SE452624B - SET TO PREPARE N? 722-ARYLSULPHONYL-L-ARGININAMIDES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF - Google Patents

Description

452 624 2 is an integer 0 or 1, (2) 114 m 5 1 m 'where R 1 * is -COOR 6, wherein R 6 is hydrogen or C 1 -C 6 alkyl, each R 5 is hydrogen or C 1 -C 10 alkyl, and R 11 is an integer 1 or 2, R fi is substituted in the 2- or 3-position, and R 5 may be substituted in the 2-, 3-, 4-, 5- or G-position, (3) æOH -N m 2 (a) CDOH -N O 2 / or (5) OOH -N and Ar is a phenyl group substituted with at least one substituent selected from amino, C 1 -C 6 alkylamino, C 1 -C 8 acylamino, C 1 -C 6 alkyl hydroxyalkyl, phenyl, C 7 -C 7 phenylalkyl and C 1 -C 10 O-hydroxyalkoxy; a phenyl group substituted with at least one substituent selected from hydroxy, C 1 -C 1 alkyl and C 1 -C 6 alkoxy, and at least one substituent selected from C 7 -C 12 aralkyl, C 1 -C 6 alkylcarbonyl and phenyl; a phenoxyphenyl, dibenzothienyl, 9,9-dioxodibenzothienyl, phenoxatinyl, quinolyl, 1,2,3,4-tetrahydroquinolyl or acridinyl group, each of which is unsubstituted or substituted by one or more groups selected from hydroxy, C alkoxy and C 1 -C 6 alkyl; 2,3-dihydro-quinoxaline-Zβ-dione; a C 9 -C 18 cycloalkylphenyl, fluorenyl, thioxantenyl or ZH-chromenyl group, each of which is unsubstituted or substituted by one or more groups selected from hydroxy, C 1 -C 10 alkyl, Cl -C 1 -alkoalkyl, C 2 -C 6 -alkoxycarbonyl and oxo; or β-cyclohexyl-β-ethoxycarbonyloxyphenyl; and pharmaceutically acceptable salts thereof.

Typical compounds of the invention include: 1- [Nz- (quinoline-S-sulphony fi-L-arginyl) -4-methyl-Z-piperidinecarboxylic acid 1- [N2- (3-methylquinoline-S-sulphony fl-L-arginyl] -4 -methyl-Z-piperidinecarboxylic acid 1- [Nz- (B-ethylquinoline-S-sulfonyl-L-arginyl] -β-methyl-Z-piperidinecarboxylic acid - Nz- (Z-phenoxathinylsulfonyl) -L-arginyl-N-tetrahydrofurfuryl-glycine Nz- (Z-fluorenesulfonyl) -L-arginyl-N- (Z-methoxyethyl] glycine 1- [2- (1β-methoxy-β-cyclohexylbenzene-1-sulfonyl-L-arginyl] -1] methyl-Z-piperidinecarboxylic acid.

According to the invention, the compounds of formula I are prepared by a) removing the NG substituent from an NG-substituted N 2 -arylsulfonyl-L-argininamide of the formula HN. * c _ n - cnzcnzcuzclxacon un ”I | n "H-Ns fl z R '1 Ar where R and Ar have the meaning given above, R' and R" are selected from hydrogen and protecting groups for the guanidino group and at least one of R 'and R "is a protecting group for the guanidino group, by acidolysis or hydrogenolysis, or b) an N 2 arylsulfonyl-L-arginyl halide of the formula nu \ c - n - c fl gcngcnzcucox f | “zu i; rmso 2 I Ar 1D 15 452 624 4 where Ar has the meaning given above and X is halogen, react with an amino acid derivative of the formula RH where R has the meaning given above, or c) react an L-argininamide of the formula HN \ C ~ 1: 1 ~ CllzClizC fl z-CEHCOR H Na Hzn 2 where R has the meaning given above, react with an arylsulfonyl halide of the formula ArSO 2 X where Ar has the meaning given above and X is halogen, and that, if desired, the resulting reaction product is hydrolyzed, and optionally a resulting compound of formula I is converted to a pharmaceutically acceptable salt thereof.

The removal of the NG substituent from an NG-substituted-N 2 -arylsulfonyl-L-argininamide according to process variant a) above can be as follows: aN \ _ _ HN / c - m ~ cugcagc fl gcncoa r »| I .R "HN R '| Ru!" Net V c - N - cagcngc fl gc fl con (xïx) H' / I | 'IR "NH2 RI uušš c - N - cugcugc fl gcacon (xx) .HN. /, | | R" Hwsoz Rn _ l A1' Arsogx is illustrated on the following (V) - * å (VII) 10 15 20 25 30 452 624 HN \ ___; c - N - crlacugclxgcncon (I) / l "1 H2N n imsog 1 Ar In the formulas above, R, Ar, X, R ', R" and R' "have the meaning given above.

The N 2 -arylsulfonyl-L-argininamide (I) is prepared by removing the NG substituent from an NG-substituted N 2 -arylsulfonyl-L-argininamide (XX) by acidolysis or hydrogenolysis.

The acidolysis is usually carried out by contacting the NG-substituted-N 2 -arylsulfonyl-L-argininamide (XX) with an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid without solvent or in a solvent such as an ether (tetrahydrofuran, dioxane) an alcohol (methanol, ethanol) or acetic acid at a temperature from -10 ° C to 100 ° C, preferably 10 ° C to 60 ° C, and most preferably at room temperature, for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excess acid or by tearing with a suitable solvent, followed by filtration and drying.

Due to the use of excess acid, the products are usually acid addition salts of the N 2 -arylsulfonyl-L-argininamides (I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily obtained by hydrogenolysis.

At the same time, the benzyl ester component, which may be part of the R group, is converted to a carboxyl group by the hydrogenolysis.

The hydrogenolysis is carried out in a reaction-inert solvent, e.g. methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen activating catalyst, e.g. Raney nickel, palladium or platinum, in a hydrogen atmosphere at a temperature from 0 ° C to the boiling point of the solvent, and preferably 10 ° C to 80 ° C, for a period of from 2 hours to 120 hours.

Hydrogen pressure is not critical and atmospheric pressure is sufficient.

The N 2 -arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst, followed by evaporation of the solvent and can be purified in the same manner as described below for process variant c).

The NG-substituted-Nz-arylsulfonyl-L-argininamides (XX) used as starting materials can be prepared by condensing an NG-substituted-NZ-substituted-L-arginine (III) (usually the NG substituent is nitro or acyl, and the N 2 substituent a protecting group for the amino group such as benzyloxy (carbonyl, tert-butoxycarbonyl or the like) and a corresponding amino acid derivative (IV), (formulas III and IV are given below in connection with process c)), selective cleavage of only the N 2 substituent from an NG-substituted-N 2 -substituted-L-argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then condensing the NG-substituted-L-argininamide (XIX) thus obtained with an arylsulfonyl halide (VII), preferably a chloride, in the presence of a base in a solvent. These reaction conditions are as described below for the condensation of an L-argininamide with an arylsulfonyl halide and the removal of an NG substituent from an NG-substituted-N 2 -arylsulionyl-L-argininamide above.

The condensation of a N 2 -arylsulfonyl-L-arginyl halide with an amino acid derivative according to process variant b) above can be illustrated as follows: H HN 2 | C ~ N - CH 2 CH 2 CH 2 CHCOOH II and; + Arsozx (v11) __; HN \ * f HN / c - N - cugcugcugcucoon (rocï) -> 2 I HNso2 I Ar m '* si * HN / C - N - c fl zc fl zc fl zcricox (un) 2 I rmsoz I Ar + RH (Iv) -> unš * f / c - N - cazcnzcugoucon (I) HN 2 HNS02 | Ar 10 15 20 25 30 35 452 624 7 In the formulas above, R, Ar and X have the meaning given above.

The Nz-arylsulfonyl-L-argininamide (I) is prepared by condensation of a Nz-arylsulfonyl-L-arginyl halide (XXII), preferably a chloride, with at least an equimolar amount of an amino acid derivative (IV).

The condensation reaction can be carried out without added solvent in the presence of a base. However, satisfactory results are obtained when using a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).

The amount of solvent that can be used is not critical and can be varied from about 5 to 100 times the weight of the N2-arylsulfonyl-L-arginyl halide (XXII).

Preferred condensation reaction temperatures are in the range from -10 ° C now so ° c and preferably from zo ° c: in so ° c. The reaction is not critical, but varies with the amino acid derivative (IV) used. In general, a period of time from 5 minutes to 10 hours is useful. The resulting NZ-arylsulfonyl-L-argininamide can be isolated and purified in the same manner as described above.

The Nz-arylsulfonyl-L-arginyl halide (XXII) required as a starting material for the condensation can be prepared by reacting an NZ-arylsulfonyl-L-arginine (XX1) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus trichloride. phosphorus tribromide. The halogenation can be carried out with or without added solvent.

The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of solvent to be used is not critical and can range from about 5 to 100 times the weight of Nz-arylsulfonyl-L-arginine (XXI).

Preferred reaction temperatures are in the range of -10 ° C to room temperature. The reaction time is not critical but varies with the halogenating agent and the reaction temperature. In general, a period of from 15 minutes to 5 hours is useful.

The Nz-arylsulfonyl-L-arginines (XXI), which are starting materials for the preparation of the Nz-arylsulfonyl-L-arginyl halides (XXII), can be prepared by condensation of L-arginine (II) with a substantially equimolar amount of arylsulfonyl. nyl halide (VII) by a method similar to that described below for the condensation of an L-argininamide with an arylsulfonyl halide (process variant c)). The condensation of an L-argininamide with an arylsulfonyl halide according to process variant c) above can be illustrated as follows: 452-624 8 HN \: LC - N - cngcngc fl gcucoou llzN | | H NH, nN \\: C ~ N ~ C fl zCllgClizCl-ICOOH HN l | l R "HN R 'I Rm + RH HN ÉC - N - CHQCHQCHQCHCOR HN II' l Ru .HN R 'I Rm HN \\: C' - N _ CH2CH2CH2CHC0R HZN l IH NH2 + ArSOQX HN ÉC - N '- CH2ClI2CH2CIlC0R In the above formulas, R and Ar have the meaning given above; X is halogen, R "'is a protecting group for the ol-amino group such as benzyloxycarbonyl or tert-butoxycarbonyl; R 'and R "are selected from hydrogen and protecting groups for the guanidine log group, such as nitro, tosyl, trityl, oxycarbonyl and the like; and at least * (II) -α (HI) (IV) -> (v) -> (VI) (v11) -> (I) one of R 'and R "is a protecting group for the guanidino group.

The Nz-arylsulionyl-L-argininamide (I) is prepared by condensation of an L-argininamide (VI) with a substantially equimolar amount of an arylsulfonyl halide (VII), preferably a chloride. The condensation reaction is usually carried out in a suitable reaction-inert solvent in the presence of excess of a base such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate) at a temperature from 0 ° C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.

The preferred solvents for the condensation include benzene / diethyl ether, diethyl ether / water and dioxane / water.

When the reaction is complete, the salt formed is extracted with water, and the solvent is removed by standard methods, such as evaporation under reduced pressure, to give the N 2 -arylsulfonyl-L-argininamide (I), which can be purified by trituration or recrystallization with any suitable solvent such as diethyl ether / tetrahydrouran, diethyl ether / methanol and water / methanol, or can be chromatographed on silica gel. The L-argininamide starting materials (VI) required for the condensation reaction can be prepared. by protecting the guanidino and α-amino groups of L-arginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylene denaturation The NG-substituted-NZ-substituted-L-arginine (III) having a corresponding amino acid derivative (IV) by a conventional method, such as the acid chloride method, the azide method, the mixed anhydride method, the activated ester method or the carbodiimide method, and then selectively removes the protecting groups from the formed NG-substituted-Nz-substituted-L-argininamide (V).

The amino acid derivatives (IV), which are the starting material for the preparation of the NG-substituted-Nz-substituted-L-argininamides (V), are represented by the following formulas: 1 HN / (xx) \ cH (ca 1 coon n 2 n 3 " z "4 coon H - (X) H_N (xx) R x -Gü is coon ooa H -N 0 H _N,, (xn) (xm) 'lo 15 20 25 452 624 10 In the formulas above, R 1, R 2 The amino acid derivatives of formula (IX) above can be prepared by condensation of a haloacetate, β-halopropionate or li-halobutyrate with a suitable amine of formula R INHZ. Org. Chem., _23 728-732 (1960)).

The condensation reaction is usually carried out without any solvent or in a solvent, such as benzene or ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of from 0 ° C to 80 ° C for a period of 10 minutes to 20 hours. When the reaction is complete, the amino acid derivative formed is separated by conventional methods such as extraction with a suitable solvent or evaporation of the reaction solvent and then purification by distillation under reduced pressure.

Among the amino acid derivatives, the amino acid tert-butyl ester derivatives are preferred because they are readily converted to other ester derivatives by acidolysis in the presence of a corresponding alcohol using an inorganic acid (HCl, 142504, etc.) or an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.).

The following scheme illustrates the procedure used to prepare the Z-piperidinecarboxylic acid derivatives (X): NaOCl f; É * 'R5 "" "" * H xoH Hon \ Rs -___; R5 .___., »V N' 'cl g ( XIV) (xv) (xvI) 'Rs H 2 O - Rs (lfäïcmr (at) i (google HH (XVII) (Kl / III) In the first reaction in the scheme above, an appropriately substituted piperidine (XIV) is allowed to enter contact with an aqueous sodium hypochlorite solution at a temperature of - ° C to 0 ° C. The product formed (XV) is isolated by extraction with a solvent, for example diethyl ether, and then treated with potassium hydroxide in a lower alkanol as solvent to form 1 The action of cyanating agents, for example hydrogen cyanide or sodium cyanide, converts the LZ-dehydropiperidines (XVI) to the corresponding Z-cyan analogues (XVII) Hydrolysis of the 2-cyanopiperidines (XV11) to the Z-pyridine treatment of the Z-cyanopiperidines (XVII) with an inorganic acid such as hydrochloric acid or sulfuric acid a. The arylsulfonyl halides (VII) which are the starting materials for the preparation of. The Nz-arylsulfonyl-L-argininamides (I) can be prepared by halogenating the desired arylsulfonic acids or their salts, for example sodium salts, by conventional methods well known to those skilled in the art.

In practice, the halogenation is carried out without solvent or in a suitable solvent, e.g. halogenated hydrocarbons or DMF, in the presence of a halogenating agent, for example phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, at a temperature of from -, 1.0 ° C to 200 ° C for a period of 5 minutes to 5 hours. When the reaction is complete, the reaction product is poured onto ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.

The arylsulfonyl content can be purified by recrystallization from a suitable solvent such as hexane, benzene or the like.

It is well known to those skilled in the art that an ester derivative of the Nz-arylsulfonyl-L-argininamide (I), where RB or Ré is alkyl, can be prepared from a carboxylic acid derivative of the Nz-arylsulfonyl-L-argininamide, where Ra or RE is hydrogen, by conventional esterification methods well known to those skilled in the art. It is also well known that the carbonic acid derivative can be prepared from the ester derivative by conventional hydrolysis or acidolysis methods. The conditions under which the esterification, hydrolysis or acidolysis is to be carried out are obvious to a person skilled in the art.

In the N 2 -arylsulfonyl-L-argininamides (I) according to the invention, acid addition salts with a variety of inorganic and organic acids are formed. Some of the N2-arylsulfonyl-L-argininamides, which contain a free carboxyl group, wherein RB or RS are hydrogen, form salts with a variety of inorganic and inorganic bases. The product of the reactions described above can be isolated in free form or in saithe form. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, succinic acid, lactic acid, lactic acid, lactic acid , benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like. Similarly, the product can be obtained as pharmaceutically acceptable salts by reacting a free carboxylic acid with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, N-ethylpiperidine or similar.

Likewise, treatment of the salts with a base or acid leads to regeneration of the free amide. As mentioned above, the NZ-arylsulfonyl-L-argininamides and salts thereof obtained according to the present invention are characterized by their highly specific inhibitory activity in mammals against thrombin and by their significant lack of toxicity, and these compounds are therefore useful as diagnostic reagents for determining thrombin in blood and / or for medically controlling or preventing thrombosis.

The compounds are also useful as inhibitors of platelet aggregation. The antithrombotic activity of the NZ-arylsulfonyl-L-argininamides of the invention was compared with the corresponding activity of a known antithrombotic agent, Nz- (p-tolylsulfony fi-L-arginine methyl ester, by determining the fibrinogen coagulation time.) The measurement of the fibrinogen coagulation time Equivalent samples of 0.8 ml of fibrinogen solution, prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction 1), obtained from Armor Inc., in 40 ml of a borate-salt buffer (pH 7.4) were mixed with 0.1 ml of borate salt buffer, pH 7.4 (control) or a sample solution in the same buffer, and 0.1 ml of thrombin solution (5 units / ml), obtained from Mochida Pharmaceutical Co., Ltd., were added to the solutions on an ice bath.

Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 2 ° C.

The coagulation time was determined as the time between the transfer to the 25 ° C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds. The experimental results are summarized in Table 1. The expression "concentration necessary to prolong the coagulation time by a factor of two" is the concentration of an active substance required to prolong the normal coagulation time from 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factor of two was for the known antithrombotic agent NZ- (p-tolylsulifonyD-L- arginine methyl ester 1,100 μm. The inhibitor substances are shown in Table 1 with information on R and Ar in formula (I) and on the additive component. .

When a solution containing an Nz-arylsulfonyl-L-argininamide of the invention was administered intravenously to animal carcasses, the high antithrombotic activity in the circulating blood was maintained from one to three hours.

The half-life of the antithrombotic compounds of the invention in circulating blood was shown to be about 60 minutes; the physiological conditions of the host animal (rats, rabbits, dogs and chimpanzees) were well maintained.

Experimental reduction of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by co-infusion of the compounds of the invention.

Acute toxicity (LD10) values were determined by intravenous administration of substances of formula (I) to mice (male, 20 g) and ranged from about 150 to 600 mg per kilogram of body weight. Representative LD 50 values for the compounds prepared according to the invention are shown in the following table: i Compound HN \, u N> c - Nu - (crrgßoi-icon LDSO (mg / kg) 2 fmsogar Ar R i [í:] \ 0CH «/ C53 * § ::>" ° “3 25o - Boo \ cn3 coon \ C113 ÛÜNZF i -N m 'coon / C nf; 2 5 ~; ::> ~ cu3 - 300 N. Coon / CHQ- By way of comparison, the LDw values of Nz-dansyl-N-butyl-L-argininamide and Nz-dansyl-N-methyl-N-butyl- L-argininamide less than 10 mg per kilogram.

The therapeutic agents of the present invention may be administered to mammals, including humans, separately or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, the mode of administration chosen and standard pharmaceutical practice. 10 15 20 25- -30 35 452 624-. For example, the compounds can be injected parenterally, i.e. intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, enough saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules or granules, containing suitable excipients such as starch, lactose, sugar and the like. The compounds may be administered sublingually in the form of lozenges or tablets, in which each active substance is mixed with sugar or corn syrup, flavoring agents and coloring agents and then dehydrated sufficiently to make the mixture suitable for solid pressing. The compounds may be administered orally in the form of solutions, which may contain coloring and flavoring agents. The physician will determine the dosage of the present therapeutic agent which is most suitable for human use, and the dosage will vary with the mode of administration and the particular compound selected. In addition, the dosage depends on the particular patient to be treated.

When the composition is administered orally, a larger amount of active substance is required to produce the same effect as a smaller amount given parenterally.

The therapeutic dose is generally 10-50 mg / kg of active substance parenterally, 10-500 mg / kg orally per day. Following this general description of the invention, a more complete understanding thereof may be obtained by reference to certain particular examples, which are included only to illustrate the invention and are not intended to limit it, unless otherwise indicated. A pharmaceutical composition containing a compound of the invention as active ingredient may be in the forms described above. In particular, such compositions are in unit dosage form.

Example To a well-stirred solution of 83.6 g of L-arginine in 800 ml of 1096 g of potassium carbonate solution was added 112.7 g of Z-dibenzothiophenesulfonyl chloride in 800 ml of benzene. The reaction mixture was stirred for 5 hours at 60 ° C for 60 hours. After 1 hour at room temperature, the precipitate was filtered off and washed successively with benzene and water to give 127 g of (7696) Nz- (Z-dibenzothienylsulfonyl) -L-arginine.

A suspension of 4.21 g of NZ- (Z-dibenzothienylsulfonyl-D-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether gave a precipitate which was washed and filtered. 452 624 'several times with dry diethyl ether to give NZ- (Z-dibenzotlenylsulfonyl) -L-arginyl chloride.

To a stirred solution of 2.67 g of N-butylglycine-tert-butyl ester in 20 ml of chloroform was carefully added the above-obtained N2- (2-dylphenylene) methylene-methylene-methylphenylene-methylphenylene-methylphenylene-methylphenyl. was allowed to stand at room temperature for 1 hour.

At the end of this time, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of diethyl ether to give an amorphous solid. This was collected by filtration and precipitated from ethanol / ethyl ether to give 3.1 g (4996) of NZ- (Z-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine-terL-butyl ester.

LR. (can: 3350, mo, 1625 cm -1 Analysis - calculate: for c 28 H 39 O 5 N 5 S 2.1 / 2H 2 SO 3 (percent fi: C, 53.31; H, 6.39; N, 11.10 Found (percent): C, 53.21 To a solution of 2.00 g of Nz- (Z-dibenzothienylsulfonyl-D-L-arginyl-N-butylglycine-terL-butyl ester in 20 ml of chloroform was added 50 ml of 1596 HCl; H, 6.146; N, 10.89 .mu.l. / ethyl acetate.

The reaction mixture was stirred for 5 hours at room temperature. Then the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaio SK 102 ion exchange resin (200-300 mesh, 1-Ü form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 396 μg. ammonium hydroxide solution.

The fraction eluted with the 3% ammonium hydroxide solution was evaporated to dryness to give 0.9 g (5396) of Nz- (Z-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine as an amorphous LR. (KBr): 3350, i.e., 1210 cm -1 Analysis calculated for C 21 H 31 N 5 O 5 S 2 (percent): C, 54.01; H, 5.86; N, 13.12 Found (percent) C, 53.78; H, 5.97; N, 12.96 Example 2 W Eekdibsfläefnsnylssä ° ß kar tkar: imdàtQ-mstsæietxlklysinei fl ae: To a stirred solution of 2.42 g of N- (Z-methoxyethyl fi glycine ethyl ester and 4.0 ml of triethylamine in 50 ml chloroform, which was cooled on an ice / salt bath, was added portionwise 7.0 g of Nz- (Z-dibenzothienylsulfonyl-D-L-arginyl chloride obtained as above. The reaction mixture was stirred overnight at room temperature, then 50 ml of chloroform was added and the chloroform solution was washed. twice with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated in the reaction mixture and chromatographed on 200 ml of Daiaion 452 624 16 vacuum The oily residue was washed with ethyl ether to give 5.5 g of powdered NZ- (Z-dibenzothienylsulfonyl-D-L-arginyl-N- (Z-methoxyethyl) glycine ethyl ester. in Analysis calculated for C 25 H 23 O 6 N 5 S 2 J / 2H 2 SO 3 (percent): C, 50.49; l-i, 4.07; N, 11.78 C, 50.22; H, 4.18; N, 11.51 (ß) 1.1Ešflibsf fi efšavlsslßßn fl kk-afsm flfl šâ-L fl sæáafrika / sia Found (percent): A solution of 5.5 g Nz- (Z-dibenzothienylsulfonyD-L-arginyl-N- (Z-methoxyethyl ethyl 15 methanol and 15 ml of 2N NaOH solution were heated to 40 ° C and kept at this temperature for 10 hours, then SK 102 concentrated ion exchange resin (200-300 mesh, Hiform, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol / water (1: 4) and eluted with ethanol / water / NH 4 O -1 (10: 9: 1) The main fraction was evaporated to dryness and washed with ethyl ether to give 3.05 g (62%) of N 2 - (Z-dibenzothienylsulfonyD) -L-arginyl-N- (Z-methoxyethylglycine as an amorphous solid. 1R (KBr): 3400, 1630, 1280 cm -1 Analysis - calculated for C 23 H 29 O 6 N 5 S 2 (percent) C, 51.57; H, 5, 46; N, 13.08 Found (percent): C, 51.35; H, 5.63; N, 12.86 Example 3 <4) 1SÉ-.aliíæ-.Nf-lëüelæat ° i To a stirred solution of 28.4 g of NG-nitro-N2- (tert-butoxycarbonyl) -L-arginine in 450 ml of dry tetrahydrofuran sat 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate, the temperature being maintained at -5 ° C. After 15 minutes, 35.0 g of N-butylglycine benzyl ester p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran were added, after which the mixture was stirred for 15 minutes at -5 ° C. Then the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue was taken up in 400 ml of ethyl acetate and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of 1096% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was dissolved in 20 ml of chloroform, and the solution was applied to a column (80 cm x 6 cm) of 500 g of silica gel packed in chloroform. The product was eluted first with chloroform and then with 3% methanol / chloroform. The fraction eluted from 396 methanol / chloroform was evaporated to dryness to give 26.0 g (5696) of NG-nitro-Nz- (terL-butoxycarbonyl-L-arginyl-N-butylglycine benzyl ester as a syrup). .R. (1 <ßr) = 3300, 1740, 1690 em * 10 15 20 25 30 35 452 624 17 (ß). Efi * ëLæI-fueui / kàkëafxlslxefrles fl Sxlsëe-hxt fi bëë. Nu en amrörd lösning av 26,0 g N - nino-N -urene-buroxycarbonyn-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethyl acetate was added 8.0 ml of 1096 dry HCl / ethyl acetate at 0 ° C. After 3 hours, 200 ml of dry ethyl ether was added to this solution to precipitate This was filtered and washed with dry ethyl ether to give 20.8 g of NG-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride as an amorphous solid.

(C) 09-11tfmNfíäsykæfßzyzy- fi amsëfæiieavlsilhfeßxlkla-ansmßßkfairyl- alxsifrlæn fi xësía To a stirred solution of 2.33 g of NG-nitro-L-arginyl-N-butylglycine-benzyl ester ml of hydrochloride hydrochloride and 40 ml of hydrochloride , 26 g of sodium bicarbonate and 2.2 g of β-cyclohexyl-11-methoxyphenylsulfonyl chloride at 5 ° C, and stirring was continued for 3 hours at room temperature. Then the solvent was evaporated and the residue was dissolved in 100 ml of ethyl acetate and washed successively with 10 ml of 1 N hydrochloric acid solution, 20 ml of water, 20 ml of 596 sodium bicarbonate and 10 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 396 methanol / chloroform. The phosphate eluted with 396 methanol / chloroform was evaporated to give 2.6 g (77%) of NG-nirro-Nz- (z-eykiohexyyl-11-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine benzyl ester as an amorphous solid. 1.11. (can: 3300, 2920, mo, 1640, 1250 cm * Analysis - calculated for C 31 H 18 IIGOSN 6 S (percent): C, 56.95; H, 6.87; N, 12.46 Found (percent proc : C, 56.49; H, 6.63; N, 12.38 (Dl .NÉ-íäßxlileisxxkft-æsfsefswwerl * dëavltl fi efzi / i-.Nåstzlslzëft Till a solution of 3.00 g NG-nitro-Nz- (B- cyclohexyl-11-methoxy-phenylsulfonyl-D-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water were added 0.5 g of palladium-black, after which the mixture was shaken in a white atmosphere for 50 hours at The ethanol solution was then filtered to remove the catalyst and evaporated to dryness, the residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200-300 mesh, Hiform, manufactured by Mitsubishi Chemical Industries Limit). ed) packed in water, washed with water and eluted with 396 g of ammonium hydroxide solution. The fraction eluted from 396 g of ammonium hydroxide solution was evaporated to dryness to give 1.5 g of (7296) Nz- (β-cyclohexyl-1-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine as an amorphous solid . 10 15 20 25 30 35 452 624 18 1.R. (1 <ßr) = 3350, 2920, i.e., 1250 cm * Analysis - calculated for C 25 H 21 N 2 O 3 S 1 (percent) - C, 55.63; H, 7.66; N, 12.98 Found (percent): C, 55.32; H, 7.39; N, 12.84 Example 4 r W mkbådastå-msasseffæetaxifsuysuaayy fl-fi æwn; ï-mstvkâ-xziaeziëinleëewef.

To a well-stirred solution of 2.05 g of ethyl 1- (NG-nitro-1-arginyl-11-methyl-2-piperidinecarboxylate hydrochloride and 1.26 g of NaHCO 3 in 10 ml of water and # 0 ml of dioxane were added portionwise 2.2 g of β-cyclohexyl-1-methoxybenzenesulfonyl chloride, keeping the temperature at 0 DEG C. The reaction mixture was stirred at room temperature overnight, then the reaction mixture was evaporated to dryness, the residue was taken up in 50 ml of ethyl acetate and the ethyl acetate solution was washed in order. 1096 g of citric acid, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, the ethyl acetate solution was evaporated and the residue was chromatographed on silica gel packed in chloroform and eluted with chloroform containing 396 g of methanol. - [NG-Nitro-Nz- (β-cyclohexyl-1β-methoxybenzenesulfonyl-L-arginyl) -1-methyl-2-piperidinecarboxylate.

LR. (KBÛ: 3400, 17321635, 1250 cm -1 (B) šw; kißlzdâ-sikbhesidieffiemëe fl xlsulfe fl xQ-Lfssi fl zllütfaeiyl-Z- aineiiéinleabswši-ecifet Till a solution of 2.6 g ethyl-N-cyclo (NGx (11-methoxyphenylsulfonyl-D-L-arginyl) -1-methyl-Z-piperidinecarboxylate in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid were added 0.5 g of palladium black, after which the mixture was shaken in a hydrogen atmosphere for 15 hours at room temperature. was filtered to remove the catalyst and evaporated to give an oily product.

Ethanol / diethyl ether precipitation gave 2.4 g of ethyl 1- [Nz- (β-cyclohexyl-11-methoxyphenylsulfonyl-L-arginyl] -11-methyl-Z-piperidinecarboxylate acetate.

(C) 1-1E fl fxlë fl ztiexxkkmäfaxifewë¶ís> fyD; 1-; a: s¿wi); & fnë fl é; A solution of 2.4 g of ethyl 1-phenyl- (B-cyclohexyl-11-methoxyphenylsulfonyl-L-arginyl] -1H-methyl-Z-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of N NaOH solution was stirred The reaction mixture was then concentrated and dissolved in 10 ml of water, the solution was neutralized with 2 N HCl solution to give a white gummy precipitate which was dissolved in 150 ml of chloroform, the chloroform solution was washed with saturated NaCl solution and dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.52 g of 1- [N 2- (β-cyclohexyl-1β-methoxyphenylsulfonyl-L-arginyl] -l-methyl-Z-piperidinecarboxylic acid as a amorphous solid.

LR. (KBr): 3350, 2920, 1620, 1250 cm -1. Analysis - calculated for C 26 HMO 6 N 5 S (percent) - C, 56.60; H, 7.149; N, 12.70 Found (percent): C, 56.51; H, 7.53; N, 12,68 Exemp_el5 'sogcl No nu .H 4 H am) u (cnz) gcixçoiOcxi3 ou3 No2S; 1¿.N (C “2) 3C ,, c0 © -ca3 - éooßt>“ _ NH coon: Niig 1 -1c1 i S02 (Ü 'CH W ëwet-i fl izsz-re-zvs; taalready / areast-emeeenili- fl í-ßse »11-2: sšßxll fifl siykš-iziizeàsiwls fi awyia: 10 To a well-stirred solution of 0.08 g ethyl-l- (NG-Nitro-L-arginyl-1-methyl-Z-piperidinecarboxylate hydrochloride and 3.03 g of triethylamine in 200 ml of chloroform were added portionwise to 3.69 g of β-methyl-1,2,3,4-tetrahydro-8- quinoline sulfonyl chloride, keeping the temperature at 5 ° C. The reaction mixture was stirred for 5 hours at room temperature, at the end of this period, the reaction mixture was washed with saturated NaCl solution and dried over anhydrous sodium sulfate, the chloroform solution was evaporated and the residue was chromatographed. in chloroform and eluted with chloroform containing 396 methanol The main fraction was evaporated to dryness to give 3.61 g (6296) of ethyl 1- [Nz- (B-methyl-1,2,3,1: -tetrahydro-S -quinolinesulfonyl-NG-nitro-L-arginyl) -lß -Methyl-Z-piperidinecarboxylate as an amorphous solid. m (Kan: saoo, mo, 1635 cm -1) Nmxucoaoo) δ (ppmh e, s (1H, f), 7.1 (1H, d), 7.4 (1ii, d) Nogna _.

NH; § (cu2) 3cnco -cu3 NH%? _ NH (cH2) 3cHC ° CH3 lm: I _ coomt, fu ï fl coon: so H \ u ci13coou É3 [ïlcH3 (j {ïlcn3 10 15 20 25 452 624 20 (B) šukL -Lfïziâ-L fl sfzxl; hää'tßifalufßs-åëme fi ßelße fl zâ-Lezswzll- 2-51: aftëeaexiáinkswswëtaßsea To a solution of 3.00 g of ethyl -1-1-fNz- (B-methyl-1,2,3,4-tetrahydro- -NG-nitro-L-arginyl] -4-methyl-2-piperidinecarboxylate in 100 ml of ethanol and 20 ml of acetic acid, 0.9 g of palladium black was added, and the mixture was then shaken in a hydrogen atmosphere for 15 hours at room temperature. of the catalyst and evaporated to give an oily product.

Reconstitution with ethanol / diethyl ether gave 2.38 g (78%) of ethyl 1- [N2- (3-methyl-1,2,3,4-tetrahydro-5-quinolinesulfonyl-L-arginyl] -4-methyl-2 -piperidine-carboxylate acetate.

Nuzp-m fl cxig) gciicoi -cn3 mig -N1-z (c1-r2) 3CHcONQ-CU3 "u NH coon: NH» Im COW 'so ----'- ° "> Flßa | 2 "*: in Kf? CH3 CH3 (C) L-.Ef! ÉEffsB / kllå-âä-: eielin * æåki fl sli fl sulfefn / Dá-: azsi fl xü14; L fl sfxtëráas flfl lifikafèaxzlëyse A solution of 2.00 g Ny1- l (B-). -methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl-D-L-arginyl] -4-methyl-2-piperidinecarboxylate acetate in 20 ml of ethanol and 10 ml of N NaOH solution were stirred overnight at room temperature. Then the reaction mixture was neutralized with 2N HCl and concentrated in vacuo to give a gum-like precipitate which was extracted 3 times with 150 ml of chloroform.

The chloroform solution was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.45 g of (8596) 1- (N2- (3-methyl-1,2,3,4-tetrahydro-S- quinoline sulfonyl-L-arginyl J -4-methyl-Z-piperidinecarboxylic acid as an amorine solid.

IR (KBr): 3400, 1620, 1460, 1380 cm -1 Analysis - calculated for C 23 H 35 O 5 N 6 S (percent) C, 54.31; H, 7.13; N, 16.52 C, 54.09; H, 7.00; N, 16.80 Various other Nz-arylsulfonyl-L-arginine salts or acid addition salts Found (percent): of which were synthesized according to the procedure of the above examples, and the test results are summarized in Table 1. .onwà wwá fl go within ox / o / w N .l =. 0.1 .; 638 2.3 3: »møón _ \ // \ _ \ ~ Q Å .. own fl onwå 3.3. men nwåa n o / z / n 2 1 _. _ / O umwi. 6.35 ß fi m ... Inn. nä: ox z \. I GL 5 03; .onnå mi? mëw 5.2 _ Å. n ... _. nmuREzÛ ».__ 95:" .ooin ¶ = nÅä wwé Gå:. 03 :. 63 .. "šå fl uni. åám n n. 960 n SQN 63A 3.2 å; 3.2 _. 1 _ 2 owwå .Eå fi nwé mwém n, mn moouwmu /. nmoo. ¶ w enwå .Sin åxå S6 ~ QR nmu ~ mo ~ mo ~ mu \ z © | Éuö 03; 65.4 2: 3 36 mnán: Röäu / nmö / _ |. . z .. fl onwJ .onnå moá fi fl we 2.3 n ow nmuo ~ mu ~ mo \ © zm n. noešß -må f 2 fusß pms fl ßw ».wäšø .Hwmmxw: owpm fi smmøw fl .ë | ~ om | z ..: .ha TBC. må pmm mämnfoš I fl wmw. m fl wdnwm _. _ Yzwm .Pohm. m ä M ... o l fl mum Fuum .Hmm www. mouæuwmuumuwmunzuu Hmsm fi mwswëw fi m .x fi whm ... Emnm mmâumn no fl. ¶ m lä _ Imnumwuaou _. .HHwnwmB 452'èà4 22 wo oßuå moå fl ncå mwáa m ~ 1 ._ ä. Mami .ooín ._92 min 3 .: _ owNÅ 3. En 3. n mn. .R møoowmu / N MJ-O .I Zl _. AH _ _ _. . . n: uo ~ mo ~ mu \.

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Sw: .Råå 8.3 .and .vwâ 3 ~ no 5.0 "än R mwoo z zu 2» .Hm zuo Önsšmv m2? .Wow mm .àqo fl w a | .i: m3 ämsm 2.3 .: wowww fl wwwwp -så _. .Ë Tnä .mä uwšäm "wanna Inmmm lmmcwn. .nmzw fl nmw .ëuwownw fl rz zwz Po fi m um fifi mnwn .um fi ñ ßxm fl a ... Zmpm ppm .Hmm WG moo = u ~ = o ~ = u ~ = u | = | u \ mh fi m fi mnmunmëw fl m lmxwmè 45 45 45m. = z Ûumnnb oowÄ ._ NI ._ f © m ... onnå nná fl níw äén. : sou QÛà muá fl 3. » coin 395V åwå nmïnßm ~ .. 9.6 z .. m q S. øwnå .Éé fl wnš o ~ .._ n m oLTw ¶ oïi. 62. » 3.2. “M6 .Sån moou ~ mu. _ ~ va .. ._ m5 nwwå .Énä nmé fi 3.6 nmI-n nmuowzowmu. _ _ ~ 9898 93 d .än H ßá fl nwé wßán: oou: u / / “__. . v ... _ owwå .coin wßz fi. ... JG .Rån n ma ~ _ | ~: o \., _ \ ONAL fi .Ävm fi-. N MN. have. mO.w mm-OW 1000M30 _ _ w Vz | _. ... a oNwJ 63: .. maá fl 36. aoåm nmuowzuwæu on fi å .nmnÄ 2.3 Dum Sån mooowæu \ nmu .Hw fi wnm .u o N wz .. 1 _ n: onwå 6.35 .åd fl owé woán Q: u. . z m. u .m5 »åwv fi mw lmwæ% nw m .å få. Hwmmw egg mmoww fi äwww. U <.h N _. á ï fl a .än uwšm .wnw fl b Iam ... m Sw: mm fl m fl nnw <1 emß flfi m AN: Po fi m umsxm fi mn "w fi ö mxm fifl l fifl wum ppm .Hmm www z ° u = u ~ = u ~ = ow = u | z | o \ .müm ëm mn. lmxwm .Émhm .šmbum fi fl owv, x IE ..

| M.HHÉUUQOVH 452 624 rdwmuwxuwmu “n ~. ~ Hw.nH ~ m.w wn.ww _ vmnn QSà .. w .. .. ... n UUHQ ømnå nín fl wfw wwán“ SJ 8.2 3G 2.3 nä. . w fl m cow. n. _. w .. ._ moxuwz; nn Wm fi oonå 2.2 mná Sá ... xowxowmuo nm fl å 3.2 m6 mw-on vvmnní oowà _. w Ö _29 wmån øonä wall 36 3: 3 mowmuwzuo mn flfi Nnlww ~ n.w nwån nn Ûwhnv owwh ._ w .. .. onnä 3: 2 36 ïán u: owäwä owHà ... wlä omö øoån n _ om gw fi nv oGà _. omnå 3.13 36 mïwn G. æocw.

.RHà wwáw 2. » 31%. mmquëuw Aww fi nv og. w HmPdßA w .n nn z .. .m4 onnä 913. wnš øwén IMHPHUUGOM w z z o Ön: .Nwv m5 »fi mßxmm Im fl æww. feel . fzså .Hmmmxm woumë wmowwä fl mmwwu. U <. . .ha ï fl s .mä vmåšm “mäns lsmmw lmm flfi s .mm fi má om wfwomnzn: _ -w. EXE, umzxmnwn ww flfi mxmwa l fifl mum uum .www ww mou: ww = owzuw = u..z1u \ v m mšnm fl m fi mucwaw fl m .Imxwwäß läka .šmšunc 20.3 m: JE 452 624 30 nní fl »nå. .

A w oNwÄ d .. .nu n mm S Q u .Éunnå fi å fl “än -¿._ d .. šouwmu /. m n = u ~ xuw ~ = u ~ = u \ zx Q __ / on fi m fl fn N fi- w fl WQ- fl a. O \ Aøw owoå. nä: e H r ... _ Ave. - n w .. w fl nan mná: N | : ooumzul. _ n: um ~ = u ~ __u \ ./ .. \ .J / nn. ~ / \ S: H 3.3 âd Enn O fi w ~ fi ~ ßfqï fl flfi- h fl »~ O.W wW-hm N 3.0 _. mn owwà 3.2 .. msn fl oän n; _. : w .n .bßfn m: nu Nm.m wn-nn .n nnÅv I IOQUNWU / QMÖ G omwïn un.w.n mßÅ. øN-wn. o O fi vïn .bnïïn mW-Nd N fl- N MAÜWW N. N ÉOOUNIO mwm fl üO. .. / | . nmu «mo ~ = u« = u. \ z Ö nn Uwä mn fi à mnå fl ßw.w .Sån Q V nå O fl wfn w .Hwïnßm m. u .B än. "G12 2.6 3.2 ~ .. 3%". moåfu Z I U Ade fi Q A fi äåav fl ßg fi æ W _ | mm Mmm lm w Tëc .män mössan “wanna nsww fi m uopws .wwowwa swB fi ... www m .2» msxmnmn um fi ö. mxw fl w. immune: nwmw fi uwmmcx _ m Hmsmaßpswsw fi w 1335 läwww iwwmuwmw fl www .. <.. ~ 3¿. ~ .. = w .øwwn Hmamzmwmww mou: u ~: u ~ zu ~: o | z | u \ z m m. m lä 452 624 o H.. now must. . _ ~ H om w H mo m nu on wooowmouzo / onoå .oo _... n 3.3 .. mTw wnán N | n: uo ~: u ~ = u \ z | ._ vw ON; .about .H73 3. » d fi on nä ..... zooäö \ .f nä; .coin 8.3. 3. » 3% ~ V / f 8 ä nmoo ~ = o ~ = u \ 95. . .oxo - onwJ mn - mi »oqšn a: ooošw / _ ao. / 3%; .coin .Nää 2; .R - Okmom, “m3 / _ \ ... o Én J mné fi 5. o 3. fä šoo, .. ~ q - N I \. _ fl o fl w o own n 3.3. and .Rån LA “nu / w .a fl. . . 93; mwá fi mná mwåw: oo fl _ _ w | \ _ al »Ö ä oS H .ooin 3.2: reach 3.3.

. Nm flfl 2.3 Run .Rån mooowmu o N - @; @ G AUQHQV øm fi ån: n.N.n ww-n am. mn @ I ~ = UN2U \ z m o Ön fl dnmv w fifl ä Mmm. lmdæwm z - h ..

A75; . nmmmxm vouws owwowmä fl wmu fl. l fl ooæ. .än TSG éå. umšw. Gosa Iswmm Imm flfifl. .wmnm fl www .Sïwowwzum ~> onm umsxw fl mn "w fi š mxmw fl l flfl mum uum nå .. www æoomw ~ mu ~ mo ~ = u« z | o \ zz mä fl m fl m fi munwsw fl m lmo fl mmm ... nanm: mšonn am 24 2 below are presented in the same way: In this table, the literature reference in the second column indicates a method of preparing the compound indicated in the second column 452 624 33 || I. .in S600. Nzaunøu .ßwwæ rr, n _ OIQ ._. oo: sou. mzwuao .. Enm Ra .ww within.

G28 MSOO \ ._ \ za xz m / _ z ... / l mao: nSOO nrUO .Gm fi šßwww .mami ... wmo mxmnm m .öoowzu /: o xz © zm = ~ oooo ~ __o / z:: ozwn U - a. H 3 N \ H Ö - D | r = U \: O / ZI: U: O / Z wvbwü oonn .a .a: oou fl ö / \ oun = nzwowšvooouš. / oun: o | ~ = o \ z | ® O o | ~ = u \ z: _ a _ / _ _ 4 Huwom m. n <.awumwmgwoäš ï fl wnwmwhnßum fi muuw fl v. -Emomaz. zu: Bwkmv u fl mm .Hm flfi w _ .Hz moušumäwzuv I: z 1 o4 \ o z:. fl mw fi wumëmmsmmvb mmowë .am fi mw fl umowå HMSUOHß N HHwßmB 452 624: ooo nzwuoou m2. Ha ål ".å fi m fi ëm - ©; @ @ -f @ m fl o fi u: oau n = ~ uoou Änmä må mN: name Jam: Fåšm å. Wm Sö: z .. QQ 95 z: NM _ Ho om P6 o. Nzu o Å .No n «: nal owwm .æw fi nam .... .Ésoo: OQO n: eocou _ NM A Qnø 31 ö ö = u: | = z: _ / lx Swom ./ P fi. 3 _ Aanm fl v OwNN .mmm Uimh .uQEDO: oou mm.. w. z ooou m Å w- QMQ Ö / Ö \. fl owom m .É nwummmnhmos fi å _ Amnm fi wwwn fi ßum fi wvvw fl v .ëwomaz zw: ånwu »än .Hw fl w az: ouzw zw w .. uzw fi wz. nm fl w Homomå _ pëuoš 10 15 20 25 30 v 452 624 35 Example 6 Tablets suitable for oral administration.

Tablets containing the ingredients listed below can be prepared by conventional techniques. Ingredient Amount: down tablet ms) N2- (E-cyclohexyl-11-methoxyphenylsulfonyl »L-arginyl-N-butylglycine g 250 Lactose 140 Maize starch 35 Talc in 20 Magnesium stearate 5 Total # 50 mg Example 7 Capsules for oral administration.

Capsules as below were made by carefully mixing batches of the ingredients and filling the mixture onto hard gelatin capsules. Ingredient Amount of capsule ma) i-O-cyclohexy-α-methoxyphenylsulfonyl-L-arginyl-N-butylglycine 250 Lactose 250 Total 500 mg Example 8 Sterile solution for infusion.

The following ingredients were dissolved in water for intravenous perfusion and the resulting solution was sterilized.

Ingredients Amount (g) NZ- (β-cyclohexyl-1-methoxy] phenylsulionyl-D-L-arginyl-N-butylglycine Buffer System Desired Glucose 25 'Distilled Water 500 After this complete description of the invention, it will be apparent to one skilled in the art that many changes and modifications may be made within the scope of the basic idea of the invention as set forth herein.

Claims (5)

1. 452 624 36 PATENTK RAV l. Process for the preparation of a Nz-arylsulionyl-L-argininamide having the element 1 'in HN c - N - cuzcuzc fl zcncon (1) H N / I 1 2 n rmso | 2 Ar where R is (I) R / 1 is a (C 2 -C 20 alkyl 3 R 2 where R 1 is C 2 -C 6 alkyl, C 2 -C 8 alkoxyalkyl, C 2 -C 6 alkylthioalkyl, (C 2 -C 10 alkylsulfinylalkyl, C 7 -C 18 alkyl) aralkyl, C 1 -C 10 cycloalkyl, C 1 -C 6 cycloalkylalkyl, C 1-4 pyridylmethyl, 2- or 1-pyridylmethyl or phenyl; R 2 is hydrogen or C 1 -C 10 alkyl; R 3 is hydrogen or C 1 -C 10 alkyl; -C 2 alkyl; and n is an integer 0 or 1; (2) R 4 where Ru is -COORQ wherein R 5 is hydrogen or C 1 -C 10 alkyl, each R 5 is hydrogen or C 1 -C 6 alkyl 'and m is an integer 1 or 2; Ru is substituted in the 2- or 3-position and R 5 may be substituted in the 2, 3, 11, 5- or δ-positions; (15) (IJOH -N .alpha .: (β) C 10 H 10 -N 2 O 3 .- or (5) 00 + -N and -Ar is a phenyl group substituted with at least one substituent selected from amino, C 1 -C 6 alkylamino, C 1 -C 18 acylamino C1-C1-hydroxyalkylphenyl, C7-C1-phenylalkyl and C1-C10-hydroxyalkoxy; a phenyl group substituted by at least one substituent selected from hydroxy, C1-C5-alkyl and C1-C1-alkoxy, and at least t a substituent selected from C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl and phenyl; a fG-FNXifGH1 / lw dibefltienyln 9,9-dioxodibenzothienyl, phenoxathinyb, quinolyl, 1,2,3,11-tetrahydroclinolyl or acridinyl group, each of which is unsubstituted or substituted by one or more groups selected from hydroxy, Cl -C 1-4 alkoxy and C 1 -C 11 alkyl; 2,3-dihydro-quinoxaline-2,3-dione; a C 9 -C 16 cycloalkylphenyl, oren-uorenyl, tloxanthenyl or ZH-chromenyl group, each of which is unsubstituted or substituted by one or more groups selected from hydroxy, C 1 -C 6 -alkyl, C 1 -C 11 -alkoxy, C -C 1-4 alkoxycarbonyl and oxo; or β-cyldohexyl-β-ethoxycarbonyloxyphenyl; 452 4524 and pharmaceutically acceptable salts thereof, characterized in that a) removes the NG substituent from an NG-substituted Nz-arylsultonyl-L-argininamide of the formula n. UN '* c _. u - cHZcHZcHZoucOR / i mf Ra lmsoz R '. Ar 'where R and Ar have the meaning given above, R' and R "are selected from hydrogen and protecting groups for the guanidino group and at least one of R 'and R" is a protecting group for the guanidino group, by acidolysis or hydrogenolysis, or b) gives a Nz-arylsulfonyl-L-arginyl halide of the formula "xc - N - cngcugcazcncox nn" | | 2 H 11 N 2 O 2 'Ar where Ar has the meaning given above and X is halogen, react with an amino acid derivative of the formula RH where R has the meaning given above, or c) let an L-argininamide of the formula HN \ C - III ~ C11zCllzCliz- EHCOR HZN H: m2 where R has the meaning given above, reacting with an arylsulfonyl halide of the formula ArSO 2 X where Ar has the meaning given above and X is halogen, the reaction product obtained, and optionally transferring a obtained compound of formula I to a pharmaceutically acceptable salt thereof. In that, if desired, it is hydrolyzed 2. A process according to claim 1, characterized in that compounds are prepared in which Ar is a substituted or unsubstituted 1,2, Bβ-tetrahydroquinolyl group. 3. A method according to claim 1 or 2, characterized in that the acidolysis is carried out by contacting the NG-substituted N 2 -arylsulfonyl-L-argininamide with an excess of an acid at a temperature of -1 ° C 'oo ° c. b. 4. A method according to claim 1 or 2, characterized in that the hydrogenolysis is carried out in a reaction-like solvent in the presence of a hydrogen-activating catalyst in a hydrogen atmosphere at a temperature from 0 ° C to the boiling temperature of the solvent. 5. A method according to claim 1 or 2, characterized in that the N 2 -arylsulfonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature from -lo ° c now + so ° c.