodide incubated for 2 h at room of tempea obtain 43 mg (86%) (3-)p-amidinophenoxy)-L-alanyl)-GlyAspSerOH of triptoreline (2 : 3). Melting point p.223-224aboutFrom acetic ether (isopropyl ether).

) Of the Original ester is prepared as follows:

a) cooled to 0aboutTo a solution of 1.95 g HSer(tBu) - OtBu - tosilata in DMF) was adjusted to pH 8 by adding N-methylmorpholine. To it add a solution of 2.1 g of Z-Asp(OtBu)OSU in 160 ml of DMF. After this mixture for 1 h at 0aboutWith stirred under argon and during the night stand in the refrigerator. Remaining after evaporation of the solvent the residue is placed in ethyl acetate and washed with saturated sodium bicarbonate solution, water, and 1.0% solution of potassium bisulfate and again with water, then dried, filtered and pariveda. Get 2,09 g (80%) of Z-Asp(OtBu)-Ser(tBu)OtBu the melting point of 79-80aboutFrom ethyl acetate /n-hexane;

b) 1,9 d - Asp(OtBu)Ser(tBu)OtBu hydronaut in 100 ml of methanol in the presence of 0.1 g of the catalyst, 10% Pd/C. After absorption of theoretical amount of hydrogen filtered and evaporated to dryness. Chromatography on silica gel with methylene chloride (MeOH (98 : 2) to give 1.28 g (91%).

H-Asp (OtBu)Ser(tBu)OtBu, MS : 389 (M + H)+< / BR>
c) same as described in paragraph (a from Z-Gly OSU and HAsp(OtBu) Ser(tBu)OtBu get Z-Gly-Asp(OtBu) Ser(tBu)OtBu, the output is 86%

[ ]D- 6,9about(from 0.9 Meon);

d) than the od of 75%, MS : 446 (M + N)+;

e) to a solution of 200 mg of N-Z-3-(p-cyanophenyl)alanine and 294 mg

HGly - Asp (OtBu)-Ser(tBu)OtBu in 10 ml of DMF added under argon 67 mg N-methylmorpholine and 250 mg NVTU and incubated the mixture during the night. Obtained after evaporation of the solvent, the oil was dissolved in ethyl acetate, the solution washed with 5% sodium bicarbonate solution and water, dried and evaporated. The remainder chromatographic on silica gel with acetic ether. Receive 160 mg compounds

(N-Z-3-(p-cyanophenyl)-L-alanyl)-Gly-Asp(OtBu)-Ser(tBu) -OtBu (1 : 1 mixture of epimeres). Melting point 117-119aboutFrom ether/n-hexane.

f) a solution of 362 mg of the compound obtained according to paragraph e, in 40 ml of pyridine and 3 ml of triethylamine after saturation it H2S, incubated for 2 days, after which it is kneaded with water and extracted with ethyl acetate. Product chromatographic on silica gel with methylene chloride/methanol. Obtain 270 mg of the compound (N-Z-3-(p-thiocarboxamide)-L-alanyl)-Gly - Asp(OtBu)-Ser(tBu)OtBu (a mixture of epimeres (1 : 1) MS : 786 (M +H+);

d) thioamide obtained in the preceding stage, dissolved in 30 ml of acetone, mixed with 0.6 ml under the conditions and within 3 hours, heated under phlegm. After filtration and concentration the product is precipitated by adding ether. Get 181 mg (57% ) (N is placed 136-138aboutC;

h) a solution of 180 mg odila (obtained in the previous phase) in 30ml Meon mix with 37 mg of ammonium acetate and heated at 60aboutC for 5 hours After cooling and filtering, the product is precipitated with ether. Get 89 mg (51%) (N-Z-3-(p-amidoethyl)-L-alanyl)-Gly-Asp(OtBu) -Ser (tBu)-OtBu-hydroiodide (a mixture of epimeres 1 : 1), melting point 150aboutC (decomp.), from acetic ester /g-hexane.

i) in the same way as described in paragraph b, when the hydrogenolysis of the product obtained according to paragraph (h, get (3-)p-amidinophenoxy)-L-alanyl) -Gly-Asp (OtBu)-Ser(tBu)-OtBu-hydroiodide (a mixture of epimeres 1 : 1), melting point 163-164aboutWith acetic ether/n-hexane, yield 70%.

P R I m m e R 2. A) analogously to that described in example 1A, using N-BOC-3)p-amidinophenoxy)-L-alanyl) Gly-Asp(OtBu)-Val-OtBu-hydroiodide (1 : 1) receive (3-(p-amidinophenoxy)L-alanyl)-Gly-Asp-Val-OH-triptorelin (1 : 1), melting point 174aboutC (decomp.) from methanol/acetic ether, yield: 75%.

) Of the original material can be obtained in the following way:

(a) by condensation of Z-Asp(OtBu)-OH and HValOtBu get Z-Asp(OtBu)-ValOtBu, melting point 75aboutWith (n-hexane), yield 93%;

b) by hydrogenolysis of the product obtained at STU-Asp(OtBu)-ValOtBu get Z-Gly-Asp(OtBu)-Val-OtBu, melting point 132about(Acetic ether), yield 87%;

d) by hydrogenolysis of the product obtained at stage s, get H-Gly-Asp(OtBu)-ValOtBu exit 87%, [ ]D- 33,2about(From 0.6 Meon);

e) through a combination of rat. N-BOC-3-(p-cyanophenyl) alanine and H-Gly-Asp(OtBu)-Val-OtBu get a connection (N-BOC-3-)p-cyanophenyl)-L-alanyl)-Gly - Asp(OtBu)-Val(OtBu), the melting point of 140-145aboutWith, of acetic ether/isopropyl ether, yield 66%;

f) similarly as described in example 1B, f, d, h, from the previous connection through (N-BOC-3-(p-dicarboxy - modafinil)L-alanyl)-Gly-Asp(OtBu)-Val - OtBu (a mixture of epimeres 1 : 1), yield 96%, MS : 708 (M+H)+and through the (N-BOC-3-(p-methylthiocarbamate)-L-alanyl)-Gly-Asp(OtBu)-Val-OtBu-hydroiodide (a mixture of epimeres (1 : 1), melting point 100aboutC (decomp. ), yield 82% , receive (N-BOC-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp(OtBu) - Val-OtBu-hydroiodide-acetate (a mixture of epimeres 1 : 1), melting point 154-156aboutC (decomp.) (acetic ether), yield 89%.

P R I m e R 3. A) 95 mg (N-BOC-3-(p-guanidinium)-L-alanyl) Gly-Asp(OtBu)-Val-OtBu dissolved in 10 ml ethyl acetate and mixed with 5 ml of 2.5 N Hcl. After 4 h stirring at room temperature, filtered and the precipitate washed with acetic ether. Get 44 mg (53%) of 3-(p-guanidinium)-L-alanyl)-Gl can be obtained in the following way:

(a) by condensation of N-BOC-3-(p-nitrophenyl)-1-alanine and HGly-Asp(OtVu)-ValOtBu get (N-BOC-3-(p-nitro - phenyl)-L-alanyl)-Gly-Asp(OtBu)-ValOtBu melting point 106aboutWith (n-hexane), yield 72%;

b) a solution of 890 mg of the product obtained at stage a, for 3 h hydronaut in 15 ml of methanol in the presence of a catalyst Pd/C. After filtration and evaporation of the solvent the remaining foam chromatographic on silica gel with a mixture of ethyl acetate-methanol (95 : 5) and crystallized from isopropyl ether. Get a 670 mg (79% ) of compound (N-BOC-3-(p-AMINOPHENYL)-L-alanyl)-Gly-Asp(OtBu)-ValOtBu, melting point 110-112aboutC;

C) a solution of 200 mg of the product obtained at stage b, and 60 mg of 3,5-dimethyl-N-nitro-IH-pyrazole-I-carboxamidine in 3 ml of ethanol is heated for 24 h with the formation of phlegmy. The solvent is evaporated and the residue chromatographic on silica gel with methylene chloride/methanol (98 : 2). After recrystallization from ethyl acetate /n-hexane obtain 148 mg (66%) (N-BOC-3-(p-nitroguanidine)phenyl)-L-alanyl)-Gly-Asp(OtBu)-ValOtBu, melting point 141-143aboutC;

d) a solution of 118 mg of the compound obtained in the previous phase in 3 ml of acetic acid, hydronaut in the presence of Pd/C catalyst (30 mg) for 3 days. After removal of solvent, the filter shall yl)-L-alanyl)-Gly-Asp(OtBu)-ValOtBu MS : 706 (M+H)+.

P R I m e R 4. A) Analogously to that described in example 3A, by means of hydrolysis (N-BOC-3-)N-aminodiphenyl)-L-alanyl) Gly-Asp(OtBu)-isobutyramide-hydroiodide receive (3-(p-amidino - phenyl)-L-alanyl)-Gly-Asp isobutyramide hydrochloride (mixture of epimeres 1 : 1), melting point 195-198aboutC (decomp.) from dioxane: a quantitative output.

) Of the original material can be obtained in the following way:

(a) prepared at -10aboutWith a mixture of 5,12 g of Z-Asp(OtBu)-OH-hydrate of 1.65 ml of N-methylmorpholine and 2 ml of isobutyl ether of Harborview acid in 15 ml of THF are added dropwise 5.5 g of isobutylamine dissolved in 5 ml of THF. After 3 h, freed from solvent, the residue is placed in ethyl acetate (sodium bicarbonate 5%) and the organic phase is washed with water. After drying, evaporation of the solvent and chromatography of the resulting oil on silica gel with ethyl acetate receive a 4.53 g (80%) of Z-Asp(OtBu)-isobutyramide, melting point 69-70aboutFrom n-hexane;

b) by hydrogenolysis of the product obtained at stage a, get H-Asp(OtBu)-isobutyramide, yield 97%, MS : 189, 171;

(C) by binding of Z-Gly-OH c product obtained at stage b, get Z-Gly-Asp(OtBu)-isobutyramide, yield 87%, MS : 436 (M+H)+;

e) poshed 42%, MS : 302 (M+N)+;

(e) by linking the rat. N-BOC-3-(p-cyanophenyl) alanine and H-Gly-Asp(OtBu)-isobutyramide get (N-BOC-3-(p - cyanophenyl)-L-alanyl)-Gly-Asp(OtBu)-ISO - butylamide (a mixture of epimeres 1 : 1), melting point 117-119about(Acetic ether/n-hexane), yield 27%;

f) similar to that described in example 1B, f, d, through the (N-BOC-3-(p-thiocarboxamide)-L-alanyl)-Gly-Asp(OtBu)-Isobe-telemed (a mixture of epimeres 1 : 1) and after (N-BOC-3-(p-methylthiopyrimidine)-L-alanyl)-Gly-Asp(OtBu)-isobutyramide-guide-raided (a mixture of epimeres 1 : 1), melting point 145-147aboutC (decomp.), yield 72%, receive connection (N-BOC-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp(OtBu) -isobutyl - amide-hydroiodide (a mixture of epimeres 1 : 1), melting point 175-178aboutWith an output of 60%.

P R I m e R 5. A) Analogously to that described in example 1A, get, using (N-Z-3-(p-amidinophenoxy)-L-alanyl) Gly-Asp(OtBu)-isobutyramide, the compound (N-Z-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp-isobutyronitrile - setat (a mixture of epimeres 1 : 1), melting point 141-143aboutC (ether), yield 91%.

) Of the Original material can be obtained in the following way:

a) through a combination of rat. N-Z-3- (p-cyanophenyl)alanine and H-Gly-Asp(OtBu)-isobutyramide get (N-Z-3-(p-cyanophenyl)-L-Alani 91%;

b) analogously to that described in example 1B, f, d, h, through (N-Z-3-(p-thiocarboxamide)-L-alanyl)-Gly-Asp(OtBu)- isobutyramide (a mixture of epimeres 1 : 1) and after (N-Z-3-(p-methylthiopyrimidine)-L-alanyl)-Gly-Asp(OtBu) isobutyramide-hydroiodide (a mixture of epimeres 1 : 1) get (N-Z-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp(OBut) -isobutyramide-hydro - iodide (mixture of epimeres 1 : 1), melting point 160-163aboutWith the release of 37%.

P R I m e R 6. A solution of 400 mg HArg-Gly-Asp-ValOH, and 143 mg of pyridine. HBr and 15 ml of DMF is added to 435 mg of Z-(Aeg)Z-OSU. Using N-methylmorpholine the reaction mixture is brought to pH 8.5 during the night stirred and evaporated. The residue is dissolved in 0.3 N. acetic acid and then chromatografic of 0.2 N. acetic acid on the polysaccharide resin (Sephadex G-10). The same fractions are combined and lyophilized. The aqueous solution freeze-dried chromatographic on a polystyrene resin in the acetate form (Dowex 44). The eluate lyophilizer. Obtain 143 mg of Z-Aeg(Z)-Arg-Gly-Asp-ValOH MS 814 (M+H)+.

P R I m e R 7. In the same way as described in example 1B, b, a solution of 120 mg of Z-Aeg(Z)-ArgGly-Asp-ValOH (example 6) in 20 ml of 0.1 G. of acetic acid hydronaut in the presence of a catalyst Pd/C. the Catalyst is filtered off and the filtrate lyophilizer. Obtain 72 mg of the compound Aeg-Arg-Gly-Asp-ValO 242 mg Z-Aeg-(Z)-OSU and 0.11 ml of N-methylmorpholine. The reaction mixture for 18 h mix and then using acetic acid adjusted to a pH of 5.3. Then the reaction mixture was extracted with ethyl acetate. The aqueous phase is mixed with Pd/C catalyst and hydronaut within 2 hours the Catalyst is filtered off, the filtrate lyophilizer. The lyophilisate is dissolved in 0.2 N. acetic acid and chromatographic on a column of polysaccharide resin (Sephadex G 25 S) Of 0.2 N acetic acid. United uniform fraction lyophilizer. Receive 150 mg Aeg-Arg-Gly-Asp-SerOH acetate (1 : 2), MS : 534 (M+H)+.

P R I m e R 9. The solution 237,5 mg of H-Arg-Gly-Asp-ValOH in 5 ml of acetone and 5 ml of water successively treated with 226 mg naphthalene-2-sulfanilamide and 168 mg of sodium bicarbonate NaHCO3. After 2 h stirring acidified with acetic acid and distilled acetone. Water balance chromatographic of 0.2 N. acetic acid on a column of Sephadex G-25 S. combined homogeneous fractions lyophilizer. Obtain 172 mg of (2-naphthylmethyl)-Arg-Gly-Asp-ValOH MS : 636 (M+H)+.

P R I m e R 10. A suspension of 3 g of the base (carrier), composed with the remaining p-benzyloxybenzyl alcohol styrene - 1% divinylbenzene, in 30 ml of DMF sequentially mixed with 0.6 g Fmoc-Nal(I)OH, 523 mg NWTU, 16,8 mg 4-dimethylaminopyridine and 0.24 ml DRE the hydroxyl group within 30 min acetylide in 30 ml of DMF in the presence of 1.13 ml of acetic anhydride and 2.02 ml of N-atilde-Isopropylamine. The following describes the whole cycle of synthesis.

Protocol synthesis: Step Reagent Time 1 DMF) 2 x 1 min 2 20% Piperi-

Dean/DMF 1 x 7 min 3 DMF) 5 x 1 min 4 2,5

Fmoc-amanakis-

lot/DMF)

+ 2,5 collected the AEO certificate. NVTU

+ 2,5 collected the AEO certificate.-N-ethyl-

Diisopropylamine 1 x 90 min 5 DMF) 3 x 1 min 6 Isopropyl

alcohol 2 x 1 min.

At each step of the synthesis uses 30 ml of solvent. Fmoc-Asp(OtBu) - OH. FmocGlyOH. FmocArg(HCl)OH communicates according to the above Protocol. Boc-Arg (Boc) - OSU is introduced into the peptide chain. After synthesis, the peptide resin was dried. It is suspended in 10 ml of TFA/5 ml of CH2Cl2and 1 ml of N2Oh and shaken for 90 minutes the Resin is then filtered off, the filtrate is evaporated. Sediment lyophilizer out of the water. The lyophilisate chromatographic of 0.2 N. acetic acid on a column of Sephadex C-25S. United uniform fraction lyophilizer. The lyophilisate, in turn, chromatographic on Dowex 44. The eluate lyophilizer. Get 49 ml NAeg-Arg-Gly-Asp-Nal(I) - OH acetate (1 : 1), M S : 644, (M+N)+.

P R I m e R 11. In the same way as described in example 10, according to 1.05 g of Fmoc-NeOH get 73,5 mg connection Aeg-Arg-Gly-Asp-DIe-OH. TFA (1 : 1), M S : 560 (M+H)+.

P R I m e R 12. A) a solution of 230 mg of BOC-Lys (Z) Gly-Asp(OBzl)ValOBzl in 10 ml of methanol hydronaut in the, using 2 N. NaOH adjusted to pH 9.5 and mixed with 109 mg methylacetamide Hcl. The pH again adjusted to 9.5. After stirring for 90 min, the reaction mixture using 1 N. HCl acidified to pH 4 and chromatographic of 0.2 N. acetic acid on a column of Sephadex G-25S. The homogeneous fractions are combined and lyophilizers. Obtain 72 mg (N2-Boc-N6-(1-iminoethyl)-L-lysyl)-Gly-Asp-ValOH MS : 559 (M+H)+.

) Of the Original material can be obtained in the following way: a solution of 583 mg HGly-Asp(OBzl)-Val-OBzl (example 15V, b) and 477,5 mg of BOC-Lys(Z)-OSU in 10 ml DMF) using N-methylmorpholine adjusted to pH 8.5. After 18 h stirring it thickens, the residue is placed in acetic ether and water. The organic phase is washed with saturated sodium bicarbonate solution, 5% KHSO4.10% K2SO4-solution and saturated NaCl solution, then dried and filtered. The filtrate is concentrated, the residue is crystallized from ether. Obtain 385 mg of BocLys(Z)-Gly-Asp(OBzl)-Val-OBzl, temp. melting 95-101aboutC.

P R I m e p 13. A) 370 mg of o-(Z-Arg(Z2)-Gly-Asp(OtBu)-NH)-benzoic acid are dissolved in 50 ml of methanol and hydronaut in the presence of a catalyst Pd/C. the filtrate from the catalyst, concentrated in vacuo, the residue is dissolved in 50 ml of DMF and mixed with 46 mg of pyridine. HCl and 0.07 ml DREA. 203 mg of NOWTO 20 h add 101,5 mg to NOWTO and 0.035 ml DREA. The reaction mixture was stirred for 18 h and evaporated. The residue is dissolved in a mixture of methanol-water and chromatographic on column Dowex 44. The eluate evaporated ("gathering"), the residue is dissolved in 20 ml of TFA and after 30 min thicken. After chromatography of a solution of 0.1% TFA-ethanol is chemically modified silicagel (Lichrosorb RP 18) obtain 103 mg of triptoreline N-(o-azidobenzoyl-Arg-Gly-Asp)-Anthranilic acid (1) MS : 611 (M+H)+.

) Of the original acid may be prepared as follows:

a) a solution of 1.6 g of Z-Asp(OtBu)-OH in 2 mg of tolerate benzyl ester of Anthranilic acid in 10 ml of DMF is mixed with 1.92 g of the TOVT and of 1.78 ml DREA. After stirring for 20 h the reaction mixture was divided in phases ethyl acetate and water. The organic phase is washed with a solution of 5% KHSO4/ 10% K2SO4, water, saturated sodium bicarbonate solution, again with water and saturated NaCl solution, then dried by means of Na2SO4. The drying agent is filtered off and the filtrate is condensed. After crystallization from ethanol 0.75 g of N-(Z-Asp(OtBu) Anthranilic acid, temp.melting point 123-124aboutC.

b) same as described in example 7, by hydrogenation of the product obtained at stage a, get 401 mg N (which give 612 mg of Z-Gly-OSU. Using N-methylmorpholine the reaction mixture was adjusted to pH 8.5 and 4 hours to mix. Then the reaction solution is treated with a value of 0.52 ml diethylaminoethylamine, stirred for 10 min and then placed in acetic ether and 5% KHSO4/ 10% K2SO4-solution. The organic phase is washed with saturated sodium chloride solution and dried. After filtration, the filtrate is condensed. The residue is dissolved in methanol and hydronaut in the presence of Pd/C. the Catalyst is filtered off, the filtrate is evaporated. The residue is dissolved in 10 ml of DMF, mixed with 673 mg of Z-Arg(Z2)OSU and using N-methylmorpholine adjusted to pH 8.5. After stirring for 18 h the product precipitated by infusion into a solution of 5% KHSO4/ 10% K2SO4. Using chromatography with a mixture of methylene chloride/methanol on silica gel, after recrystallization from ethanol obtain 410 mg of O-(Z-Arg(Z2)-Gly-Asp(OtBu)-NH)-benzoic acid, melting point 102-103aboutC.

P R I m e R 14. A) To a solution of 109 mg of the BOC-Arg-Gly-Asp-ValOH in 3 ml of 0.2 M sodium borate buffer (pH 9) type of 55.5 mg 1,2-cyclohexandione, after which the mixture is stirred under argon for 24 hours the Reaction solution is acidified with acetic acid to pH 4 and chromatographic of 0.2 N. acetic acid is 3A, 4,5,6,7,7-hexahydro-3A,7a-dihydroxy-IH-benzimidazole-2-yl)L-Omnitel),Gly-Asp-ValOH, MS : 658 (M+H)+.

C) For the initial preparation of the acid to a solution of 1 g of H-Arg-Gly-Asp-Val-OH and 340 mg of pyridine. HBr in 15 ml of dioxane and 15 ml of water successively added 480 mg of di-tert-BUTYLCARBAMATE and 0.59 g of NaHCO3. After stirring for 18 h the reaction mixture was evaporated (in vacuo). The residue is distilled mixture of water/ethanol on porous strategydevelopment resin (MCl-Gel SNRR). United uniform fractions evaporated and lyophilizers out of the water. Obtain 260 mg of Boc-Arg-Gly-Asp-ValOH MS : 546 (M+H)+.

P R I m e R 15. A) to a solution of 275,5 mg of N-Boc-3-(p-AMINOPHENYL)-L-alanyl-Gly-Asp-ValOH in 3 ml of water are successively added 138 mg K2CO3and 124 mg aminomethanesulfonic acid. After 18 h stirring, the reaction mixture was acidified with glacial acetic acid and chromatographic of 0.2 N. acetic acid on a column of Sephadex G-25S. United uniform fraction lyophilizer. Get 205 mg (N-Boc-3-(p-guanidinium)-L-alanyl)-Gly-Asp-ValOH-potassium salt (1 : 1), MS : 632 (M+H)+.

C) starting material can be prepared as follows:

a) To a cooled to -20aboutWith the solution and 32.3 mg of BOC-Asp(OBzl)-OH in 150 ml of DMF was added 11 ml of N->TheWith and mix with cooled to -20aboutWith the suspension 37,95 g of H-Val-OBzl tosilata and 11 ml of N-methylmorpholine in 150 ml of DMF. The reaction mixture for 10 min, stirred at a temperature below -10aboutC and for 2 h at room temperature, then filtered, the filtrate evaporated. The residue is dissolved in ethyl acetate, washed with 5% KHSO4/ 10% K2SO4- solution, water, saturated sodium bicarbonate solution, water and saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried. The organic phase is evaporated. Get to 52.9 mg of BOC-Asp(OBzl)-Val-OBzl. From it 10,24 g dissolved in 30 ml of TFA and then evaporated. The residue is crystallized from a mixture of ethylacetate. Gain of 8.3 g of H-Asp(OBzl)-Val-OBzl. TFA (1 : 1), temp. melting point 147-148aboutC;

b) to a solution of 4.2 g of H-Asp(OBzl)-Val-OBzl TFA in 50 ml of ethyl acetate successively added 2,72 g BOC-Gly-OSU and 0.88 ml of N-methylmorpholine, after which the mixture for 72 h and stirred at 20aboutC. the Reaction mixture is then treated with ethyl acetate and water and the organic phase is separated and washed with 5% KHSO4/ 10% K2SO4, water, saturated sodium bicarbonate solution, water and saturated NaCl-solution. After drying evaporated. The residue is dissolved in 30 ml trips ethyl acetate/ hexane get 3.5 g HGly-Asp(OBzl)-Val-OBzl. TFA (1 : 1), temp. melting point 150-151aboutC.

(C) to a solution of 1.08 g of N-Boc-3-(4-nitrophenyl)-alanine and 2,04 g HGly-Asp(OBzl)-Val-OBzl TFA in 15 ml of DMF successively added 1.4 g NRT and 1.23 ml of N-ethyldiethanolamine. After stirring for 3 h the reaction mixture was placed in ethyl acetate and water. The composition process as described in paragraph b, and after recrystallization from a mixture of ethyl acetate/hexane obtain 1.8 g of N-Boc-3-(4-nitrophenyl)-L-alanyl-Gly-Asp(OBzl), the rate - temperature melting point 155-157aboutC.

d) a solution of 1.5 g of N-Boc-3-(4-nitrophenyl)-L-alanyl-Gly-Asp(OBzl) -Val-OBzl in 50 ml of 90% glacial acetic acid hydronaut in the presence of 10% Pd/C. the filtrate from the catalyst lyophilizer out of the water. Obtain 910 mg of N-Boc-3-(4-AMINOPHENYL)-L-alanyl-Gly-Asp-ValOH MS : 552 (M+H)+.

P R I m e R 16. A) analogously to that described in example 1A, by acidolysis (N-BOC-3-(p-amidinophenoxy)-L-alanyl) - Gly-Asp(OZB)-Nal(I)-OH get the compound 3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp-Nal(I)OH) TFA (1 : 2) (a mixture of epimeres 1 : 1), melting point 170aboutC (decomp.) (ethanol/acetic ester).

C) starting material can be prepared as follows:

a) analogously to that described in example 1B and, by linking the Z-GlyOH and HAsp(OtBu)get OMe Z-Gly-Asp(OtBu)OMe the previous stage temperature in 200 ml of acetone while cooling was added dropwise 70 ml of 1 N. NaOH for 2 h the mixture is stirred. By adding 10% aqueous citric acid solution of pH of the mixture is set to 4, the solvent is evaporated, while falls the desired crude product. After recrystallization from a mixture of ether/hexane get 19,04 g of Z-Gly-Asp(OtBu)-OH, melting point 101-104aboutC, yield 70%;

C) is similar to that described in example 1B, and, through a combination product of the previous stage with the Nal H(I)get OMe Z-Gly-Asp(OtBu) Nal(I)OMe, melting point 59aboutC (hexane), yield 34%;

d) analogously to that described in example 1B, b, by means of hydrogenolysis of the product obtained in the previous step, get H-Gly-Asp(OtBu)-Nal(I)OMe, melting point 67-68aboutC (hexane), yield 72%;

e) analogously to that described in example 1B, e, by condensation of N-BOC-3-(p-cyanophenyl)-L-alanine with the product obtained in the previous step, get (N-BOC-3-(p-cinogenic)-L-alanyl)-Nal(I)OMe (epimere), the output is quantitative, MS : 730 (M+H)+;

f) analogously to that described in example 1B, f, by tonirovania of the product obtained in the previous step, get (N-BOC-3-(p-thiocarbamoyl - yl)phenyl)-L-alanyl) Gly-Asp(OtBu)-Nal(I)OMe (epimere), melting point 110-112aboutWith the model at the previous stage, get (N-BOC-3-(p-methylthio)formimidoyl)-L-alanyl)-Gly-Asp(OtBu)-Nal(I)OMe-hydroiodide (epimere), melting point 128-130aboutC (ether), yield 64%;

h), similarly to that described in example 1B, h, by reaction of the product obtained in the previous step, with NH4OAc get (N-BOC-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp(OtBu) -Nal(I)-OMe-hydroiodide (epimere), melting point 139-141aboutC (ether), yield 70%;

i) in the same way as described in paragraph b, of the product obtained in the previous step, get (N-BOC-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp(OtBu)Nal(I)OH (epimere), melting point 206about(Acetic ether), yield 97%.

P R I m e R 17. To a solution of 70 mg of [3-(p-amidinophenoxy-L-alanyl]-Gly-Asp-Val-OH-trifenatate (1 : 2) (a mixture of epimeres 1 : 1) (example 2) in 0.6 ml DMF at room temperature while gassing with argon add 30 mg of triethylamine and 24 mg of di-tert-BUTYLCARBAMATE, the mixture is stirred for 75 minutes After adding acetic acid to establish a pH of the mixture is evaporated and the residue contribute in acetic ether for crystallization. After recrystallization from a mixture of methanol/acetic ether to obtain compound [N-BOC-3-(p-amidinophenoxy)-L-alanyl]-Gly-Asp-ValOH (a mixture of epimeres 1 : 1), yield 63%.

P R I m e R 18.

aboutWith vyhodi 61%.

In) source ether can be prepared as follows:

a) analogously to that described in example 1B, e, by linking Z-Gly-Asp(OtBu) - OH (example 16B, b) and 4-fortunetelling with NRT receive Z-Gly-Asp(OtBu)p-forfeiting, MS : 502 (M+H)+,

b) analogously to that described in example 1B, b, by means of catalytic hydrogenolysis of the product obtained in the previous step, get H-Gly-Asp(OtBu)p-forfeiting, MS : 368 (M+H)+;

C) is similar to that described in example 1B, e, by linking the rat. N-BOC-3-(p-cyanophenyl)alanine product of the previous stage get (N-BOC-3-(p-cyanophenyl)-L-alanyl)-Gly-Asp (OtBu)p-fortuneteller (1 : 1 epimer), MS : 662 (M+IIa)+;

d) analogously to that described in example 1B, f, by reaction of the product obtained in the previous step, with N2S receive (N-BOC-3-(thiocarbamoyl)phenyl)-L-alanyl)-Gly-Asp(OtBu)-p-fortuneteller (1 : 1 epimer), MS : 674 (M+H)+.

e) analogously to that described in example 1B, d, by means of the reaction product, receive alamid-hydroiodide (1 : 1) (epimere), melting point 134-136aboutC (decomp.) (ether);

f) analogously to that described in example 1B, h, by reaction of the product obtained in the previous step, with ammonium acetate receive (N-BOC-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp(OtBu)-p-forfeiting-hydroiodide (1 : 1 epimer), melting point 90-92aboutC (decomp.) from the ether.

P R I m e R 19. A) analogously to that described in example 1A, using (p-amidinohydrolase)-Gly-Asp(OtBu)-Nal(I)-OH get (p-amidinohydrolase)-Gly-Asp-Nal(I)-OH-triptorelin (1 : 1), melting point 196 to 199aboutC (ethanol) (ether), yield 48%.

C) starting material can be prepared as follows:

a) analogously to that described in example 1B, e, by linking 3-(p-cyanophenyl)propionic acid and H-Gly-Asp(OtBu)-Nal(I)-OMe (example 16B, d)) receive (t-cyanohydrine)-Gly-Asp(OtBu)-Nal(I)OMe, melting point 112-113aboutC (CH2Cl2/hexane);

b) analogously to that described in example 1B, f, d, h, by reaction of the product obtained in the previous step (C) sequentially, N2MeI and ammonium acetate receive (t-amidinohydrolase) -Gly-Asp(OtBu)-Nal(I)-OMe hydroiodide, melting point 140-142aboutC (ether);
< / the previous stage, get (t-amidinohydrolase) -Gly-Asp(OtBu)-Nal(I) HE, melting point 236-237aboutWith (water).

P R I m e R 20. In the same way as described in example 1A, using N-BOC-3-(p-amidinophenoxy)-D-alanyl)-Gly-Asp(OtBu)-Val-OtBu of hydroiodide receive (3-(p-amidinophenoxy)-D-alanyl)-Gly-Asp-Val-OH triptorelin (1 : 2), melting point 128aboutC (decomp.) (ether) output - quantitative.

P R I m e R 21. A) analogously to that described in example 16B, b, by saponification (N-(N-BOC-3-(p-amidinophenoxy)-L-alanyl) Gly-Asp(OtBu)-p-amino)benzoic acid-methyl ester - hydroiodide (epimer 1 : 1) get (N-(N-BOC-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp-p-amino) benzoic acid (1 : 1 epimer), the melting point of 205-206aboutC (methanol), yield 48%.

C) starting material can be prepared as follows:

a) analogously to that described in example 1B, and by binding of Z-Gly-Asp(OtBu) - OH and benzyl ester of p-aminobenzoic acid get benzyl ester (N-(Z-Gly-Asp(OtBu)-p-amino)benzoic acid, yield 32%, MS : 590 (M+H)+;

b) analogously to that described in example 1B, b, by means of hydrogenolysis of the product obtained in the previous step, get (N-Gly-Asp(otBu)-p-amino) benzoic acid, tegsa stage, by methylation with diazomethane receive the methyl ester of N-(Gly-Asp(OtBu)-p-amino) benzoic acid, melting point 78-82aboutC (hexane), yield 77%;

d) analogously to that described in example 1B, e, by linking the rat. N-BOC-3-(4-cyanophenyl)alanine and the product obtained in the previous step, get methyl ester (N-((N-BOC-3-(p-cyanophenyl)-L-alanyl)-Gly-Asp(OtBu)-p-amino)benzoic acid (a mixture of epimeres 1 : 1), melting point 108about(Acetic ester/ hexane), yield 51%;

e) analogously to that described in example 1B, f, d, by tonirovania and methylation of the product obtained in the previous step, get methyl ester (N-((N-BOC-3-(p-methylthiomethyl)phenyl)-L-alanyl) Gly-Asp(OtBu)-p-amino)benzoic acid hydroiodide (epimer 1 : 1), melting point 150-151aboutC (ether), yield 77%;

f) analogously to that described in example 1B, h, on the basis of the product obtained in the previous step, by ammonolysis it is obtained methyl ester (N-((N-3-(p-amidinophenoxy)-L-alanyl)- Gly-Asp(OtBu)-p-amino)benzoic acid hydroiodide (epimer 1 : 1), melting point 179-181aboutC (decomp.) (ether), yield 79%.

P R I m e R 22. In the same way as described in example 1A,p-amino) benzoic acid (epimer 1 : 1), melting point 214-216aboutC (methanol), yield 78%.

P R I m e R 23. A) a solution of 180 mg (t-cyanohydrine)-Gly-Asp-Val-OH in a mixture of 10 ml of methanol/concentrated aqueous ammonia (2 : 1) hydronaut in the presence of 180 mg of Raney Nickel. After 20 h, the solution was filtered from the catalyst and evaporated to dryness. The residue is purified on ion-exchange resin in the H+-the form and then placed in hexane for crystallization. Get (t-aminomethylpyrrolidine)-Gly-Asp(OtBu)-Val-OH, tempo. melting point 175aboutC (decomp.), the output 25%.

) Of the original nitrile is prepared similarly as described in example 1A, by acidolysis (t-cyanohydrine)-Gly-Asp(OtBu)-Val-OtBu (example 24 (a), melting point 132-134about(Acetic ester / hexane), yield 69%.

P R I m e R 24. A) analogously to that described in example 19A, on the basis of (t-amidinohydrolase)-Gly-Asp(OtBu)- Val-OtBu-hydroiodide receive (t-amidinohydrolase) Gly-Asp-ValOH triptorelin (1 : 1,1), melting point 141-143aboutC (ether), yield quantitative.

In) source ether can be prepared as follows:

a) analogously to that described in example 1B, e, by linking p-cyanohydrins acid with H-Gly-Asp(OtBu)-Val-OtBu (the course 87%;

b) analogously to that described in example 1B, f, by tonirovania of the product obtained in the previous step, get N-(thiocarbamoyl)hydrocinnamic-Gly-Asp(OtBu)-Val-OtBu - melting point 70-73aboutC (hexane), yield 72%;

C) is similar to that described in example 1B, d, by methylation of the product obtained in the previous step, get p(methylthio)formimidoyl)hydrocinnamic-Gly-Asp(OtBu)-Val-OtBu-guide - raided, melting point 55-60aboutC (ether-hexane), yield 94%;

d) analogously to that described in example 1B, h, by ammonolysis product obtained in the previous step, get (p-amidinohydrolase)-Gly-Asp(OtBu)-Val-OtBu-hydroiodide, melting point 116-120aboutC (hexane), yield 90%.

P R I m e R 25. In the same way as described in example 1A, from N-BOC-3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp(OtBu)- Val-OtBu-hydroiodide receive (3-(p-amidinophenoxy)-L-alanyl)-Gly-Asp-Val-OH-three - fluoroacetate (2 : 3), melting point 164-166aboutC (EtOH/AeOEt), yield 75%.

P R I m e R 26. A) analogously to that described in example 1A, by acidolysis ((p-amidinophenoxy)acetyl-Gly-Asp(OtBu)-Val-OtBu-hydroiodide using TFA receive (p-amidinophenoxy)-acetyl-Gly-Asp-ValOH of triftoratsetatov as follows:

a) analogously to that described in example 1B, e by binding p-cyanoprokaryotes acid and H-Gly - Asp(OtBu)-Val-OtBu get (p-(cyanotoxin)acetyl)-Gly-Asp(OtBu)-Val-OtBu, melting point 55about(Acetic ester/hexane), yield 81%;

b) analogously to that described in example 1B, f, d, by reaction of the product obtained in the previous phase, with H2S get (p-(thiocarbamoyl)phenoxyacetyl) - Gly, yield 80%, MS : 595 (M+H)+;

C) is similar to that described in example 1B, by reaction of the product obtained in the previous phase with methyliodide get (p-(methylthio)formimidoyl)-phenoxy-acetyl-Gly-Asp(OtBu) -Val-OtBu-hydroiodide, yield 83%, MS : 609 (M+N)+;

d) analogously to that described in example 1B h, by reaction of the product obtained in the previous step, with ammonium acetate get p(Amidinophenoxy)acetyl-Gly-Asp(OtBu)-Val-hydroiodide having a melting point of 102 to 106about(Acetic ester/hexane), yield 84%.

P R I m e R 27. A) analogously to that described in example 1A, using (p-amidinophenoxy)acetyl-Gly-Asp(OtBu)-Val-OtBu - hydroiodide, get (p-amidinophenoxy)acetyl-Gly-Asp-ValOH-triptorelin 5 : 4, melting point 175-178about(Acetonitrile/methanol), yield 53%.

P R I m e R 28. A) 216 mg of N-(N-(N-(benzyloxycarbonyl)-3-(n-(N-(benzyloxycarbonyl - nil)amidino)phenyl)-L-alanyl)glycyl) -aluminasilica ether and 72 mg of 5% Pd/C for 28 h mix in 4.3 ml of a mixture of ethanol/acetic acid (19 : 1) under hydrogen. Product chromatographic on silica gel with a mixture of methanol/acetic acid (9 : 1). Purified fractions evaporated, the residue is dissolved in dilute hydrochloric acid, filtered, neutralized with dilute ammonia, again filtered and the filtrate is again evaporated. The rest bring in methanol, filtered, the filtrate is admixed to the air. The precipitation is centrifuged, washed with ether and dried. Obtain 28 mg of N-(N-(3-(p-amidinophenoxy)-L-alanilglitsina)- -allindividuals, MS : 336 (27, M+H)

C) for the initial preparation of the ester of N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-L-Ala is unopened)-L-alanyl)glycyl)- -alanine benzyl ester, melting point 134-135aboutC. Proceeding from him, using the hydrogen sulfide and triethylamine in pyridine, receive N-(N-(N-(-benzyloxycarbonyl)-3-(p-(thiocarbamoyl)phenyl) -L - alanyl)glycyl - alanine benzyl ester, melting point 150-151aboutC. the Reaction methyliodide in acetone, then with ammonium acetate in methanol and keeping with benzyl ether of Harborview acid and triethylamine in THF to give N-(N-(N-(benzyloxycarbonyl)-3-(n-(N-(benzyloxycarbonyl - nil)amidino)phenyl)-L-alanyl)glycyl- -alanyl-benzyl ester, MS : 694 (100, M+H).

P R I m e R 29. In the same way as described in example 1, on the basis of 178 mg of N-(N-(N-(p-Amidinophenoxy)acetyl)glycyl)-3 - tert-butoxy-L-alanyl)-3-phenyl-L-alanine tert-butyl ester hydroiodide by keeping it with triperoxonane acid in methylene chloride, to obtain 91 mg of triptoreline N-(N-(N-(p-amidinophenoxy)acetyl)-glycyl)-L-aspartyl)-3-phenyl-L-alanine, melting point 175-179aboutC.

The source material can be prepared as follows:

a) analogously to that described in example 1B and, by linking 7.0 g of Z-Asp(OtBu)-OSU from 4.72 g Phe-OtBu HCl, after processing, chromatography on silica gel (acetic ether) and recrystallization gain of 7.1 g of tert-BUTy 94-95aboutC;

b) after catalytic hydrogenation of the product obtained in the previous step (10.3 g), in ethanol in the presence of 10% Pd/C at room temperature and normal pressure, after chromatography on silica gel with acetic ether get 5,94 g of H-Asp(OtBu)-Phe-OtBu [ ]D= +9,16o(c = 0,6, CH3OH);

C) is similar to that described in example 1B, and by the reaction of 4 g of H-Asp(OtBu)-Phe-OtBu of 3.43 g of Z-Gly-OSU, after chromatography on silica gel with acetic ether to obtain 3.9 g of N-(N-((benzyloxy)carbonyl)glycyl)-3-(tert-butoxycarbonyl - nil)-L-aspartyl)-3-phenyl-L-alanine-tert-butyl ether;

d) analogously to that described in example 1, by hydrogenolysis of the product obtained in the previous phase (2,19 g) after chromatography (CH2Cl2/CH2OH 9 : 1) and recrystallization receive 909 mg tert-butyl ether N-(N-glycyl-3-(tert-butoxycarbonyl)-L- ] -aspartyl-3-phenyl-L-alanine, melting point 99-100aboutC;

e) analogously to that described in example 1B, e, by linking 675 mg of the product obtained in the previous step, with 266 mg p-cyanoprokaryotes acid, after chromatography on silica gel (acetic ether) and recrystallization receive 687 mg tert-butyl ether N-(3-(tert-butok Sunny ether/hexane);

d) analogously to that described in example 1B, f, by reaction of the product obtained in the previous step (650 mg), hydrogen sulfide, after chromatography (acetic ether) and crystallization get 405 mg tert-butyl ether N-3-(tert-butoxycarbonyl)-N-(N-((p-dicarba - mail)phenoxy)acetyl)glycyl)-L-alanyl)-3-phenyl-L-alanine, melting point 83-86aboutC (hexane);

a) analogously to that described in example 1B, d, by methylation of the product obtained in the previous step (390 mg), get 375 mg of the compound is N - (3-(tert-butoxycarbonyl)-N-(N-((n-(1-IU - tilty)formimidoyl)phenoxy)acetyl)gli - cyl)-L-alanyl)-3-phenyl-L-alanine-tert-Buti - levy ether - hydroiodide having a melting point of 162about(Acetic ether/methanol);

p), similarly to that described in example 1B, h, by reaction 358 mg of the product obtained in the previous step, with ammonium acetate obtain 267 mg of the compound N-(N-(N-((n-Amidinophenoxy)acetyl)glycyl)-3-tert-butoxy-L-alanyl)-3-phenyl-L-alanine-tert-butyl ether - hydroiodide, decomposition temperature 76about(Acetic ester/hexane).

P R I m e R 30. Processing 140 mg of N-(N-(N-((2-(p-amidinophenoxy)-1,3-dioxolane-2-yl) acetyl)glycyl)-3-(tert-butoxycarbonyl)- L-alanyl)-3-phenyl-L-a-(N-((2-p-amidinophenoxy)-1,3-dioxolan-3-yl)acetyl)glycyl)-L-aspartyl)-3-phenyl-L-alanyl-triptorelin (1 : 1). Part of the obtained product was then purified by chromatography (RP-18, elution with water, then a mixture of water/acetonitrile 2 : 1) and recrystallization, and receive a product with a melting point 242-245aboutC.

The source material can be prepared as follows:

a) a mixture of 8 g of 4-cyanobenzoic acid ethyl ester, 80 ml of ethylene glycol, 0.3 p-toluensulfonate acid and 250 ml of toluene is boiled with water separator. After the reaction the solvent is removed, the residue is placed in methylene chloride and 0.1 n sodium hydroxide solution. The organic extract was dried, filtered and evaporated. After chromatography (silica gel, hexane/acetic ester 1 : 1) to obtain 4.4 g of colorless oil, which was dissolved in 30 ml of ethanol. While cooling in an ice bath was added dropwise 15 ml of a 1 N. sodium hydroxide and, finally, leave the mixture for 6 h at room temperature. After removal of the ethanol aqueous phase is extracted with acetic ether and neutralized 1 N. hydrochloric acid. The precipitated crystals filtered off, washed with water and dried. Obtain 2.3 g of atelectasia 4-cyanobenzoic acid, melting point 151-152aboutC;

b) analogously to that described in example 1B, after chromatography and recrystallization obtain 390 mg of the compound N-(3-tert-butoxycarbonyl)-N-(N-((2-(p-cyanophenyl)-1,3-dioxolane-2-yl)ACE-Tyl)glycyl)-L-alanyl)-3-phenyl-L-alanyl - tert-butyl ether, melting point 81-82aboutC (hexane);

C) is similar to that described in example 1B, f, by reaction of the product obtained in the previous step (360 mg), hydrogen sulfide receive 323 mg tert-butyl ether N-(3-tert-butoxycarbonyl)-N-(N-((1-(t-thiocarbamoyl)phenyl)-1,3-dioxolane-2-yl)acetyl)glycyl)-L-Ala-Neil)-3-phenyl-L-alanine, melting point 96-98aboutC (hexane);

d) analogously to that described in example 1B, d, by methylation 280 mg of the product obtained in the previous step, obtain 324 mg of the compound N-(3-(tert-butoxycarbonyl)-N-(N-((2-(p-)1-methylthio)formimidoyl)phenyl)-1,3-dioxo - LAN-2-yl)acetyl)glycyl)-L-alanyl)-3-phenyl - L-alanine-tert-butyl ether - hydroiodide (1 : 1), melting point 110-112aboutC (acetone/diethyl ether);

e) analogously to that described in example 1B, h, by ammonolysis of 250 mg of the product obtained in the previous step, get 200 mg of the compound N-(N-(N-((2-(p-amidinophenoxy)-1,3-dioxolane - 2-yl)acetyl)-glycyl)-3-tert-butoxycarbonyl-nil)-L-alanyl)-3-phenyl-L-alanine-tert-Buti - levy ether - hydroiodide (1 : 1), the melting point of 129-130aboutC.

P R I m e R 31. A solution of 100 mg of the compound N-(N-(N-((2-(p-amidinophenoxy)1,3-dioxolane-2-yl)acetyl)glycyl)-L-ASP is atoi temperature. After removal of the solvent, chromatography of the residue (RP-18, elution with water, mixture of water / acetonitrile 1 : 1) and recrystallization obtain 33 mg of the compound N-(N-(N-(p-amidinophenoxy)acetyl)glycyl)-L-aspartyl)-3-phenyl-L-alanyl-triptorelin (1 : 1), melting point 225-230aboutC (decomposition).

P R I m e R 32. In the same way as described in example 1A, from 50 mg of N-(N-(N-(3-1-amidino-4-piperidinyl)propionyl) glycyl)-3-tert-butoxycarbonyl-L-alanyl)-3-phenyl-L-alanine tert-butyl ether, after recrystallization obtain 32 mg of compound N-(N-(N-(3-(1-amidino-4-piperidinyl)propionyl)glycyl)-L-aspartyl)-3-phenyl-L-alanyl-triptorelin 1 : 1), melting point 146-148about(Ether, decomposition). The source material can be prepared as follows:

a) to a solution of 553 mg S-methyl-isothiocyanateconjugated 3.2 ml of 2n. caustic soda in 2aboutWith added 500 mg of 4-piperidinemethanol acid. After keeping the reaction mixture overnight at room temperature, the precipitated crystals filtered off, washed with water, acetate and ether and dried. Receive 600 mg of 1-amidino-4-piperidinemethanol acid, melting point above 275aboutC;

b) same as described in the accordance 928 mg of pyridinium hydrochloride obtain 2.1 g of tert-butyl ether N-(N-(N-(3-(1-amidino-4-piperidinyl)Pro-pional)glycyl)-3-tert-butoxycarbonyl-L-alanyl)-3-phenyl-L-alanine, melting point 104-106about(Diisopropyl ether, decomposition).

P R I m e R 33. In the same way as described in example 1A, from 17 mg of 1-((N-(N-(t-amidinohydrolase)glycyl)-3 -(tert-butoxycarbonyl)-L-alanyl)amino)- cyclopentanecarboxylic acid after crystallization receive 15 mg of the compound 1-((N-(N-(t-amidinohydrolase)gli - cyl)-1- -aspartyl)-amino)-cyclopentanecarbonyl acid - triptorelin (1 : 1), the melting point of 136-138about(Ether, decomposition). The source material can be prepared as follows:

a) analogously to that described in example 1B, e, based on 761 mg of Z-Gly-Asp(OtBu)-OH (example 16) and 359 mg of the compound 1-aminocyclopentane acid methyl ester hydrochloride in tetrahydrofuran, after chromatography on silica gel with acetic ether, get the 920 ml butyl ether N-(N-benzyloxycarbonylglycine)-3-((1-meloxicam - nil)-cyclopentyl)carbarnoyl) - alanine, MS (FAB), 506 (M+I)+;

b) analogously to that described in example 1B, b, by means of hydrogenolysis 880 mg of the product obtained in the previous step, get 620 methyl ester 1-((3-(tert-butoxycarbonyl)-N-glycyl-L - alanyl)amino)cyclopentanecarboxylic acid, MS (FOB) : 372 (M+I)+;

C) you and 600 mg of product, obtained at the previous stage, after chromatographic purification (silica gel, acetic ether, acetic ether/methanol 9 : 1) receive 635 mg methyl ester 1-((3-(tert-butoxycarbonyl)-N-(N-(p-cyanohydrine)glycyl)-L-alanyl)amino)cyclopentanecarboxylic acid, MS : 546 (M+NH4)+;

d) analogously to that described in example 1B, f, d, h, through the sequential reaction of 600 mg of the product obtained in the previous step, hydrogen sulfide, methyliodide and ammonium acetate receive 279 mg of the compound methyl ester 1-((N-(N-(p-amidinohydrolase)glycyl)-3-(tert-butoxycarbonyl)-L-alanyl)amino)cyclopentanecarboxylic acid hydroiodide, melting point 98aboutC (decomposition), MS (FAB) : 546 (M+I)+;

e) analogously to that described in example 16B, b, C, by alkaline hydrolysis of 157 mg of the product obtained at the previous stage, receiving 24 mg of 1-((N-(N-(p-amidinohydrolase)glycyl)-3- (tert-butoxycarbonyl)-L-alanyl)amino)qi - kapetanovi acid, melting point 163-164aboutC.

P R I m e R 34. The solution 275,5 mg of N-BOC-3-(4-AMINOPHENYL)-L-alanyl-Gly-Asp-ValOH (example 15C, d)) in 3 ml of water using 1 N. NaOH to bring the pH to 9.5. This solution is mixed with 219 mg methylacetamide HCl, meant the T. 1 N. HCl to pH 4 and chromatographic of 0.2 N. acetic acid on a column of Sephadex G-25. The main fraction lyophilizer and purified on a column of Lichrosorb RP 18 with a mixture of 0.05 M ammonium acetate - ethanol. Homogeneous fractions lyophilizer out of the water. Receive 25 mg (3-(n-(acetimidoyl)phenyl)-N-(tert-butoxycarbonyl) -L-alanyl)-Gly-Asp-ValOH, MS : 593 (M+H)+.

Derivatives of glycine of the formula I and their salts inhibit the binding of fibrinogen, fibronectin and Millerandage at fibrinogenic receptor blood cells (glycoprotein II series/IIIa), as well as linking them and other adhesive proteins such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. The aforementioned compounds have, thereby, influence on cell - cell and cell - matrix interaction. They prevent especially the formation of blood clots blood particles and can be used to fight or overcome diseases such as thrombosis, brain concussion, cardiac infarction, inflammation and arteriosclerosis. Further, these compounds have effect in relation to tumor cells, because they inhibit the formation of metastases. Thanks to this, they can also be used as antitumor agents.

Glycoprotein IIb/IIIa is obtained from Triton X-100 extract of blood cells of human blood and purified by lectin-affinity chromatography and chromatography on Arg-Gly-Asp-Ser-affinity column.

Thus obtained the receptor protein is associated with microtitre plate. Specific binding of fibrinogen from the immobilized receptor is determined using EI IS A system.

The following IC50-values correspond to the concentration of the test substance, which is used to slow down by 50% the binding of fibrinogen in immobilized receptor (see table).

The described compounds have very low toxicity. So the product of example 2 has LD5= 600 mg/kg when administered intravenously to mice.

The tests have shown that these compounds have low toxicity and have the ability to inhibit the binding of fibrinogen in fibrinogenic receptor blood cells.

Derivatives of glycine General formula

R - CONH - CH2- CONH - CH (R1) - CH2COOH,

where R is a group of the formula

-(CH) - (NH - Ra) - (CH2)1-6- NH - Rb( R - 1)

- (T)m- C6H4- CH2NH2(R - 2)

- (T)d, COO-C1- C4-alkyl, Z-COC6H4N3, - SO2-naphthyl or-COCH2N(Y)=CH2CH2NH-Y,

Y is hydrogen, BOC, or Z;

Rcgroup of the formula-C(NH)(CH2)o-3-CH3or

< / BR>
or, if Ragroup of the formula COC6H4N3, -SO2-naphthyl or-COCH2N(Y)= CH2CH2NH-Y, Rb- amidinopropane;

n = 1 or 0;

L - amino group or, if n = 1, L is -(CH2)0-3-CH3;

T is a group of formula-CH2-(O)nn = 0 or 1; -CH(Rd)-CH2- or-CH2CO-, and one is contained in the T-group of the carbonyl groups can exist in the form of ketala;

Rd- hydrogen or-NH-Ra;

R1- hydrogen or-CO-R0;

R0- -NH-C1- C4-alkyl, -NH(CH2)1-4-C6H4-Hal, -NH-C6H4- COOH or a radical linked through the amino group-aminocarbonyl acid,

or their physiologically acceptable salts, having the ability to inhibit the binding of fibrinogen in fibrinogenic receptor of platelets.

Priority signs:

23.02.89 when R - (R - 1), (R - 2) and (R - 3), and (R - 3) L = NH2;

29.11.89 when R - (R - 3), and L = -(CH2)0-3-CH3, (R - 4) at T = -CH2CO-p

 

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The invention relates to Bioorganic chemistry, namely to new tribromide 6-(glycyl-glycyl - L-arginyl - L-arginyl)aminonaphthalene - 1-cyclohexylsulfamate and 6-(benzyloxycarbonylglycine-glycyl - L-arginyl - L-arginyl)aminonaphthalene - 1-cyclohexylsulfamic

The invention relates to boron-containing peptides, a new biologically active compounds that may find application in biochemistry as inhibitors trypsinogen serine proteases, such as thrombin, kallickrein plasma and plasmin

The invention relates to medicine, namely, neurology

The invention relates to medicine, the pharmaceutical industry and relates to the creation of new dosage forms containing interferon
The invention relates to medicine, namely to infectious diseases and dermatology, and can be used for the prevention and treatment of viral rhinitis, diseases of the skin and/or mucous membranes caused by herpes simplex virus
The invention relates to medicine, namely to dermatology, and can be particularly used for the treatment of infectious skin diseases
The invention relates to the field of medicine and relates to a treatment for astrologicheskih diseases

The invention relates to medicine, namely to methods for treatment of viral respiratory diseases and can be used in clinical practice
The invention relates to veterinary medicine and can be used in the treatment of purulent-inflammatory diseases of any etiology and localization

The invention relates to medicine, namely to Pediatrics, and can be used for the treatment of musculoskeletal disorders in children

The invention relates to the medical industry and can be used in the manufacture of dosage forms of insulin

The invention relates to medicine, namely to methods for treating thrombocytopenia defeats of vessels

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of acetylamidiniophenylalanylcyclohexylglycilpypidinioalanin amides of formula I , wherein X anions are physiologically acceptable anions, and analogous thereof. Said compounds are effective inhibitors of fibrillation factor Xa and are useful, for example, in prevention of thrombosis. Claimed method includes coupling of 2-[2-acetylamino-3-(4-amidinophenyl)-propionylamino]-2-cyclohexylacetic acid, obtained from 2-[2-acetylamino-3-(4-cyanophenyl)acryloylamino]-2-cyclohexylacetic acid by assimetric hydration and converting of cyano group to amidine, or salt thereof with 3-(2-amino-2-carbamoylethyl)-1-methylpyridinic acid or salt thereof. Also are disclosed starting materials and intermediated used in this method, process for production the same and acetyl-(S)-4-amidiniophenylalanyl-(S)- cyclohexylglycil-(S)-(1-methyl-3-pypidinio)alanin amide in form of ditosylate.

EFFECT: simplified method; increased commercial availability of compounds with applicable anion.

14 cl, 16 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)

,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

23 cl, 61 ex

FIELD: chemistry of peptides, microbiology, biotechnology.

SUBSTANCE: L-alanyl-L-glutamine is prepared by incubation of a mixture containing a microorganism able to produce L-alanyl-L-glutamine from L-alanine ester and L-glutamine, L-alanine ester and L-glutamine, and isolation of the end product. Using the invention allows simplifying the process for preparing L-alanyl-L-glutamine. Invention can be used in pharmacy and food processing industry.

EFFECT: improved preparing method of dipeptide.

3 cl, 3 tbl, 1 ex

Peptide compounds // 2281955

FIELD: chemistry of peptides, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents benzofuranyl substituted with halogen atom or styryl substituted with halogen atom; R2 represents substituted hydroxyl substituted with mercapto-group or substituted sulfonyl, or its pharmaceutically acceptable salts. Compound of the formula (I) and its pharmaceutically acceptable salts possess the strong inhibitory effect on production of nitrogen oxide (NO) and can be useful in prophylaxis and/or treatment of NO-mediated diseases in humans and animals.

EFFECT: valuable medicinal and biochemical properties of compounds.

FIELD: pharmaceutical dosage forms.

SUBSTANCE: invention relates to compositions and methods for delivery of drugs. Composition according to invention represents powdered composite containing polymer, therapeutical agent, and complexing agent, said polymer containing one or more cyclodextrin fragments. Polymer interacts with complexing agent in a host/guest or guest/host manner resulting in formation of inclusion complex. Both polymer of composite and complexing agent may be used in a way to introduce functionality into therapeutical composition. Invention also discloses a method for preparing composition and to a method for delivering therapeutical agent.

EFFECT: widened choice of drug delivery methods.

26 cl, 31 dwg, 1 tbl, 65 ex

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