CS236772B2 - Process for preparing N2-arylsulfonyl-L-argininainides - Google Patents

Abstract

A process for the preparation of N2-arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts, which have been found to be effective pharmaceutical agents for the inhibition and treatment of thrombosis in mammals.

Description

The invention relates to a process for the preparation of N ² -arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts, which have excellent antithrombotic properties and low toxicity.

In the past, much effort has been made to obtain new and improved preparations for the treatment of thrombosis. It has been found that N ² -(p-folilsulfonyl)L-arginine esters are one type of preparation that can be used and are effective in dissolving blood clots (U.S. Patent No. 3,622,615). It has been found that a particularly useful highly effective thrombin inhibitor in the treatment of thrombosis is the ester or amide of N-Mansyl-L-arginine (U.S. Patent No. 3,978,045). However, there is still a need for a highly specific thrombin inhibitor for the treatment of thrombosis that has lower toxicity.

It has now been discovered that N ² -arylsulfonyl-L-arginine amides exhibit antithrombotic activity and also a lower level of toxicity at the same relative potency compared to N ² -dansyl-L-arginine ester or amide.

The subject of the invention is a process for the preparation of N ² -arylsulfonyl/-L-argininamides of the general formula I

HN

C— N—CH2CH2CH2CHCOR / I I

H2N η NHSOz (I)

Ar where R is a group (1)

Ri

Z —N \

CH(CH2) _n COOR3

R2 where

R1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, tetrahydro-4-pyranylmethyl, 2- or 3-pyridylmethyl and phenyl,

R2 is hydrogen or alkyl of 1 to 10 carbon atoms,

R3 is hydrogen or alkyl of 1 to 10 carbon atoms, and n is an integer of 0 or 1.

(2)

where

Ri is — COORe, where Re is hydrogen or alkyl of 1 to 10 carbon atoms, Rs is hydrogen or; alkyl of 1 to 10 carbon atoms and m is an integer of 0 or; 2, R4 is in position 2 or 3 and Rs may be in position 2, 3, 4, 5 or 6 (3)

COOH

where p is an integer 1 or 2, (4)

COOH

or (5)

COOH

and Ar is phenyl substituted with at least one amino group, alkylamino group with 1 to 10 carbon atoms, acylamino group with 1 to 10 carbon atoms, hydroxyalkyl group with 1 to 10 carbon atoms and hydroxyalkoxy group with 1 to 10 carbon atoms, phenyl substituted with at least one hydroxy group, alkyl with 1 to 5 carbon atoms and alkoxy group with 1 to 10 carbon atoms and at least one aralkyl with 7 to 12 carbon atoms, alkylcarbonyl with 2 to 6 carbon atoms and phenyl, phenoxyphenyl, dibenzothienyl, 9,9-dioxobenzothienyl, phenoxathiinyl, ΙΗ-indazolyl, quinolyl, indolinyl, phenazinyl, ohinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroO'Quinolyl or an acridinyl group, any of which is unsubstituted or substituted by at least one hydroxy group, an alkyl group with 1 to 10 carbon atoms and an alkoxy group with 1 to 10 carbon atoms, a cycloalkylphenyl group with 9 to 16 carbon atoms, a fluorenyl, thioxanthenyl or 2H-chromenyl group, any of which is unsubstituted or substituted by at least one hydroxy group, an alkyl group with 1 to 10 carbon atoms, an alkoxy group with 1 to 10 carbon atoms, an alkoxycarbonyl group with 2 to 10 carbon atoms, and an oxo group, a 3-cyclohexyl-4-ethoxycarbonyloxyphenyl or phenyl group substituted by at least one alkyl, alkoxy group, haloalkoxy group, alkoxyalkoxy group and alkoxycarbonylalkoxy group, said substituents containing 3 to 7 carbon atoms and said the substituted phenyl group is further optionally substituted with at least one methyl, ethyl, methoxy, ethoxy, hydroxy and halogen, and pharmaceutically acceptable salts, characterized in that the N ^G -substituent is removed from the N ^G -substituted -N ² -arylsulfonyl-L-argininamide of general formula II

HN

C—N—CH2CH2CH2CHCOR

HN R" HNSO2 (II]

R' Ar where

R and Ar are as defined above and R' and R" are hydrogen and protecting groups for the guanidino group and at least one of the substituents R' and R" is a protecting group for the guanidino group, by means of acidic hydrolysis or hydrogenolysis and optionally the reaction product obtained above is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or is liberated by reaction of the salt with a base or acid amide.

Typical compounds obtained by the method of the invention include:

1-(N ² -quinoline-8-sulfonyl-L-arginyl)-4-methyl-2-piperidinecarboxylic acid 1-(N ² -/3-methylquinoline-8-sulfonyl/-L-arginyl)-4-methyl-2-piperidinecarboxylic acid

1-(N ² -/3-ethylequinoline-8-sulfonyl/-L-arginyl)-4-methyl-2-piperidinecarboxylic acid

1-(N ² -/3-is.butoxybenzene-1-sulfonyl/-L-arginyl] -4-methyl-2-piperidinecarboxylic acid

1-(N ² -[3,5-dimethyl-4-isopropoxybenzene-1-sulfoyl]-L-arginyl)-4-methyl-2-piperidinecarboxylic acid

1-(N ^{2 -} /2,4-dimethoxy-3-butoxybenzene-l-sulfonyl/-L-arginyl)-4-methyl-2-piperidinylcarboxylic acid

N ² - (2-phenyloxythioninesulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine N'-(2-fluorenesulfonyl)-L-arginyl-N-/-2-methoxyethyl)glycine 1-(N ² -/4-methoxy-3-cyclohexylbenzene-1sulfonyl)-L-arginyl)-4-methyl-2-piperidinecarboxylic acid and pharmaceutically acceptable salts of the above compounds.

The removal of the N ^G -substituent from N ^G -substituted-N ² -arylesulfonyl-L-argininamide can be illustrated by the following scheme:

HN

C— N—CH2CH2CH2CHCOOH / I I

HN R" HN

R' R"' (IVj + RH (V) ->

HN \

C—N—CH2CH2CH2CHCOR / I I

HN R" HN

R' R"' (VI) ->

HN \

C—N—CH2CH2CH2CHCOR / I !

HN R" NHz

R' (VII)

ArSO2X (VIII)

HN \

C—N—CH2CH2CH2CHCOR / I I

HN R" HNSO2

R' Ar (Π)

HN

C—N—CH2CH2CH2CHCOR /1 I

H2N H HNSO2 ; ,i

Ar(I)

In the above formulas, R, Ar, X, R', R" and R"' have the meanings given above.

The N ² -Arylsulfonyl-L-argininamide of formula I is prepared by removing the N ^G -substituent from the N ^G -substituted-N ² -arylsulfonyl-L-argininamide of formula II by acid hydrolysis or hydrogenolysis.

Acid hydrolysis is generally carried out by reacting the N ^G -substituted-N ² -arylsulfonyl-L-argininamide of formula II and an excess of acid, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without solvent or in a solvent, such as ether (tetrahydrofuran, dioxane], alcohol (methanol, ethanol) or acetic acid at a temperature in the range of -10 to 100 degrees C, preferably 10 to 60 °C and most preferably at room temperature for 30 minutes to 24 hours. The product is isolated by evaporation of the solvent and excess acid or by precipitation in a suitable solvent followed by filtration and drying.

Since the products obtained when using excess acid are the acid addition salts of N ² -arylsulfonyl-L-argininamide of formula I, they can be easily converted to the free amide by neutralization.

Removal of the nitro group and the oxycarbonyl group, for example, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished by hydrolysis.

At the same time, the benzyl ester residue, which may be contained in the R group, is converted by hydrogenolysis into a carboxyl sikupine.

Hydrogenolysis is carried out in an 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 in the range of 0°C to the boiling point of the solvent, preferably 10 to 80°C, for a period of 2 to 120 hours. The hydrogen pressure is not critical and atmospheric pressure is sufficient.

The N ² -Arylsulfonyl-L-argininamides of formula I are isolated by filtering off the catalyst and then evaporating the solvent.

N ² -Arylsulfonyl-L-arginineimides can be purified by trituration or recrystallization from a suitable solvent, such as diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol mixtures, or they can be chromatographed on silica gel.

The N ^G -substituted-N ² -arylsulfonyl-L-argininamides of formula I used as starting materials can be prepared by condensing the N ^G -substituted-N ² -substituted-L-arginine of formula IV (generally the N ^G ~substituent is a nitro group or acyl and the N ² -substituent is an amino protecting group, such as benzyloxycarbonyl, tert.butoxycarbonyl or the like) and the corresponding amino acid derivative of formula V, selectively removing only the N ² -substituent of the N ^G -substituted-N ² -substituted-L-argininamide of formula VI by catalytic hydrogenolysis or acidic hydrolysis and then condensing the N ^G -substituted-L-argininamide of formula VII thus obtained with an arylsulfonyl halide of formula VIII, preferably a chloride in the presence of a base in a solvent, according to the following reaction scheme:

HN

C—N—CH2CH;CH2CHCOOH / I I

HaN Η NH2 (VII) HN

C ~-N—-CH2CH2CH2CHCOOH / I I

HN R" HN

R‘ R“‘ (IV) ' + RH (V) -ηΗΝ

C—N—CH2CH2CH2CHCOR / I I

HN R" HN

R' R"' (VI) HN

C—N—CHsCHžJCHžCHCOR / I I

HN R" NH2

R' (VII) + ArSOzX (VIII) -> (II)

In the above formulas, R and Ar are as defined above. X is halogen, R"' is a protecting group for an α-amino group, such as benzyloxycarbonyl or tert-butoxycarbonyl, R' and R" are hydrogen and a protecting group for a guanidino group, such as nitro, tosyl, trityl, oxycarbonyl and the like; and at least one of the substituents R' and R" is a protecting group for a guanidino group.

The amino acid derivatives of general formula V, which are starting materials for the preparation of N ^G -substituted-N ² -substituted-L-argininamide of general formula VI, are expressed by the following general formulas:

(IX)

Rl /

H—N

CH— (CH2]„COOR3

Rz (X)

In the above formulas, R 1 , R 2 , R 3 , R 1 , R 5 , n, m, p have the meanings previously given.

Amino acid derivatives of the above formula X can be prepared by condensation of a halopropionate or 4-halobutyrate with a suitable amine of the formula R3NH2. (See J. Org. Chem. 25 728-732 (1960).)

The condensation reaction is generally carried out without a 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 0 to 80°C for 10 minutes to 20 hours. After the reaction is complete, the formed amino acid derivative is separated by conventional methods such as extraction with a suitable solvent or evaporation of the solvent, and then purified by distillation under reduced pressure.

Among the amino acid derivatives, tert-butyl esters of the amino acid are suitable because they are easily converted into 11a, other esters by acidic hydrolysis in the presence of the appropriate alcohol and using inorganic acid (HCl, H2SO4, etc.) or organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.). The procedure used for the preparation of 2-piperidinecarboxylic acid derivatives of general formula XI can be illustrated by the following scheme:

Mix)

In the first reaction of the above scheme, an appropriately substituted piperidine of formula XV is contacted with an aqueous solution of sodium hypochlorite at a temperature of -5 to -0 degrees C. The product of formula XVI obtained is isolated by extraction with a solvent, for example diethyl ether, and then reacted with potassium hydroxide in a lower alkanol as a solvent to obtain 1,2-dehydropiperidine of formula XVII. The 1,2-dehydropiperidine of formula XVII is converted to the corresponding 2-cyanoanalky of formula XVIII by the action of reagents such as hydrogen cyanide or sodium cyanide. The hydrolysis of 2-cyanopiperidines of formula XVIII to 2-piperidinecarboxylic acids of formula XIX is carried out by reacting 2-cyanopiperidines of formula XVIII with an inorganic acid such as hydrochloric or sulfuric acid.

The arylsulfonyl halides of the general formula VIII, which are the starting materials for the preparation of the N ² -arylsulfonyl-L-argininamides of the general formula I, can be prepared by halogenation of the desired arylsulfonic acids or their salts, for example sodium salts, by conventional methods known from the literature.

In practice, halogenation is carried out without a solvent or in a suitable solvent, for example halogenated hydrocarbons or dimethylformamide, in the presence of a halogenating agent, for example phosphorus oxychloride, thienyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, at a temperature of -10 to 200 ° C for a period of 5 minutes to 5 hours. After the reaction is completed, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.

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

N ^c -Substituted--N ² -substituted-L-argininamides of formula VI, the starting materials required for the condensation reaction, can be prepared by protecting the guamidino- and α-amino groups of L-arginine of formula III by nitration, acetylation, formylation, phthaloylation, atrifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed N ^G -substituted-L-arginine of general formula IV with the corresponding amino acid derivative of general formula V, such as an acid chloride, azide, mixed anhydride, activated ester or carbodiimide, in the usual manner.

It is well known from the literature that the ester derivative of N-arylsulfonyl-L-argininamide I, where R2, R5 is alkyl, aralkyl or aryl, can also be prepared from the carboxylic acid derivative of ^N- arylsulfonyl-L-argininamide, where R2, R5 is hydrogen, by conventional esterification methods well known from the literature. It is also well known that the carboxylic acid derivative can be prepared from the ester by conventional hydrolysis or acid hydrolysis. The conditions under which the esterification, hydrolysis or acid hydrolysis would be carried out are given in the literature.

The N ² -arylsulfonyl-L-argininamide of formula 1 according to the invention forms addition salts with various inorganic or organic acids. Some N ² -arylsulfonyl-L-argininamides containing a free carboxyl group, where R 2 , R 5 is hydrogen, form salts with various inorganic or organic bases.

The product prepared according to the above reactions can be isolated in free form or in the form of salts. Furthermore, the product can be obtained as a pharmaceutically acceptable acid addition salt by reacting the free base with an acid such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethibane sulfonic, benzenesulfonic, p-toluenesulfonic or the like.

In the same manner, the product can be obtained as a pharmaceutically acceptable salt by reacting the 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 the like.

Similarly, the free amide is regenerated by reaction of salts with a base or acid.

As previously mentioned, the N ² -arylsulfenyl-L-argininamides and their salts obtained by the method according to the invention are characterized by a highly specific inhibitory effect on thrombin in mammals and a significantly lower toxicity, and therefore these compounds are useful as diagnostic reagents and/or as drugs for the treatment or prevention of thrombosis.

The compounds obtained by the method of the invention are also useful as inhibitors of platelet aggregation.

The antithrombotic effect of N ² -arylsulfony.lL-argininamide obtained by the method according to the invention was compared with the effect of the known antithrombotic preparation N ² -(p-tolylsulfonyl)lL-arginine-methyl ester by determining the coagulation time of fibrinogen. The measurement of the coagulation time of fibrinogen was carried out in the following manner:

A 0.8 ml aliquot of fibrinogen solution, which was prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction IJ supplied by Armour Inc.) in 40 ml of borate buffer (pH 7.4), was mixed with 0.1 ml of borate buffer, pH 7.4 (control) or a sample solution in the same buffer, and 0.1 ml of thrombin solution (5 units/ml) supplied by Mochida Pharmaceutical Co., Ltd., Japan, was added to the solution in an ice bath.

Immediately after mixing, the mixture is transferred from the ice bath to a bath maintained at 25°C. The coagulation time is determined as the period between the time of transfer to the 25°C bath and the time of the first appearance of fibrin fibers. In cases where no active substance samples are added, the coagulation time is 50 to 55 seconds. The experimental results are shown in Table 1. The term "concentration required to increase the coagulation time by a factor of 2" is the concentration of active substance required to increase the normal coagulation time of 50 to 55 seconds to 100 to 110 seconds.

The concentration required to prolong the coagulation time by a factor of 2, which is necessary for the known antithrombotic preparation N ² -(p-tolylsulfonyl)-L-arginine-methyl-ester, is 1.100 ug. The inhibitors are listed in Table 1 by indicating R and Ar in formula I and the acid residue.

When a solution containing N ² -arylsulfonyl-L-argininamide obtained by the method of the invention is administered intravenously to animals, a high antithrombotic effect is maintained in the blood circulation for 1 to 3 hours. It has been shown that the half-life for the decay of the antithrombotic compounds obtained by the method of the invention in the blood circulation is approximately 60 minutes; the physiological conditions of the hosts (rats, rabbits, dogs and chimpanzees) are well maintained. The experimental decrease in fibrinogen in animals caused by thrombin infusion is satisfactorily controlled by the simultaneous infusion of the compounds of the invention.

The acute toxicity values (LD50] determined by intravenous administration of compounds of formula I in mice (males) 20 g) range from 150 to 600 milligrams per kilogram of body weight.

Selected LD50 values for the compounds obtained by the method of the invention are given in the following table.

HN

Compound

C—NH—(CH2)3CHCOR / I

Han HNSOaAr

Ar R LD50 (mg/kg)

300

CH^COOH

260

In contrast, the LD50 values for N-Mansyl-N-butyl-L-argininamide and ^N2 -dansyl-N-methyl-N-butyl-L-argininamide are less than 10 milligrams per kilogram.

The therapeutic compositions of the invention may be administered to mammals, including humans, alone or in combination with pharmaceutically acceptable carriers, the amount of which is determined by the solubility and chemical nature of the compound, the route of administration, and standard pharmaceutical practice.

For example, the compounds may be administered by injection, parenterally, i.e. intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules or granules containing suitable carriers such as starch, lactose, white sugar and the like.

The compounds may be administered sublingually in the form of lozenges in which the active ingredient is mixed with sugar or corn syrup, flavorings, and coloring agents and then sufficiently dehydrated to obtain a mixture suitable for compression into a solid form. The compounds may be administered orally in the form of solutions which may contain colorings or flavoring agents. The dosage of the therapeutic preparation which would be most advantageous to humans is determined by the physician and will vary with the route of administration and the particular compound selected. In addition, the dosage will depend on the condition of the patient.

When the mixture is administered orally, a larger amount of the active ingredient is required to achieve the same effect as is achieved with a smaller amount parenterally.

The therapeutic dose per day is 10 to 50 milligrams/kg for parenteral administration, 10 to 500 mg/kg for oral administration.

The invention is illustrated by the following examples.

Example 1

A. N ^G -Nitro-N ² -(tert.butoxycarbonyl)-L-arginyl-N-butyl-glycine-benzyl ester:

To a stirred solution of 28.4 g of N-[ ^(N-[gamma ]-nitro-N ^- tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate while maintaining the temperature at -5 degrees C. After 15 minutes, 35.0 g of N-butylglycine benzyl ester of p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran were added, and the mixture was then stirred for 15 minutes at -5 degrees C.

At the end of this time, the reaction mixture is warmed to room temperature. The solvent is evaporated and the residue is 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 10% citric acid solution and 200 ml of water. The ethyl acetate solution is dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is dissolved in 20 ml of chloroform and the solution is applied to a column (80 cm X 6 cm) of 500 g of silica gel packed in chloroform.

The product is eluted first with chloroform and then with a 3% methanol-chloroform mixture. The fraction eluted from the 3% methanol-chloroform mixture is evaporated to dryness to give 26.0 g (56%) of N ^G -nitro-N ² -(tert.butoxycarbonyl-)-L-arginyl-N-butylglycitide-benzyl ester as a syrup.

Infrared spectrum (KBr):

3300, 1740, 1690 cm%

B. N ^G -Nitro-L-arginyl-N-butylglycine-benzyl ester hydrochloride:

To a stirred solution of 26.0 g of N ^G -nitro-N ² - (tert.butoxycarbonyl jL-arginyl-N-butylglycine-ibenzyl ester in 50 ml of ethyl acetate is added 80 ml of a 10% solution of dry HCl-ethyl acetate at a temperature of 0 ^C C. After 3 hours, 200 ml of dry ethyl ether is added to this solution and a viscous oily product precipitates.

This product was filtered off and washed with dry ethyl ether to give 20.8 g of N- ^N -nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride as an amorphous substance.

C. N ^G -Nitro-N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl j -L-arginyl-N-butylglycine benzyl ester:

To a stirred solution of 2.33 g of N ^G -nitro-L-arginyl-N-butyl-glycine benzyl ester hydrochloride in 10 ml of water and 40 ml of dioxane are added successively 1.26 g of sodium bicarbonate and 2.2 g of 3-cyclohexyl-4-methoxyphenylsulfonyl chloride at 5 °C and stirred for a further 3 hours at room temperature. At the end of this time the solvent is evaporated and the residue is dissolved in 100 ml of ethyl acetate and washed successively with 10 ml of 1N hydrochloric acid solution, 20 ml of water, 20 ml of 5% sodium bicarbonate solution 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 a 3% methanol-chloroform mixture. The fraction eluted from the 3% methanol-chloroform mixture was evaporated to give 2.6 g (77%) of N ^G -nitro-N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine-benzyl ester as an amorphous solid.

Infrared spectrum (KBr):

3300, 2920, 1740, 1640, 1250 cm ^-1 .

Analysis for: C32H46O8N6S calculated:

56.95% C, 6.87% H, 12.46 θ/ο N; found:

56.49% C, 6.63% H, 12.38 0/ ₀ N.

D. N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl-L-arginyl-N-butylglycine:

To a solution of 3.00 g of N ^G -nitro-N ² -(3-cyclohexyl-4-methoxy-phenylsulfonyl)-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water is added 0.5 g of palladium black and then the mixture is shaken for 50 hours under a hydrogen atmosphere at room temperature. At the end of this time, the ethanol solution is filtered to remove the catalyst and evaporated to dryness. The residue is washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200 to 300 mesh,

H ⁺ form, manufactured by Mitsubishi Chemical Industries Limited) filled in water, washed with water and eluted with 3% ammonium hydroxide solution.

The fraction eluted from the 3% ammonium hydroxide solution was evaporated to dryness to give 1.5 grams (72%) of N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine as an amorphous solid.

Infrared spectrum (KBr):

3350, 2920, 1630, 1250 cm ¹ .

Analysis for: C25H41N6O5S1 calculated:

55.63% C, 7.66% H, 12.98% N; found:

55.32% C, 7.39 _% H, 12.84% N. Example 2

A. Ethyl 1-[N ^G -nitro-N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate:

To a well-stirred solution add 2.05 g of ethyl

1-(N ^G -nitro-L-arginyl) -4-methyl-2-piperidinecarboxylate hydrochloride and 1.26 g of sodium bicarbonate in 10 ml of water and 40 ml of dioxane are added portionwise 2.2 g of 3-cyclohexyl-4-methoxybenzenesulfonyl chloride while maintaining the temperature at 0 °C. The reaction mixture is stirred overnight at room temperature. At the end of this time, the reaction mixture is evaporated to dryness.

The residue is taken up in 50 ml of ethyl acetate and the ethyl acetate solution is washed successively with 10% citric acid solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The ethyl acetate solution is evaporated and the residue is chromatographed on silica gel packed in chloroform and eluted with chloroform containing 3% methanol.

The main fraction was evaporated to dryness to give 2.6 g of ethyl 1-[N ⁸ -nitro-N ² -(3-cyclohexyl-4-methoxybenzenesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate.

Infrared spectrum (KBr):

3400, 1735, 1635, 1250 cm-1.

B. Ethyl 1-(N ¹ -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinylcarboxylate-acetate:

To a solution of 2.6 g of ethyl 1-[N ^G -nitro-N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid was added 0.5 g of palladium black, and then the mixture was shaken for 15 hours at room temperature under a hydrogen atmosphere. The solution was filtered to remove the catalyst and evaporated to give an oily product.

Reprecipitation from an ethanol-diethyl ether mixture yields 2.4 g of ethyl 1-[N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate acetate.

C. 1-[ N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid:

A solution of 2.4 g of ethyl 1-[N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-.L-arginyl]-4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of N sodium hydroxide solution was stirred overnight at room temperature. The reaction mixture was then concentrated and dissolved in 10 ml of water.

The solution was neutralized with 2N hydrochloric acid to give a white gummy precipitate which was dissolved in 150 ml of chloroform. The chloroform solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.52 g of 1-[N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl]L-arginyl}-4-methyl-2-piperidinecarboxylic acid as an amorphous solid.

Infrared spectrum (KBr):

3350, 2920, 1620, 1250 cm ¹ .

Analysis for: C25H41O6N5S calculated:

56.60% C, 7.49 _% H, 12.70% N; found:

56.51% C, 7.53% H, 12.68% N.

Various other N ² -arylsulfonyl-L-argininamides and/or their acid addition salts were prepared according to the procedure in the above examples, and the test results are shown in Table 1.

3 B .7 7 2 \cd £ d φ δ > ο» Τ ^- '

P-I

Φ -μ CQ >ο úd sz μ cu CL f-> and those * cd 'cd § 'cd

-2 £ GG φ cd >O ng ω tí a-3 >· 2 'Cd > ^G ,(—i 'd G tí

ÍH p£ ¹ o

'ó £ £ '£ Í2 cn >5 o fcl > β a>G f ^N a, 'CO , >-< o tí o C

- > a>N G5 β ' o „ ú o ω» o T3 o O t) s c cd

R O -Z Q Q rřj Cd o cd 2 o g >g a tí úd cď 'i—l d >00 '* tí g* a Jd w

o o About About About About About About About what what OO CM ID Those who WHAT WHAT what rH D D rH CQ CO rH rH rH CM r-T r-t r-t rH rH

About About About About About o o About About LO bs About CQ WHAT? O 00 O 00 WHAT CM CM oqco^ WHAT oo r-T oo rH oo r-T OO rH CorH

WHAT WHAT CD M-i 00 what tr^OO °l· 00 TF τ—1 CO ooo cm cm cm cm cm t< c< 2 2 rH rH rH i—l I am rH τ-H rH Η Η

i—1 <N what rH r-t co rH LO CO CD co co co cd ďq cq !>. t< CO CD CO^ co co τ-t cd lolo CM CDs CM CD 00 CM LO t> D uq About what CO 00 LO CM CD CO- ooo ooo t>> WHAT LoLo CD what WHAT what LO LO LO LO LO IO ’Φ L

o oo m cm what

ό fi φ

>

fi

Φ >Φ

Φ

A fi fi e

hey hey

CQ fa fa

7)

about o o About About About o o CM CM IO WHAT CM fa WHAT WHAT WHAT CD CM^ l>» CM what What is it? fa cm fa fa fa fa fa fa

o o o o with ° About About LO about what about what About the father LO CD WHAT? what fa <D Yes ^{, yes} . CO^CM^ what what what's up what's up What is it? what's up what's up

fi

M fi fi fi

Si—I fi fi 'fi fa 'fi a

S fi t; φ >CJ N O 03 > fi fa

CO CM fa 03 What is it? what WHAT? σγ fa^ rt cn fa θ' rH CM_ o. t< cm cm rti o cm cm what what fa fa fa fa rti rH fa fa fa fa

CM CD CO fa co co

WHAT WHAT CM CM

WHAT

CD What is it about?

CO CM fa D co CO

CO CO CM^ CO co co fi « « ω β cí a o fi φ ό r—i -fi '· fa li

About honor

N

fi 73 fi 73 fi about fi > fi fi P<>s- SrH >fi and

i , 'Honor , fi o fi o fi . 5 and φ c-ι ω > Od^°^ e >S ft xj

Ctig^ fa fa

what CD about CD About fa fa 1>γ 00 CO CD CO OD WHAT fa^ cm I M what what what what what what LO lo lo LO LO LO LO LO LO

O

L.O. cm

Sample No. HN H Ending- Method Physics Elemental analysis Infrared | race of preparation of own- calculated spectrum

C—N—CH2CH2CH2CHCOR claimed (ex. no.) lower: found (KBr) / ) for pro- C Η N (cm ^-1 )

H2N H—N—SO2—Ar Further stretching

0 About 0 0 0 0 (β IO what WHAT CM 1Γ) CM LO CM LO what 03 OT tN CO^rH CO^rH r-l r-f cm' r-í rH rH rH r-l

About About About About About About About About About About About LO 0 what LO CM WHAT? WHAT? Φ^Φ Φ rH What is CD? what^what WHAT CM CO r-T what~ r-T CO rd CO r-T CO* r-T

what CO~ CM t—I

WHAT Φ CO About WHAT WHAT WHAT M H· bx °0^I> ts 0 0^0^ JM JMl cm cm cm cm cm what what [V] 00 r-l rH r-l rH tH rd r-l cn

CM CD LO <D CO rH CO tx 0 tH CD' Φ^ Φ^κγ WHAT Φ WHAT what what [< t> what what

Φ what WHAT About r-l Φ what 10 Ttf what CM^fD <D UO WHAT ABOUT CM Φ l>> [>. t>T what what what 10 what ts LO LO LO LO LO LO LO LO LO LO

238772 \φ §5 Η _ £ tí β CQ tí >y tí m <D ” o tl CL ''tí ^ω

WHAT?

SX 'CO « «'2 tí c § cO >O tsl O tí

S >:§ i 'CO > E fí 'z! tí tí tí

Θ g Q H

XJ

Λ χ3 ’n $ ® Eití o fe > « a >

£ 2>tí »tí &>U Ctí;-, n. ^N 'Cfl ) tí L tí > š o tí tí &>N £ ,C0

- j3 O W) *< ** φ O

O - Ω u tíí g tíO § ftx3 44 tí -. g 'tí O £ S? those ° ^ΰ a.

cO \r—I β >CZ5 rd O cO 3* Q >ď

About about about About About About About CM CO rd what rd CM 05 CM CQ rd 0 <o CON About rd r-1 rd rd rd rd rd rd LO LO About About About WHAT ABOUT LO O About About tx CO LO about what About WHAT t>. CO About LO WHAT WHAT CO rd rd ^CO CO^M^ rF CM what is it CO rd CO rd what is it CO rd CO rd CO CM WHAT WHAT WHAT rd O CO 05 WHAT lo^oo what what CM WHAT WHAT WHAT rd^OT co cm LO cm cm τ~^0Ο bs t> CO^ cm cm rd rd rd rd rd rd rd rd rd rd rd rdd LO rd About CM About WHAT CM CO WHAT!>· what what ’Φ ΙΌ what what what what what rd CO ΙΌ ΙΌ CM CO virus virus rdCO what what WHAT WHAT t< l< what what 00 00 t> LO ΙΌ 00 what what CM t> CM^O~ rd CO rx <0 cp 00^ 00 WHAT CM ooo ooo what rd CM . what what WHAT tC t< ΙΌ LO ΙΌ ΙΌ LO LQ LO LO LO LO LQ Lf)

CM

CM

CM

CM

CM

CM what about

IO_ about

χ® tí φ

>

φ +ť m ΰ >U AS π rr4 rt“i *** f Ί

Honor Φ Φ CL •j. ., rz* tí 2 a '<e tí tí rj £ φ W >O N ,_ Ó Φ g Ř tí £ 'cti >

those

Fr

About lips

O 'tí 'g > 7 ° tí >o

Thank you.

°£ a>d

O<'φ CL ,1 I 'Cti , \«—Í ι tJotíetí^jSó,-! Z? JcSCLtíLití^tíl^tl^n tí p >&>n β 5,, ¹⁸ ω 2

O Φ — - tí ό ÓZ) XM r. & fí ££τ3Ρθτ3^φθ'® 3j_ otí£L,-H^o _u +-' ϋ W L. >g ň-tí AS tí

Ίγ-Η Oj >w -ř cd Λ tí rj a£

CA

O

CM

WHAT

About ’Φ

O o O *Φ ’Φ τΗ

About that about that *^1 that τΦ

ABOUT WHAT what oh what

CM CM τΦ O

O § £ co P to ·γ-ι >w o o to co CO τΦ o

§2

O o CM CO CO tH

Q

O °s o to CM to CO Τ—I τφ Τφ

O O) O CD CO

O CO CO CD CM «φ φΓ to to to what

Φ Φ Φ Φ Φ Φ

CDs WHAT •Φ it About) Q About) WHAT 03 Tue-Sat Φ that about CM CM r-l CM CM t> what With

About CM this CD about that what is it> what Ή WHAT^WHAT^ what <o rH CD^ CDs 03 what what what what that's cm that's it what is cn that's it that's it that's it that's it in io

CM

CM

CM

CM o o

ffi

About

O

-ppj ffi o

'Φ £

>

O uo co uo CO A ca ω jť ca ΰ >o 4tí m G ca φ A, o Fh CL '— ¹ A 7)

TÍ § 'Honors what G £! § ca >o n

About φ

With x 'honor > β

fa fa 53 M 22 M

EJ honors fa > β fa <-7 β honors >CJ 73 t_j o a fa

Ρη'γ* Oh fa ¹ '2 5 o ΰ § fa g ω g

T3 á 2 « faxes

O £ G β

5d φ ί>» A G fa^-g S)«s g &

O O -ů « CD

J«H r-M O Q

F-<

About XJ

O uo O O O uo what what what no what uo

CO rd CO A CO rd

about uo About 2 about ID about About About UO rs uo in 7? 6th grade 00 LO lo lo oh oh oh what cm~ eo g CO t—i WHAT? Honor WHAT CM WHAT* A* what” ~ ΓΗ d What is what WHAT* A*

is about CM A What is it? 00 © 00 CM CM^O~ WHAT A~ ČM~ A^ in cm~ uo~cp_ what what WHAT* WHAT CM CM* what* what* what* what A A A A A A A A A A

cn what what ts U0 What is CD? WHAT U0 About A A A^ About A CM A^ CM^rd i< ts* i>* bunch* t<řs* Es.* ts? Cs*c<

UO Es· what 1.0 UO A A A A WHAT what WHAT CM^CO^ CM CM* CM* A* ^* CM* CM* r-Γ A A UO UO oh oh oh UO lO oh oh oh IO

A CM A

UO

AND

CO* ca '>-1 G >73 A r—» CS, CO

Qfa

s a _ £ S^v <B S m tí cB dB * O

F-< CL, ¹ — ¹ aw wo oo om

WHAT WHAT WHAT WHAT WHAT Ttl

CO ι-H CD i—I CO i-l

0 0 0 About ID ID 0 what About CDs !>. ID CM sF CM~ CO^CM^ CO* r4 CO* r-f CO* r-f

cú N '>1 r—Ή ca a

ca \r—I you 'ca

WHAT IS CM CD £2 U?

cd σ) what what cfi

CM CM

CO CO ti 'ca ti ca +-j

I >CJ ó

>» >

P-i

About lips

4—» ’tí W £«ž >

D

CD «th

Ph tsi +j tí

Φ

About you

O

CM CO τ-H rH 'ca tí

N

Φ ι—I ca tí tí ι—I

About us

CD

About the three ř> · ca >o ř-l .

>r-H Q, >r-i

Λ , 'those of those >

Φ about

About those fH .those those

CD ID what WHAT CO r-f CM O TM Tfl CM CO r< t<

r-f CD CM t-H

CO f>> CO CD r-f ID CM CD

WHAT WHAT TjT WHAT CM

D D D D D D

1'

CM i—l — 2 48.73 6.82 13.53 3.300 1.620

CHzCOOH 48.93 6.90 13.48 1.110 tí I r-( t»,^ ,k! g CL >N ,Q g cB Q) -1 — U)<- LI « ω oo U „3 0 £ ⁰⁷³ tí

Q three three

B

CD í-i <

ID

CM θ' ’Φ

Pi o

about κ

O<N £

at

CM

To

X o

about Pi V)

AND

ί-ι <

'2 ffi

O.

>df>

CM

WHAT <C

AND

ID cn čq

238772

Lj —j $ g 2 Ξ ω -μ pq τ: c!

>O 4th μ P cd <25 ±L o td Cl '—· cd

S '« cd ro tj c · _ cd >on '-2 3 \cd > — fa fa +5 an|§ fa 3 s ífi Ě' ⁴ ^ ns > §2 ^{>ϋ N} fa~ .». i 'ca ο ΰ /—< oco cd · —4 g &,>ΝΛ=ί M §>g

O CD g ” 3 O Ďpc- (_, fe fa! 2 «j&3 o

fa cd yf-h rj >73 .Í3 sf

OT

Th <

Εo o cm in CD yH

O Q LQ CO what what

WHAT'S UP

what

CD

About IQ LQ

CO Y-f

O

WHAT

CD

O o O IQ ’Φ γ-i o

t>.

O O o what Φ what

LQ 03 CD IQ 03 00 rd CD WHAT CM CO dp UD CM* CM* CM* CM* WHAT* WHAT yH t-H γ-H yH γ—1 H yH tH H yH

what 12 rH O 03 CO CM 'Sf ¹ og cq what WHAT CM^CM^ t> LQ^ c-Ct·' t< [< !>** O·* t< l>*

σι 23 what χ. what <p IQ rH WHAT WHAT l?> ^* mT lo LQ

CD LQ CD yH co* ^F* LQ IQ ® s o- °° h}T m m

CM

CM

WHAT

E

O

O ; o ' E y

fa

O

O

E facm

E-fa

CM

E-fa

CM about

About

WHAT <

CM

·· 3?

oh my

XJ

TH

O

N >

what what what

oh

WHAT

CD co 'φ fí rj φ Β íh £ íh íh Φ -μ CQ >Φ Jtí & cd φ Í1Í_L

ÍH Q, *3 tt «3 ca tí cd 'ed £

cd >cd

S íh 'Cd >o ó

Λ >>

>

φ

N

Φ

I—( cd tí

Φ \l—I 0! ÍH o

Λ about

i.e

o o About About About about me o m WHAT what what what is it? what is it COrH what^ CO^rH WHAT CO^rH r-l i—< i—1 r-l τ—1 r-l r-l r-l r-l

about about

Three

what what

CO τ—I m co co co cm cm o o o o mm cm b>

CO 1—1 ’Φ CM

About About About r-l 05 CM WHAT *φ CM Class CM

CO r-l CO rH

What r-l

CO r-l co OQ o o b* r-l CM Tř

About 05 About 05

About CM About 00

CM CM CO CO

CM o Tř oo m t> cm i—l f~> 03 i—I O ^3 b- >T co co b> t>?

b> WHAT i>. m t< !>· b- what b> 05 b» t<

what is OQ oh what m cd what is it m η ω CO r-l m_ t>. what is it Χφ '’φ' b* b> cm cm m m m m m m Class *φ m m m m m m

Jití -M .r-ι c/3 [XJ >

, *<ΰ i i

About her OG. « Λ _a CliCÚ O > Kvn 'L>Q,>N Λ g. ee <TJ '9? 03 at 3 o'clock 2? ^<w M ί:32°Ό5<ΐ3 ^α ^ £ * .&TJ >d ^u cd

IH <

CM

CM CM

Oh my

about ffi «κ ac a

O

OPI (Z)

IH <

IH

About :>

*yes

With ω

>

Φ

about o o About About About About what what What is CD? What is CD? cd what what CD CD WHAT ABOUT H H H H H H H

φ +ť ra tí >O tití VJ fi cd Φ t_L o fM fií 'tj M β

About About About About About About About About LO CD LO what About what About About C^H what what C0.H WHAT H what T"f what r-f CO r-f what the heck

β ² >S. 'β 3? G xca « S β β η! Φ CO >HE

Š g SgE ,cd > ^R

CO CO CD f> LO O b* CM

WHAT LO WHAT CM WHAT H^IO^

H r-f CM CM Cm Cm CM C\f

H rH Η H Η Η Η H

CD H CD CM H LO rH CO lo~co~ <oh cm^h ©h t>t>N tx Cv í>s í>> E>s t>

<3 '3 .5 So° ω £ ³³ W

I> LO CO H rl Q t\ H

O CD OH íň Λ H CÓ hh h r-f cm h cd cd

LO LO LO LO LO HH

4th 43 •rj w ω N cd ó

Η c* fe > ^S o £“-? O ca >ow £ .

^N

CM

CM ¹ '5

O β β CO Λ, £j ' ¹ ň. cd ír Φ 73 tS £>mo

- -- 2 o ř-t 3 S OO-tjCdaiO^a Ís< Η O o Cr

Q -§ ca >n .&Ό

4th σ>

about cd tí >ζΛ ·β β & czí

\φ § a „ s s φ t; W a >y Β

Φ Φ CL O ti Λ C3 uí <0 'Cd g 'CO CO CO rt ο ϋ 3 ca >y n '- o 03 g & g ffi 'CO t> 4-J g'3tí a ~ φ

Ξ ¹

Aunt

-w Zl N 8 § e

fct >

— about what >u 52 f-ι . «tí O|>tt and what _, — and fl3« 3 ’ϊ §

Ó M«w tt fe tí g a ° a o o 44

WHAT '1—<

>W Ά tí sCD f-i <

about what about

CM what about

CM

WHAT'

Or

O

CM

WHAT

o o o lo about About About WHAT? About CDs LO what lo lo WHAT Φ xf^<D C0_0 00 what-T what the heck Yes” r-l what the heck

CM 00 cm cm

τ—1 CQ 00 ™ what is it> CM^rH that σ>Ί> cm cm r-Γ rH tH t-I Ή τ-f Ή rH r-l

LO 00 LO rH CO 2J About «0 LO CM^ LO CQ what~ xfrl CM_ t> hx hh hh < IN

What the heck WHAT IS IT? IX CM r-l °0 WHAT 00 LO about ’Ί WHAT CM cm cm cm cm ψ-j; what” what” lO lo LO LO in in m in

About

To the cjΊ ffi

CJ ffi

C.J.

AND

ÍC—g cq _>

About what?

CJ, from

fq

To >o tí o

N >

ffi <N

E

O

X To E o o p M fH I O o CJ this To CJ from To CJ CJ —y

£O

£ £ 1 ? about about P KO about In y xp about about

WHAT •Φ o

IN?

X*

About

<<1

X

By x ^No

Mole <•0 rft

X$>

X ¹ o

x·* «o

CM 'Φ φ

>

P~ι

Φ >Φ cd θ

ί-ι

CQ ř-i

About LO O About About About About what CO 03 CM 03 CM 03 what what WHAT about <00^ rH r-Γ r-í i—i r-i τ—i rH

ο 2 ο what μι ο, οί

o o About LO About LO b> oo LO LO IO LO WHAT IS IT? WHAT WHAT M^ CO r-T WHAT THE FUCK What r-T

C0 ΙΜ '>» r—1 <ΰ β

C0 'C0 β

cd \γ—4

WHAT what WHAT What I have what what about what ίο ío IO'CO' 03 O cm CM τ—1 rH rH Ή τ-Γ cm γΗ Ή The Or Or t*H tH

β 'Φ >ο ό

Rη >>

>

'cd β

Φ

CM

Φρ

WHAT

M^ cq

xji About T-H About LO r-i CM IO~ WHAT WHAT My My' what what what what what

βφ

and φ

£ rá \γ—4 β

The

T3

-ό η M S2 ^ω

S, «* ο &4 > Η

Ο (5 >Ο 73 ie •3 &>£ ^and £ &

'cd ί β ο cd · >.-3 rW ití g X, ca Z ω >.-3 φ - £ &>Ν ,Ο 3 ΰ “ O r? 3 O M 3 ΆΧ5 ao cd o

cd ¹ β >73 »r4 §73

>with CM C*5 03 WHAT About rH WHAT> CO «Ψ, CO^CM^ CQ th ¹ what' what irT irí' Lolo cn cn LO LO irí in 10 LO in »3

what about

COOH is £

Φ £ M rt >y sz B pH rTS r y cd & 'g ř—j 2 *cd cd cd rj β ti ω «>y n

S Jí g 'CO > ^B +->

β .β 'β ω β β

Going ω

AS tí ZJ β Í2 «3

ĚLJ2 2 fc<> « those £·-? ”2 ^>ϋ tí ¹ 'ES ¹ do β O c- ¹ pi ca n ή, cd n ω >.d AS S ^H S ft *s Λ 5,« yo á z O £ StíSstí 5ω wr~y _ β y ,2 o S ,3 “ O β Ή β tí ⁷³ o AS *-< ® &Ό A=i

S XD ,ÍS φ > tí >w 73 & 5 g O 4ď en mo o o o o o

NO) CO 05 CM CM 05

WHAT ABOUT WHAT what what what

Η H rH τ—I τ-Η Η H

O O ΙΩ CO CO co rH o in O ir> CO r-T s °

About 00 o'clock

CO G-T

ΙΩ 1Ω t>> in co^ co r-T

O H Q O CD CM Cx

CD CM Λ CO CM~ O5~ CO

rS rd CM CM rH rH rH tH Or Or rH rH r4 rH rH tH 00 O) 1/5 05 CM ΙΩ 00 TJ1 IT5 CO °o CD CD About tH what what WHAT this

what what LO 05 00 WHAT 05 O About 1-H CM WHAT CM About CM

-CfT Tji θ’ O ΙΠ uT r-Γ τ-Γ min WIÍ5 LOU5

CM

T<

O

CVI

TO

To ω

I ffi—2

Pi

O £ u—z ¢4 I

Ϊ! I ac

About Pi (Z) í-l <

>o

ΙΩ m

O

IΩ

O

WHAT

β bj '>> r—1 β

β β

β

S-4 'β 'β β

β >ο

The ft >

'β β

Φ

N

Q Ο CM CO tx o

LD

What is it?

ο © The What The CM «φ <Ο τφ cd what rH θθ rH

Φ >

β β

í>

About τΜ CO CM CO φ

C0 Ο0 CO

rH rH rH rH o o rH rH N β ft O o Ir—C About rH CO what <φ C£> β ř-t 'β cd what o? o t-H Φ

β ?-ι

The ft β

The ft

Λ<5 4» £. •β « ω g.« ° fe > ^ΰ

Λ > Τ ° £ ^>u Κ.Ί >ř-l .

^Ν a'“ , 'Honors , 1 g,Š 2 §

W ⁵ o 3 ? cd

Λ ° ň CD £ ω ο ^ΰ CJ ^ «Ή č ce >ll-H Cd >Φ .β * & ο.3 ιη <£

3_ £co ό

C0 ψ

what what

Οφ

σ) οο 1>Χ CO cm <Ν 1D ΙΓ) £

The

The

Oh it's £

Q

Φ β

N β

βφ

φ

I—Η β

Λ β

+->

The

4-» 'Φ

Φ fQ

Oh my

οβ ft

N

Honors

The

The £

ο£ ω

Czech Republic £

The £

The the

(Ζ>

and £

IH <

ί-ι

The

N >

£

The

The £

the

ΛΙ £

the the

the

M £

The eH «Ό

X X υ ο

,β φ ·β ft Φ Φ ft > ο £ .&Ν >5Η ag ομ f2 ft ‘ Φ > β

C0

X

The the

\

X o

the ^ί4 the

Γθ ϊ ⁴ υ

oh so

X «•η

X

4η

5 ⁴ o

X*

The <Ό

X

Ά_Λ~°

-0<τΌ

ΧΖ

The

Oh, oh

'ft >φ β β ft Ο βσ! ω 'β >-. β >

. β > ?Η ft \φ S—I β ft Φ ft _ Φ fQ > ο β φ ^p οβ >>& Γ-t Ν

WHAT

CM

WHAT

G ' Φ >φ β

£.

oh

and

The

Number ArSOzCl or ArSO3H Starting material Product or salt Amino acid ester (literary reference] HN

Helv. chem. Ant., 46, 727 (1963)

-number ArSOsCl or ArSCbH Starting substance Product

-or salt Ester -amino acid (literary reference) HN

Japanese Patent Publi-shed 26975/1964 No. ArSOžCl or ArSOsH Starting material Product or salt Amino acid ester (literary reference] HN

Number ArSOsCl or ArSOjH Starting substance Product or salt Amino acid ester (literary reference) HN

Zhur Obschei Khim 1S, 1459 (1948)

238772

Number ArSOzCJ or ArSOsH Starting material Product or salt Amino acid ester (literary reference) HN

. Pharm. Soc. Japan 73, 1878 (1953)

238772

Number ArSOzCl or ArSOsH Starting material Product or salt Amino acid ester (literary reference) HN

Photophysik Photochem 58, 3 (1963)

Number ArSOžCl or ArSOsH Starting substance Product •or salt Amino acid ester (literary reference) HN

Number ArSOzCl or ArSOsH Starting material Product or salt Amino acid ester (literary reference) HN

238772

Chem. Soc., 57, 1533 (1935)

Number ArSOžCl or ArSOsH Starting substance Product or salt Amino acid ester (literary reference) HN

Beilstein 11, II, 135

Example 3

Tablets suitable for oral administration.

Tablets containing the ingredients listed below can be prepared in a conventional manner.

Component Quantity per tablet (mg) N ² - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine lactose corn starch talc magnesium stearate 250 140 35 20 5 total 450 Example 4 Oral capsules Capsules of the following composition are made by thoroughly mixing the ingredients and filling hard gelatin capsules with the mixture. Folder Quantity per capsule (mg) N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine lactose 250 250 total 500 Example 5 Sterile solution for infusion The following ingredients are dissolved in water for intravenous perfusion and the resulting solution is then sterilized. Component Quantity (g) N ² -(3-Cyclohexyl-4-methoxyphenylsulfonyl]-L-arginyl-N-butylglycine buffer system glucose distilled water 25 upon request 25 500

Arylsulfonyl chlorides (A) Sodium 3-butoxy-2,4-dimethoxybenzenesulfonate

To a well-stirred solution of 50.8 g of 2-butoxy-1,3-dimethoxybenzene in 160 ml of carbon tetrachloride was added dropwise at 0 to 4° C. 16.1 ml of chlorosulfonic acid. The reaction mixture was stirred for 1 hour at room temperature, poured onto crushed ice, and then diluted to 300 ml with water.

After evaporation of the carbon tetrachloride, the resulting aqueous layer was extracted with ether and then neutralized with 2N sodium hydroxide solution, and white crystals precipitated, which were filtered off and dried to give 63.3 g (85.1%) of sodium 3-butoxy-2,4-dimethoxybenzenesulfonate.

(B j 3-butoxy-2;4-dimethoxybenzenesulfonyl chloride

To a stirred suspension of 60.0 g of dry, powdered sodium 3-butoxy-2,4-dimethoxybenzenesulfonate in 150 ml of dry dimethylformamide was added dropwise over 20 minutes at room temperature 69 ml of thionyl chloride.

The reaction mixture was stirred for 15 minutes and poured gradually into 1000 ml of ice water and stirred thoroughly. After 1 hour, the aqueous layer was decanted and the remaining oil was extracted with benzene, washed with water, dried over anhydrous sodium sulfate, distilled to remove the solvent, and then redistilled in vacuo to give 47.5 g (80.1 percent) of 3-butoxy-2,4-dimethoxybenzenesulfonyl chloride (b.p. 154-155°C/133 Pa. Analysis for: C12H15CIO5S calculated:

46.68% C, 5.56% H;

found:

46.71% C, 5.60% H.

The following arylsulfonyl chlorides, not previously reported in the chemical literature, were prepared by the above procedure.

Ar—SOzCl

Ar

Boiling point (melting point)

165 to 166 °C/133.3 Pa (57.5 to 58.5 °C)

112 to 115°C/133.3 Pa (33 to 35°C)

127 to 129°C/66.65 Pa

148 to 150 °C/133 Pa

143 to 145 °C/133 Pa (48 to 51 °C)

CH^CH^CH^ (41 to 42 °C)

OCH.

CH'

CH ₃

ÓCH ₃ ^XcH Z ^CH 3

139 to 140 °C/133 Pa

129.5 to 132 °C/133 Pa

0CH ₃ ch ₃

I o(chj,

145 to 148 °C/133 Pa

CH.

oích _z ^ch ₃

CH.

151.5 to 153.5°C/199.65

CH,

CH,

155 to 156 °C/266 Pa

Ar—SO2Cl

Ar

Boiling point (melting point)

(44 to 45°C)

187°C/133Pa

198 to 200 °C/266 Pa

210 to 220 °C/133 Pa

OCH

160 to 162 °C/266 Pa

OCH'

154 to 155 °C/133 Pa

170 to 172 °C/266 Pa

183 to 185 °C/133 Pa (46 to 47 °C)

131 “C/133 Pa

Cl

Ο(ΟΗ^ ₃ ΟΗ ₃

Boiling point (melting point)

Ar—SO2Cl

Ar

about ( _CH2 / _{2CH3 )}

OCH$ O(CH ₂ J ₃ CH ₃ ^0{CH _z ) ₃ CH ₃

O(CH^ ₃ CH ₃ (65 to 66 °C) (30 to 32 °C)

208 to 210 °C/133 Pa oic^c^

OCO _Z C^

178 to 179 °C/266 Pa oily substance

165 to 168 °C/133 Pa oily substance

109 to 110 °C/199.65 Pa 'OC _n H,

From ⁿ 5

111 to 116 °C/133 Pa oily substance oily substance

2'3 6 7 7 2 ik.

Ar—SO2Cl

Ar

O(CH ₂ \ ^ch 3 'í'' xh ₃

00^5

CH^ * ^from

CH '3

OCH.

CH, _x ch ₃

CH.

Boiling point (melting point)

148 to 150 °C/133 Pa

152 to 153 °C/266 Pa

133 to 134 °C/133 Pa

142 to 143 °C/133 Pa

121 to 122 °C/133 Pa

133 to 135 °C/133 Pa

136 to 139 °C/133 Pa (95 to 96 ft] (101 to 103 °C)

Number

Ar—SO2Cl Ar

Boiling point (melting point)

OCH, (y~OCH _from CH _from ClY

142 to 144 °C/133 Pa (50 to 51 °C)

158 to 160 °C/133 Pa

CH·

159 to 160 °C/133 Pa

CH,

OCH,

151 to 152 °C/133 Pa

158 to 159 °C/133 Pa

Claims (3)

Přìmeme invention A process for the preparation of N ² -arylsulfonyl-L-arginamide amides of formula I HN \ C — N — CH2CH2CH2CHCOR / III H2N H NHSO2 Ar where R is a group (1) Rl —N \ CH (CH ₂ ) n COOR 3 R2 where R 1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, (C 4 -C 10) cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-4-pyranylmethyl, 2- or 3-pyridylmethyl and phenyl, R2 is hydrogen or (C1-C10) alkyl; R 3 is hydrogen or alkyl of 1 to 10 carbon atoms, and n is an integer of 0 or 1. 2. A process according to claim 1, wherein the acid hydrolysis is carried out by reacting the N @ ^c -substituted N @ ² -arylsulfonyl-L-argininaroid of formula II and an excess of acid at a temperature in the range of -10 ° C to 100 ° C. 3. The process of claim 1, wherein the hydrogenolysis is carried out in an inert solvent in the presence of a hydrogen activating catalyst in a hydrogen atmosphere at a temperature ranging from 0 ° C to the boiling point of the solvent. 4. Process according to claims 1-3, characterized by eliminating the N-substituent of ^G -substituted-N ² -arylsulfonyl-L-arginmamidu formula II HN G - N - CH 2 CH 2 CH 2 GHCOR HN! R ‘ HNSO2 Ar where R is HN (II) 230772 Ri CH (CH 2) _; .COOR ₃ R2 HN R ‘ C — N — CH2CH2CH2CHCOR R “HNSO2 AND Ár where R is the group where (1) R 1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, and (C 4 -C 10) cycloalkylalkyl, R 2 is hydrogen or C 1 -C 5 alkyl, R 3 is hydrogen or alkyl of 1 to 10 carbon atoms, n is 0 or 1, and Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl and phenyl, phenyl substituted with at least one hydroxy, C 1 -C 5 alkyl, and alkoxy, C 1 -C 10 and at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinynyl 1,2,3,4-teitrahydro, quinolyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl, or fluorenyl, thioxanthenyl or 2H a chromenyl group, any of which is unsubstituted or substituted with at least one hydrox C 1 -C 10 -alkyl, C 1 -C 10 -alkoxy, C 2 -C 10 -alkoxycarbonyl and oxo; and R 'and R' are hydrogen and guanidino protecting groups and at least one of R 'and R' is guanidino protecting group, by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid into a pharmaceutically acceptable an acid addition salt or liberated by reaction of the salt with a base or an acid amide. 5. Process according to claims 1-3, characterized by eliminating the N-substituent of ^G -substituted-N ² -arylsulfonyl-L--argininamide formula II COOH and (2) COOH and Ar are phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, phenazinyl, quinoxalinyl, phthalazinyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10alkoxy, C1-C10alkoxy carbon atoms and R 'and R' are hydrogen and guanidino protecting groups and at least one of R 'and R' is guanidino protecting group by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid to a pharmaceutically acceptable an acid addition salt or liberated by reaction of the salt with a base or an acid amide. 6. Process according to claims 1 and 3, characterized in that the removal of the N-substituent of ^G -substituted-N ² -arylsulfonyl-L--argininamide formula II HN C — N — CH2CH2CH2CHCOR HN R ‘ R ‘where R is HNSO2 Ar Ra (II) -N (R where R 1 is -C-R 6 where R 5 is hydrogen or alkyl of 1 to 10 carbon atoms, R 5 is hydrogen or alkyl of 1 to 10 carbon atoms and m is 1 or 2, Rd is in its 2-position at 3 and R 5 can be in the position 2, 3, 4, 5 or 6 a Ar is phenoxyphenyl, dibenzothienyl, phenoxathiinyl, ind-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted with at least one alkoxy group with at least one hydroxy group C 10 -C 10 alkyl or C 1 -C 10 alkyl, or fluorenyl, thioxantenyl or 2H-chromenyl, any of which is unsubstituted or substituted with at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy , (C 2 -C 10) alkoxycarbonyl and oxosuipine, and R 'and R' are hydrogen and guanidino protecting groups and at least one of R 'and R' is guanidino protecting group, by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid into a pharmaceutically acceptable an acid addition salt or liberated by reaction of the salt with a base or an acid amide. 7. Process according to claims 1 to 3, characterized in that the removal of the N ^{c c} N-substituent of -sulbstituovaného N ² -arylsulfonyl-L--argininamide formula II HN C — N — CH2CH-CH5CHCOR / III; HN R 'HNSO.2 (II) I I R ‘Ar where R is a group (1) Ri / —N \ CH (CH2) 'COOR' R2 where R1 is tetrahydrofurfuryl or tetrahydro-4-pyranylmethyl, R2 is alkyl of 1 to 10 carbon atoms, R 3 is hydrogen or alkyl of 1 to 10 carbon atoms. n is the number 0 or 1, and (2) COQH ^ ^N - ( ^CH 2 ^J p - ^ where ip is the number 1 or 2, a Ar is a phenyl group substituted with at least one amino group, a (C 1 -C 10) alkylamino group, a C 1 -C 10 acylamino group, a C 1 -C 10 hydroxyalkyl and a phenyl group, a phenyl group substituted with at least one hydroxy group, a C 1 -C 5 alkyl group C 1 -C 10 alkoxy having at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, ind-indazolyl, quinolyl, indolinyl, phenazinyl, phazinyl, quinoxalinyl 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10-alkoxy and C1-C10-alkyl or fluorenyl, thioxanthenyl or 2H-chromenyl, any of which is unsubstituted and substituted with at least one hydroxy group, and (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, (C 2 -C 10) alkoxycarbonyl and oxo group; and R 'and R' are hydrogen and guanidino protecting groups and at least one of R 'and R' is guanidino protecting group, by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid into a pharmaceutically acceptable an acid addition salt or liberated by reaction of the salt with a base or an acid amide. 8. Process according to claims 1-3, characterized by eliminating the N-substituent of ^G -substituted-N ² -arylsulfonyl-L-arglnamidu formula II HN \ C — N — CH GH (CH 2) CHCl 2 / J 1 HN R ^! HNSO ?. (II) R 'Ar where R is Rl / —Ν \ CH (CH 2) _n COOR 3 R2 where R1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, (C 4 -C 10) cycloalkylalkyl and phenyl; R2 is alkyl of 1 to 5 carbon atoms, R 3 is hydrogen or alkyl of 1 to 10 carbon atoms and n is 0 or 1, and Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl and phenyl, phenyl substituted with at least one hydroxy, C 1 -C 5 alkyl, (C 1 -C 10) alkoxy group with at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, finoxalinyl, quinoxalinyl A 2,3,4-tetrahydroquinolyl or acridinyl group, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl, or C 9 -C 16 cycloalkylphenyl, fluorenyl a group, a thioxanthenyl or a 2H-chromenyl group, any of which is unsubstituted or substituted with at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkoxycarbonyl and oxo, and R 'and R' are hydrogen and guanidino protecting groups and at least one of R &apos; and R &apos; is a protecting group for guanidino, by acid hydrolysis or hydrogenolysis, and optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or liberated by reaction of a salt with a base or an acid amide. 9. Process according to claims 1-3, characterized by eliminating the N-substituent of ^G N ^G N -suhstituovanéiho ² -arylsulfonyl-L--argininamide formula II HN C — N — CH2CH2CH2CHCOR HN R ”HNSO2 (II) R ‘Ar where R is a group (1) Ri / —N \ CH (CH 2) n COOR 3 R2 where R 1 is furfuryl and tetrahydrofurfuryl, R2 is hydrogen or alkyl of 1 to 10 carbon atoms, R 3 is hydrogen or C 1 -C 10 alkyl and n is 0 or 1, (2) COOH) - ' -N ^ J and (3) COOH and Ar is phenyl substituted with at least one amino group, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl and phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, quinolyl , quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted with at least one hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl, C 9 to C 9 cycloalkylphenyl group 16 carbon atoms, fluorenyl, thioxanthenyl or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10alkyl, C1-C10alkoxy, C2-C10alkoxycarbonyl and oxo; and R 'and R' are hydrogen and guanidino protecting groups and at least one of R 'and R' is guanidino protecting group, by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid into a pharmaceutically acceptable addition agent an acid salt or is liberated by reacting the salt with a base or an acid amide. 10. A process according to any one of claims 1 to 3, characterized in that the N- ^G- substituent is removed from the N- ^G- substituted N ² -arylsulfonyl-L-argininamide of the formula II. The H N of the substituted N ² -arylsulfonyl-L-argininamide of formula II HN \ C - N - CH 2 CH 2 CH 2 CHCOR / I! HN R 'H.NSO2 (II i i I R ‘Ar where R is a group (U Ri HN R ‘ C — N — CH2CH2CH2CHCOR R “HNSO2 Ar (Π) CH (CH 2) _n COOR 3 R2 wherein R is where R N (RO where R 4 is -COOR 6 wherein R 6 is hydrogen or C 1 -C 10 alkyl, R 5 is hydrogen or C 1 -C 10 alkyl, and m is 1 or 2, R 4 is at the 2 or 3 position and R 5 can be in the "position" 2, 3, 4, 5 or 6, and Ar is phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxallnyl, phthalazinyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10alkoxy, C1-C10alkoxy or a cycloalkylphenyl group of 9 to 16 carbon atoms, fluorenyl, thioxanthenyl or 1H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkoxycarbonyl is substituted with From 2 to 10 carbon atoms and oxo; and R 'and R' are hydrogen and guanidino protecting groups and at least one of R 'and R' is guanidino protecting group, by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid to a pharmaceutically acceptable a suitable acid addition salt or liberated by reaction of the salt with a base or an acid amide. 11. The method according to claims 1-3, characterized by eliminating the N-substituent of ^G N ^G -subRi is alkyl of 2-10 carbon atoms, alkoxyalkyl having 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl C 2 -C 10 -alkyl, C 7 -C 15 -alkylalkyl, C 3 -C 10 -cycloalkyl, C 4 -C 10 -cycloalkylalkyl, furfuryl, tetrahydrofurfuryl and tetrahydro-4-pyranylmethyl (2) R 4 is -COOR 6 wherein R 6 is hydrogen or alkyl of 1 to 10 carbon atoms, R 5 is hydrogen or alkyl of 1 to 10 carbon atoms and m is 1 or 2, R 4 is in the 2 or 3 position and R 5 may be in the position 2, 3, 4, 5 or 6. (2) where R 4 is -COOR 6 wherein R 8 is hydrogen or C 1 -C 10 alkyl, R 5 is hydrogen or C 1 -C 10 alkyl and m is an integer of 0 or 2, R 1 is at the 2 or 3 position and R e can be at the 2, 3, 4, S, or 8 (3) COOH 16 carbon atoms, fluorenyl, thioxanthenyl, or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkoxycarbonyl, and oxo, 3-cyclohexyl-4-ethoxycarbonyloxyphenyl or phenyl substituted with at least one alkyl, alkoxy, haloalkoxy, alkoxyalkoxy and alkoxycarbonylalkoxy group, said substituents containing from 3 to 7 carbon atoms and said substituted phenyl group further optionally substituted with at least one methyl, , ethoxy, hydroxy and halogen, and pharmaceutically acceptable salts thereof, characterized in that the N 0 -substituent is removed from the N ^G -substituted -N ² -arylsulfonyl-L-argininamide of formula II wherein p is an integer of 1 or 2; COOH HN IN HM ^Z i R 'kcle C — M — C H r C H r C Ib C H C O R R " HNSO :! Ar clay) or (5) COOH and Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl, C 7 -C 10 phenylalkyl and C 1 -C 10 hydroxyalkoxy carbon, phenyl substituted with at least one hydroxy group, alkyl of 1 to 5 carbon atoms and alkoxy. C 1 -C 10 -alkyl and at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, 9,9-dioxobenzothienyl, phenoxathiinyl, ind-indazolyl, quinolyl, quinolyl, indolinyl, phenazinyl, phenazinyl, phenoxy , phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkyl and C 1 -C 10 alkoxy, C 9 -C 8 -cycloalkylphenyl group and Ar is as defined above and R 'a. R "' is hydrogen and gnanidino protecting groups and at least one of R 'and R' 'is guanidino protecting group, by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid to form a pharmaceutically acceptable acid addition salt or liberating r by reaction of a salt with a base or an acid amide. (3) where p is the number 1 or 2 (4) COOH and (5) COOH and Ar is a phenyl group substituted with at least one alkyl, alkoxy, haloalkoxy, alkoxyalkoxy and alkoxycarbonylalkoxy group, said substituents containing from 3 to 7 carbon atoms and said substituted phenyl group optionally further substituted with at least one methyl, ethyl, methoxy, halo, ethoxy, hydroxy, ethoxy and R 'and R' are hydrogen and guanidine phosphcupine protecting groups and at least one of the substituents R 'and R' is guanidino protecting group, by acid hydrolysis or hydrogenolysis, and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid to a pharmaceutically acceptable an acid addition salt or liberated by reaction of the salt with a base or an acid amide.