DK150521B - METHOD OF ANALOGUE FOR THE PREPARATION OF N2-ARYLSULPHONYL-L-ARGININAMIDES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

Description

150521

The present invention relates to an analogous process for the preparation of novel and useful N -arylsulfonyl-L-arginamides or the pharmaceutically acceptable salts thereof which have a particular value due to their excellent antithrombotic properties and low toxicities.

So far, many attempts have been made to prepare new and improved agents for the treatment of thrombosis. N - (p-toluenesulfonyl) - L-arginine esters have been found to be of the type of agent that can be used, and these have been found to be effective in dissolving blood clots. (United States Patent Specification No. 3,622,615, issued November 23, 1971). One class of compounds which has been found to be particularly useful as very specific inhibitors of thrombin in the fight against thrombosis is the N -dancyl-L-arginine ester or amide. (Our United States Patent Application No. 496,939, filed August 13, 1974, now U.S. Patent No. 3,978,045). However, there is a continuing need for a very specific and less toxic thrombin inhibitor to combat thrombosis.

It has now been found that the N? -Aryl-sulfonyl-L-argininamides prepared according to the invention have antithrombotic activity and even lower toxicity levels at the same relative strengths than the known N -dancyl-L-arginine esters and - amides.

The present invention therefore relates to an analogous method 2

for the preparation of N -arylsulfonyl-L-arginine amides of general formula I

HN

\

C - N - CH ^ CH-CH ^ CHCOR I

/ I I

Η-, Ν H HNSO ~ 12

Ar where R is selected from the class consisting of 150521 2 / R1

(1) - IT

S is CH (CH 2) n COOR 3 i 2 where R 2 represents C 2 -C 10 alkyl, C 2 -C 8 alkoxyalkyl, C 2 -C 8 alkylthioalkyl, C 2 -L 10 alkylsulfinylalkyl, C cycloalkyl, C4-10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2-pyranylmethyl, 2- or 3-pyridylmethyl or phenyl? R 3 represents hydrogen or C 1-6 alkyl; R represents hydrogen or C ^ _ Q Q alkylj and n is an integer of 0 or 1, - - <? m 4 6 6 where R represents -C00R, where R represents hydrogen or C, Ί n-

5 J- 1U

-alkyl, each R independently represents hydrogen or 4

C1-6 alkyl and m is an integer of 1 or 2; R is substituted at the 2- or 3-position and R5 is substituted at the 2-, 3-, 4-, 5-and / or 6-position, (3) COOIU-.

N, N (CH 2) J

where p is an integer 1 or 2;

COOH

<«> -N 0 or '-'

COOH

and (5) 3 15 O 5 21

Ar represents phenyl substituted by at least one substituent selected from the class consisting of amino, C 1-8 alkylamino, alkanoylamino, C 1-6 hydroxyalkyl, phenyl, C 7-10 phenylalkyl and C 1-6 hydroxyalkoxy; phenyl substituted by at least one substituent selected from the class consisting of hydroxy, C1-6 alkyl and C1-6 alkoxy, and at least one substituent selected from the class consisting of C7-8 alkyl-carbonyl, C2-6 alkylcarbonyl and phenyl ? and phenoxyphenyl-, dibenzothienyl-, 9,9-dioxodibenzothienyl-, phenoxathiinyl-, 1H-indazolyl-, quinolyl-, indolinyl-, phenazinyl-, quinoxalinyl-, phthalazinyl-, 1,2,3,4-tetrahydroquinolyl- or acridinyl group, each of which is unsubstituted or substituted by one or more groups selected from the class consisting of hydroxy, C1-6 alkoxy and C1-6 alkyl; a Cg_ g cycloalkylphenyl, fluorenyl, thioxanthenyl or 2H-chromenyl group, each of which is unsubstituted or substituted by one or more groups selected from the class consisting of hydroxy, C1_1Q alkyl alkyl, C1_1Q, alkoxy, Cj- ^ alkoxyoarbonyl and oxo? 3-cyclohexyl-4-ethoxycarbonyloxyphenyl? or a phenyl group substituted by at least one substituent selected from the class consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkoxy and alkoxycarbonylalkoxy, said substituents containing 3-7 carbon atoms and said substituted phenyl group being optionally further substituted by at least one substituent selected from the class consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halogen, or pharmaceutically acceptable salts thereof.

The compounds of the process according to the invention can be used to inhibit the action and suppress the activation of thrombin in vivo in mammals by administering to a mammal a pharmaceutical (antithrombotic) effective amount 2 of an N -arylsulfonyl-L-argininamide or a pharmaceutically acceptable salt. thereof.

The most preferred group Ar is phenyl which is substituted at least once with amino, C 1-6 alkylamino, C 1-6 alkanoylamino, hydroxyalkyl or C 1-6 hydroxyalkoxy? phenyl, which is substituted at least once with C7-C18 ara3cyl and at least once with hydroxy, C1-6 alkyl or C1-6 alkoxy; A phenoxyphenyl, dibenzothienyl, phenoxathiinyl, quinolyl or quinoxalinyl group, each of which is unsubstituted or substituted one or more times by hydroxy or C 1-6 alkyl; a Cη _ ^₂-aralkyl, C C_16 cyc-cycloalkylphenyl, fluorenyl or 2H-chromenyl group, each of which is unsubstituted or substituted one or more times with C-L_1g alkyl or C1_1g alkoxy; or a phenyl group substituted at least once with alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy or alkoxycarbonyl alkoxy, wherein the substituent contains 3-7 carbon atoms and the substituted phenyl group is optionally further substituted at least once with methyl, ethyl, methoxy, ethoxy, hydroxy or halogen.

Typical compounds prepared by the process of the present invention are: 1- [N2- (quinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid (cf. compound 33 in Table I), 1- [N2- (3-methylquinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidine-carboxylic acid (cf. compound 38 in Table I), 1- [N2- (3-ethylquinoline-8-sulfonyl) ) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid (cf. compound 42 of Table I), 1- [N2- (3-sec-butoxybenzene-1-sulfonyl) -L-arginyl] -4- methyl 2-pyridinecarboxylic acid (cf. Compound 111 in Table I), 1- [N2- (3,5-dimethyl-4-isopropoxybenzene-1-sulfonyl) -L-arginyl] -4-methyl-2 -piperidinecarboxylic acid (cf. compound 120 in Table I), o 1- [N - (2,4-dimethoxy-3-butoxybenzene-1-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid (cf. Compound 124 in Table I), 1- [N - (3-Isopropoxybenzene-1-sulfonyl) -L-arginyl] -4-methyl-2-pyridinecarboxylic acid (cf. Compound 112 in Table I), 2 N - (2-phenoxathiinylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine (cf. 21 in Table I), 2 N - (2-fluorene sulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine (cf. Compound 58 of Table I) and 2 1- [N - (4-methoxy-3-cyclohexylbenzene-1-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid (cf. compound 25 of Table I) .

5 150521

The pharmaceutically acceptable salts of the above compounds also fall within the scope of the present invention.

The process according to the invention is characterized by the characterizing part of claim 1. The preparation thus takes place according to one of the synthetic routes outlined below.

p) a) Removal of the N-substituent from an N -substituted N-aryl-sulfonyl-L-argininamide.

This approach can be illustrated as follows:

HN

C - N - CH9CH9CH9CHCOOH II - »/ I 2 2 2 | h2n h nh2

HN

X - N - CH9CH „CHoCHC00H III

/ I 2 2 2,

N R "HN

I I

R 'R' '+ RH IV -'i

HN

^ - N - CH9CH9CH9CHCO0 V -}

/ I I

HN R ”HN

i1 R "'

HN

\ - N - CH2CH2CH2CHCOR XIX ArSQ2X VI1 y e / H "NH" R * 6 150521

HN

\ - N - CHoCHoCHoCHC0R XX

/ I 2 2i HN R "HN | ° 2 1« Ar

HN

\

_C - N - CH2CH2CH2CHCOR I

H2N H HNS ° 2

Ar In the above formulas, R, Ar, Rl ° 9 R "has the meaning given above, and R" 'is an α-amino protecting group.

2 The N -Arylsulfonyl-L-argininamide of general formula I is prepared by G G 2 being removed by removing the N-substituent from an N -substituted N -aryl-sulfonyl-L-argininamide of the general formula XX by acid hydrolysis or hydrogenoly.se.

p

The acid hydrolysis is usually carried out by contacting the N -substituted, 2N -arylsulfonyl-L-argininamide of the general formula XX with an excess of an acid, e.g. hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, e.g. an ether (tetrahydrofuran or dioxane), an alcohol (methanol or ethanol) or acetic acid at a temperature in the range -10 - + 100 ° C, preferably in the range 10 - 60 ° C, and particularly preferably at room temperature, for a period of from 30 minutes to 24 hours. The products are isolated by evaporation of the solvent and excess acid or by trituration with a suitable solvent followed by filtration and drying.

Since an excess of acid is used, the products are usually 2 in the form of the acid addition salts of the N -arylsulfonyl-L-arginine amides of the general formula I which can be readily converted to the free amide by neutralization.

150521 7

The removal of the protecting groups R 'and R "in the form of nitro groups and oxycarbonyl groups, eg benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, is easily carried out by hydrogenolysis. At the same time, the benzyl ester moiety, which may be included in the group R when R represents benzyl, is converted to a carboxyl group by the hydrogenolysis.

The hydrogenolysis is carried out in a solvent inert to the reaction, 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 between 0 ° C and the boiling point of the solvent, preferably at a temperature in the range 10 - 80 ° C, for a period of from 2 hours to 120 hours. Hydrogen pressure is not critical and atmospheric pressure is sufficient.

The 2N-arylsulfonyl-L-arginine amides of the general formula I are isolated by filtration of the catalyst followed by evaporation of the solvent. The N -Arylsulfonyl-L-arginine amides can be purified by recrystallization from a suitable solvent such as hexane or benzene.

G 2

The N -substituted N -arylsulfonyl-L-argininamide starting materials of general formula XX can be prepared by protecting the guanidino and α-amino groups of L-arginine of formula II via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxy , benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation, condense the G 2 formed N-substituted-N-substituted L-arginine with the general G 2 formula III (usually the N substituent is nitro or acyl and the N substituent is a protecting group for the amino group, eg benzyloxycarbonyl or tert-butoxycarbonyl) and a corresponding amino acid derivative of the general formula IV, by selectively removing only the 2G 2 N substituent in the N-substituted N-substituted L-arginine amide with the general formula V by catalytic hydrogenolysis or

G

acid hydrolysis, and then the thus obtained N -substituted L-argininamide of the general formula XIX with a arylsulfonyl halide of the general formula VII, preferably a chloride, is condensed in the presence of a base in a solvent e.g. an organic base (triethylamine or pyridine), or a solution of an inorganic base (sodium hydroxide or potassium carbonate) at a temperature of between 0 ° C and the boiling point of the solvent for between 10 minutes and 15 hours. zen / diethyl ether, diethyl ether / water and dioxane / water.

2 b) Condensation of an N -arylsulfonyl-L-arginyl halogenamide with an amino acid derivative.

This approach can be illustrated as follows:

HN H

\ I

C - N - CH2CH2CH2CHCOOH II

H2N NH2 + ArSO2X VII -y

HN H

\ i C - N - CH2CH2CH2CHCOOH XXI -> H ~ N HNSO-

Year

HN H

\ I

C - N - CHoCH-CHoCHC0X XXII

/ 2 2 2I

H Nx 1 2 HNSO-

Ar + RH IV}

HN H

\ I

C - N - CH2CH2CH2CHCOR in HNS02

Ar In the formulas shown above, R, Ar and X have the meaning given above.

The N -arylsulfonyl-L-argininamide of the general formula I is prepared by condensing an N -arylsulfonyl-L-arginyl halide of the general formula XXII, preferably a chloride, with at least one equimo lower amount of an amino acid derivative with the general formula IV.

The condensation can be carried out without an added solvent in the presence of a base. However, satisfactory results are obtained using a solvent, e.g. basic solvents (dimethylformamide or dimethylacetamide) or halogenated solvents (chloroform or dichloromethane). The amount of solvent used is not critical and can vary from 2 to approx. 5 to approx. 100 times the weight of the N -arylsulfonyl-L-arginyl halide of general formula XXII. Preferred condensation reaction temperatures are in the range -10 - + 80 ° C, preferably in the range 20 - 50 ° C. The reaction time is not critical but varies with the amino acid derivative of general formula IV used. Usually a period of from 5 minutes to 10 hours is appropriate.

2

The N -arylsulfonyl-L-argininamide obtained can be isolated and purified in the same manner as described above.

2

The N -arylsulfonyl-L-arginyl halide starting materials of general formula XXII required for the condensation reaction 2 can be prepared by reacting an N -arylsulfonyl-L-arginine of general formula XXI with at least one equimolar amount of a halogenating agent, f .g. thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide. The halogenation can be carried out with or without an added solvent. Preferred solvents are chlorinated hydrocarbons such as chloroform or dichloromethane and ethers such as tetrahydrofuran or dioxane. The amount of solvent used is not critical and 2 can range from approx. 5 to approx. 100 times the weight of the N -arylsulfonyl-L-arginine of the general formula XXI.

Preferred reaction temperatures are in the range of -10 ° C to room temperature. The reaction time is not critical but depends on the halogenating agent and the reaction temperature. Usually a period of from 15 minutes to 5 hours is appropriate.

2 150S21 ίο

The N -arylsulfonyl-L-arginines of general formula XXI, which are 2 starting materials for the preparation of the N -arylsulfonyl-L-arginyl halides of general formula XXII, can be prepared by condensing L-arginine of formula II with an the essential equimolar amount of arylsulfonyl halide of the general formula VII by a method analogous to that described in the context of the condensation of an L-argininamide with an arylsulfonyl halide.

2

It is known that an ester derivative of the N -arylsulfonyl-L-argininamide 36 of general formula I wherein R and R are alkyl can be prepared from a carboxylic acid derivative of N -arylsulfonyl-L-argi-36 the ninamide, wherein R and R represent hydrogen, for esterification in a manner known per se. It is also known that the carboxylic acid derivative can be prepared from the ester derivative by usual hydrolysis or acid hydrolysis. The conditions under which the esterification, hydrolysis or acid hydrolysis is to be performed will be apparent to one skilled in the art.

2

The N -arylsulfonyl-L-arginine amides of the formula I disclosed herein form acid addition salts with a variety of inorganic and organic acids. Some of the N -arylsulfonyl-L-arginine amides, which contain a free carboxyl group, wherein R and R represent hydrogen, form salts with a wide variety of inorganic and organic bases.

The product of the reactions described above can be isolated in the free form or in the form of salts. 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, iodoacetic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, succinic acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Similarly, the product can be obtained as pharmaceutically acceptable salts by reacting one of the free carboxylic acids with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, Ν, Ν'-dibenzylethylenediamine or N-ethylpiperidine.

11 150521

Treatment of the salts with base or acid results in the formation of the free amide.

2

As indicated above, the N -arylsulfonyl-L-arginine amides of the present invention and their salts can be characterized by their very specific mammalian anti-thrombin inhibitory effect and their actual lack of toxicity, and these compounds are therefore useful in the medical control or prevention of thrombosis. .

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

2

The antithrombotic effect of the N -arylsulfonyl-L-arginine amides disclosed herein is compared with the action of the known anti-o-thrombotic agent N - (p-tolylsulfonyl) -L-arginine methyl ester in determining the fibrinogen coagulation time. The measurement of the fibrinogen coagulation time is performed as follows:

An 0.8 ml aliquot of fibrinogen solution prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armor Inc. in 40 ml of a borate salt buffer of pH 7.4, mix with 0.1 ml of a borate salt buffer of pH 7.4 (reference) or a sample solution in the same buffer solution, and add 0.1 ml of thrombin solution ( 5 units / ml) supplied by Mochida Pharmaceutical Co., Ltd. to the solutions in an ice bath.

Immediately after mixing, the reaction mixture is transferred from the ice bath to a bath maintained at 25 ° C. The coagulation time is calculated as the time between the transfer time to the bath at 25 ° C and the time of arrival of the first fibrin strands. In cases where no drug is added, the coagulation time is 50 - 55 seconds. The test results are listed in Table I. The term "concentration required to prolong the coagulation time by a factor of 2" is the concentration of active substance required to extend the normal coagulation time of 50-55 seconds to 100-110 seconds.

12 150521

The concentration required to require the coagulation time by a factor of 2 for the known antithrombotic agent N 2 - (p-tolylsulfonyl) -L-arginine methyl ester is ΙΙΟΟ ^ λιΜ. The inhibitors are identified in Table I by indicating R and Ar in the general formula I and the addition moiety.

o When a solution containing one of the N -arylsulfony1 - L-arginine amides disclosed herein is administered intravenously to animal bodies, the high antithrombotic effect in circulating blood is maintained for 1 to 3 hours. The half-life of the decay of the circulating blood antithrombotic compounds of this invention is found to be approx. 60 minutes; the physiological state of the host animal (rats, rabbits, dogs and chimpanzees) is well maintained. The experimental reduction of fibrinogen in animals caused by thrombin infusion is satisfactorily controlled by simultaneous infusion of the compounds of this invention.

\

The acute toxicity values (LD 2 kg body weight.

Representative LD ^ values for the compounds of this invention are shown in the table below.

Compound "C - NH - (CH2) 3CHCOR LD50 (mg / kg) H2N HNSO2Ar

Ar R

rV ^ 3 / - \ LI / ch3 -vhCH3 173 I ° ch2ch γ- 'and 3 ch3 cooh 13 150521

Table continued JL ^ OCH, CX - / ~ \ cH3 170 y- 'OCH3 cooh tk rv -N VcH3 250 - 300

Xch3) - /

COOH

^^ CH-,

r ^ rr ^ V

Λ ~ Λ 270 -nJ) - ch3

COOH

/ C2H5 300

COOH

2 The LDgo values for N -dansyl-N-butyl-L-argininamide and N2-dansyl-N-methyl-N-butyl-L-arginine amide, respectively, are less than 10 mg. kg.

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

The compounds can e.g. injected parenterally, ie. intramuscularly, intravenously or subcutaneously. In parenteral administration, the precursors may be used in the form of sterile solutions containing other solutes, e.g. a sufficient amount of salt 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 or white sugar. The compounds may be administered sublingually in the form of trochisci or lozenges, wherein the active substance is mixed with sugar or cereal syrups, flavorings and dyes and then dehydrated sufficiently to make the mixture suitable for pressing in solid form. The compounds may be administered orally in the form of solutions which may contain color and flavoring agents. The treating physician determines the size of the therapeutic agent herein most suitable for humans, and the dose varies with the method of administration and the compound selected. Furthermore, the dose depends on the individual patient to be treated.

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

The therapeutic dose is usually parenterally 10 - 50 mg / kg of active agent, and orally 10 - 500 mg / kg per day. day.

The process of the present invention is further illustrated by the following examples.

Example 1.

2 A) N - (2-Dibenzothienylsulfonyl) -L-arginine:

To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10% aqueous potassium carbonate solution add 112.7 g of 2-dibenzothiophene sulfonyl chloride in 800 ml of benzene. The reaction mixture is stirred at 60 ° C for 5 hours during which the product precipitates. After 1 hour at room temperature, the precipitate is filtered off and washed with benzene and water in that order to give 127 g (76% of theory) of 2 N - (2-dibenzothienylsulfonyl) -L-arginine.

15 150521

ISLAND

B) N - (2-dibenzothienylsulfonyl) -L-arginyl chloride: 2

A suspension of 4.21 g of N - (2-dibenzothienylsulfonyl) -L-arginine in 20 ml of thionyl chloride is stirred for 2 hours at room temperature. Addition of cold dry diethyl ether results in a precipitate which is collected by filtration and washed several times with dry diethyl ether to give N - (2-dibenzothienylsulfonyl) -L-arginyl chloride.

2 C) N - (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine tert-butyl ester:

To a stirred solution of 2.67 g of N-butylglycine tert-butyl ester in 2 20 ml of chloroform is carefully added the above-obtained N - (2-dibenzothienylsulfonyl) -L-arginyl chloride. The reaction mixture is left at room temperature for 1 hour. Then the mixture is washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness.

The residue is triturated with a small amount of diethyl ether to give an amorphous solid. This is filtered off and re-precipitated from ethanol-ethyl ether to give 3.1 g (49% of theory) of N - (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine tert-butyl ester.

IR Spectrum (KBr): v = 3350, 1740 and 1625 cm -1.

IuclX

Analysis:

Calcd for C 28 H 39 ° 5 N 5 S 2 * 1 // 2 H 2 SO 4: C 53.31 H 6.39 N 11.10 Found: C 53.21 H 6.46 N 10.89.

2 D) N - (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine: 2

To a solution of 2.00 g of N - (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine tert. buty ester in 20 ml of chloroform is added 50 ml of 15% hydrogen chloride solution in ethyl acetate. The reaction mixture is stirred for 5 hours at room temperature. The mixture is then evaporated to dryness. The residue is washed several times with dry diethyl ether and chromatographed on 80 ml of "Daiaion" SK 102 ion exchange resin (200-300 mesh, H + form manufactured by Mitsubishi Chemical Industries Limited) packed in water and washed with water, eluting with 3%. s ammonium hydroxide solution.

16 150521

The fraction eluted with 3% ammonium hydroxide solution is evaporated 2 to dryness to give 0.9 g (53% of theory) of N - (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine as an amorphous solid.

IR Spectrum (KBr): ν = 3350, 1640 and 1270 cm -1.

max

Analysis:

Calculated for C24 H31 N5 O5 S2: C, 54.01, H, 5.86; N, 13.12; Found: C, 53.78; H, 5.97;

Example 2.

2 A) N - (2-Dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycinethyl ester.

To a stirred solution of 2.42 g of N- (2-methoxyethyl) glycinethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform cooled 2 in an ice-salt bath is added 7.0 g of the above N - (2-dibenzazothienylsulfonyl) -L-arginyl chloride obtained in small portions. The reaction mixture is stirred overnight at room temperature. Then 50 ml of chloroform is added and the chloroform solution is washed twice with 25 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue is washed with ethyl ether to give 5.5 g of N - (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester in the form of a powder.

Analysis:

Calcd. For C25H2306N5S2.1 / 2H2SO4: C, 50.49; H, 4.07; N, 11.78. Found: C, 50.22; H, 4.18; N, 11.51.

B) N - (2-Dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine: 2

A solution of 5.5 g of N - (2-dibenzothienylsulfonyl) -L-arginyl-N - (2-methoxyethyl) glycine ethyl ester in 15 ml of methanol and 15 ml of 2N sodium hydroxide solution is heated to 40 ° C and maintained at this temperature for 10 hours. . Then, the mixture is evaporated and chromatographed on 200 ml "Daiaion" ® SK 102 ion exchange resin (200-300 mesh, H + form, manufactured by Mitsubishi Chemical Industries Limited), packed in ethanol-water (1: 4) and eluted with ethanol-water-ammonium hydroxide (10: 9: 1).

17 150521

The main fraction is evaporated to dryness and washed with diethyl ether to give 3.05 g (62% of theory) of N- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as an amorphous solid fabric.

IR Spectrum (KBr): νm_Y = 3400, 1630 and 1280 cm

Calcd for ^ 23 ^ 29 ^ 6 ^ 5 ^ 2 * C 51.57 H 5.46 N 13.08 Found: C 51.35 H 5.63 N 12.86.

Example 3

G 2 A) N -nitro-N - (tert-butoxycarbonyl) -L-arginyl-N-butylglycine benzyl ester.

G 2

To a stirred solution of 28.4 g of N -nitro-N - (tert-butoxycarbonyl) -L-arginine in 450 ml of dry tetrahydrofuran, 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate are added in the above order, while the temperature is kept at -5 ° C. After 15 minutes, 35.0 g of N-butylglycine benzyl ester p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran are added and then the mixture is stirred for 15 minutes at -5 ° C. Then the mixture is warmed to room temperature. The solvent is evaporated and the residue is taken up in 400 ml of ethyl acetate and washed with 200 ml of water, 100 ml of 5% aqueous sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water in the above order. 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 placed on a column (80 cm x 6 cm) of 500 g silica gel packed in chloroform.

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

IR Spectrum (KBr): wt a = 3300, 1740 and 1690 cm -1.

ΛίΙαΛ 150521 18

P

B) N-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride: Q 2

To a stirred solution of 26.0 g of N-nitro-N - (tert-butoxycarbonyl) -L-arginyl-N-butylglycine benzyl ester in 50 ml of ethyl acetate, 80 ml of 10% dry hydrogen chloride solution in ethyl acetate is added at 0 ° C.

After 3 hours, 200 ml of dry ethyl ether are added to this solution to precipitate a viscous oily product.

This is filtered off and washed with dry ethyl ether to give p 20.8 g of N -nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride in the form of an amorphous solid.

G 2 C) N-nitro-N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N - butylglycine benzyl ester:

Q

To a solution of 2.33 g of N-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride in 10 ml of water and 40 ml of dioxane is added 1.26 g of sodium bicarbonate and 2.2 g of 3-cyclohexyl-4-methoxyphenylsulfonyl chloride in the order listed at 5 ° C and stirring is continued for 3 hours at room temperature. The solvent is then evaporated and the residue is dissolved in 100 ml of ethyl acetate and washed with 10 ml of 1N hydrochloric acid solution, 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate solution and 10 ml of water in that order.

The ethyl acetate solution is dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3% methanol in chloroform. The fraction eluted with 3% methanol in chloroform is evaporated to give 2.6 g (77% of the G 2 theoretical) N-nitro-N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L - arginyl-N -butylglycine benzyl ester in the form of an amorphous solid.

IR Spectrum (KBr): v χ = 3300, 2920, 1740, 1640 and 1250 cm

Analysis:

Calculated for C 32 H 46 ° 8 N 6 S: c 56.95 H 6.87 N 12.46 Found: C 56.49 H 6.63 N 12.38.

D) N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butyl-glycine.

G 2

To a solution of 3/00 g of N -nitro-N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -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. palladium black, and then the mixture is shaken in a hydrogen atmosphere for 50 hours at room temperature. The ethanol solution is then filtered to remove the catalyst and evaporated to dryness. The residue is washed several times with dry diethyl ether and chromatographed on 80 ml of "Daiaion" ® SK 102 ion exchange resin (200-300 mesh, H + form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3%. s ammonium hydroxide solution.

The fraction eluted with 3% ammonium hydroxide solution is evaporated to dryness to give 1.5 g (72% of theory) of N 2 - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine in the form of an amorphous solid.

IR Spectrum (KBr): = 3350, 2920, 1630 and 1250 cm -1.

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Analysis:

Calculated for c25H4iN6 ° 5Sl! C 55.63 H 7.66 N 12.98 Found: C 55.32 H 7.39 N 12.84.

Example 4

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

To a well stirred solution of 2.05 g of ethyl 1- (NG-nitro-L-arginyl ·) - 4-methyl-2-piperidinecarboxylate hydrochloride and 1.26 g of sodium hydrogen carbonate in 10 ml of water and 40 ml of dioxane are added. 2.2 g of 3-cyclohexyl-4-methoxybenzenesulfonyl chloride in small portions while maintaining the temperature at 0 ° C. The reaction mixture is stirred overnight at room temperature.

The reaction mixture is then evaporated to dryness. The residue is dissolved in 50 ml of ethyl acetate and the ethyl acetate solution is washed with 10% citric acid, saturated sodium chloride solution, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution in the above order. The ethyl acetate solution is evaporated and the residue chromatographed on silica gel packed in chloroform and eluted with chloroform containing 3% methanol. The main fraction is evaporated to dryness to give 2.6 g (ethyl 1- [NG-nitro-N 2 - (3-cyclohexyl-4-methoxybenzenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate.

IR Spectrum (KBr): ν max = 3400, 1735, 1635 and 1250 cm cm ".

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

G 2

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

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By re-precipitation with ethanol diethyl ether, 2.4 g of ethyl 1- [N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate are obtained.

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

2

A solution of 2.4 g of ethyl 1- [N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of 1 N sodium hydroxide solution is stirred. overnight at room temperature. The reaction mixture is then evaporated and dissolved in 10 ml of water. The solution is neutralized with 2N hydrochloric acid solution to give a white rubbery precipitate, which is dissolved in 150 ml of chloroform. The chloroform solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in 2 vacuum to give 1.52 g of 1- [N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl 2-piperidinecarboxylic acid in the form of an amorphous solid.

IR Spectrum (KBr): v = 3350, 2920, 1620 and 1250 cm cm ".

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Analysis:

Calcd. For C 26 H 41 ° 6 N 5 S: c 56'60 H 7.49 N 12.70 Found: C 56.51 H 7.53 N 12.68.

Various other N2-arylsulfonyl-L-arginine amides or acid addition salts thereof are synthesized analogously to the procedures of the above examples and the test results are set forth in Table I.

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Example 5

S02C1 N02nS "N (cU;.) 3CUCUN ^) - C; 11: J 00C, b Νυ> ^ | ^ (θ!) 2) 3 ^ 1ΰΟλ <^) _ ΟΙ]:} ^ COOEt ^ J, n COOKt

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Q

-N-nitro) -L-arginyl) -4-methyl-2-piperidinecarboxylate.

Λ

To a well-stirred solution of 4.08 g of ethyl 1- (N-nitro-L-arginyl) -4-methyl-2-piperidinecarboxylate hydrochloride and 3.03 g of triethylamine in 200 ml of chloroform is added portionwise 3.69 g of 3-methyl -1,2,3,4-tetrahydro-8-quinoline sulfonyl chloride while maintaining the temperature at 5 ° C. The reaction mixture is stirred for 5 hours at room temperature. At the end of this time, the reaction mixture is washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.

The chloroform solution is evaporated and the residue is chromatographed on silica gel packed in chloroform and eluted with chloroform containing 3% methanol. The main fraction is evaporated to dryness to give 3.61 g (62% of theory) of ethyl 1- (N2- (3-methyl-1,2,3,4-tetra-hydro-8-quinoline sulfony)) -N nitro-L-arginyl) -4-methyl-2-piperidine'-carboxylate in the form of an amorphous solid.

IR Spectrum (KBr): δ - 3400, 1730 and 1635 cm -1.

IuciX

NMR Spectrum (CD 3 OD): δ (ppm) = 6.5 (1H, t), 7.1 (1H, d), 7.4 (1H, d).

150521 51 N02NH ^ J (C112) 3ClICO} ^]) - CH3 NII ^ -Nil (CH2) 3ClICON <^ - Cll3: = L, cooEt NH L ~ oEt

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NU2 ^ -NH (C1I2) 3C11C0. \ '^> - Cli3 MI2 ^ -N11 (C1I2) 3CiICON ^) - clI3 NH NO COOEt NH NOU ϋ0ϋΠ I. SO 2 - SO 2 Oa and CH 3 Cl, 3 52 150 521 C) 1- (N 2 - (3-Methyl-1,2,3,4-tetrahydro-8-quinoline sulfonyl) -L-arginyl) -4-methyl -2-piperidincarboxy1syre.

A solution of 2.00 g of ethyl 1- (n2- (3-methyl-1,2,3,4-tetrahydro-8-quinoline sulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylate acetate in 20 ml of ethanol and 10 ml of N sodium hydroxide solution are stirred overnight at room temperature. Then, the reaction mixture is neutralized with 2N hydrochloric acid and evaporated in vacuo to give a rubber precipitate extracted three times with 150 ml of chloroform.

The chloroform solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.45 g (85% of theory) of 1- (N2- (3-methyl-1,2,3,4-tetrahydro-hydroxy) 8-quinoline sulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid in the form of an amorphous solid.

IR Spectrum (KBr): = 3400, 1620, 1460 and 1380 cm

Analysis:

Calculated for C 23 H 36 ° 5 N 6 S: c 54'31 H 7.13 N 16.52 Found: C 54.09 H 7.00 N 16.80.

Preparation of arylsulfonyl chlorides for use as starting compounds in the process of the invention.

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 is added dropwise 16.1 ml of chlorosulfonic acid at a temperature between 0 and 4 ° C. The reaction mixture is stirred for 1 hour at room temperature, poured into crushed ice and then diluted to 300 ml with water. After evaporation of the carbon tetrachloride, the resulting aqueous phase is extracted with ether and then neutralized with 2N sodium hydroxide solution to precipitate white crystals which are filtered off and dried to give 64.3 g (85.1% of theory) of sodium 3-butoxy-2 , 4-dimethoxybenzensulfonat.

B) 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 53 is added dropwise 69 ml of thionyl chloride over 20 minutes at room temperature.

The reaction mixture is stirred for 15 minutes and gradually poured into 1000 ml of ice water and stirred vigorously. After 1 hour, the aqueous phase is decanted off and the residual oil is extracted with benzene, washed with water, dried over anhydrous sodium sulfate, distilled to remove the solvent and then distilled in vacuo to give 47.5 g (80.1% of theory). ) 3-Butoxy - 2,4-dimethoxybenzenesulfonyl chloride with boiling point 154 - 155 ° C / 1 mm Hg.

Analysis:

Calcd for C 21 H 15 ClO 5 S: c 46.68 H 5.56 Found: C 46.71 H 5.60.

The arylsulfonyl chlorides listed below, not previously described in the chemical literature, are synthesized by the above procedure.

Table

No. Ar - SC ^Cl Boiling point (melting point)

Ar 1 I | 1 165 - 166 ° C / 10 mm Hg ^ \> <ch2) 2ch3 <57'5 - 58'5 ° c> 2 f * \\ 112 "115 ° C / 1 mm Hg LA (33 - 35 ° C) O (CH2) 3CH3 3 yj | 127 - 129 ° C / 0.5 mm Hg / CH3

OCH, CH, CH

54

Table continued 150521 4 | ^ |) 148 "150 ° C / 1 ^ Hg o (ch2) 4ch3 5 ^ \, 0 (<: η2) 3 (: η3 143 ~ 145 ° C / 1 ^ Hg in J (48 - 51 ° C) 6 sL · (41 - 42 ° C)

Li CHOCH-CHo

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7 Λ / CH3 139 - 140 ° C / 1 mm Hg

I CH

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Table · Continued 150521 11 T | T 155 - 156 C / 2 mm Hg 0 (CH2) 3CH3 12 Υγ “3 (44-45¾ OCH2CH2OCH3 • y ^ Y ^ CH3 0 13 I II 187 C / l mm Hg and 2ch2ch2och3

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° CH_O

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Cl 21 131 ° C / 1 mm Hg

XX

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38 \\ C ^ 3 133 ~ 135 ° c / 1 ^ Hg (ch2) 2ch3 ch3 CH, 39 FX VCH, V-OCH 136 - 139 ° C / 1 mm Hg W ^ ch3 ch3 _ ^ CH ^ 40 _ / VoChCH3 \ _ / ° CH ^ h (95 - 96 ° C) ___ ^ CH3 · CH -3 41 fX "CH3 \) -0- (CH2} 2CH3 (101 - 103 ° C) \ - / ^ * CH, C ^ CH, _

Claims (2)

Table continued 42 I II 142 - 144 ° C / 1 mm Hg \ / 0CH3 / ^ CH 44 \ 7 ~ 0CH2CH 158 - 160 ° C / 1 mm Hg W ^ ch3 0CH3 \ / 0CH3 45 \ / OCH2CH2CIC ^ 3 159 " 160 ° C / 1 mm Hg _ ^ 3_i_ \ .OC2H5 46. CH3 151 "152 ° C / 1 ^ Hg _ ^ OC2H5_ A / CHs 47 I 158 - 159 ° C / 1 mm Hg ice / CH3 AND 0CH3 3 2 An analogous process for the preparation of N -arylsulfonyl - L-arginine amides of the general formula I HN C - N - CH _ CH ~ CH 0 CHCOR I / 11 H2N H HNS ° 2 Ar 150521 wherein R is selected from the class consisting of / R1 (1) - bt \ 3 XCH (CHO) COOR ° ΙΔ Π 2 where R1 represents C2-10 alkyl, C2-10 alkylthioxyalkyl, C2-10 alkylthioalkyl, C2-10alkylsulfinylalkyl / C g-cycloalkyl, C 1-6 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2-pyranylmethyl, 2- or 3-pyridylmethyl or phenyl? R 3 represents hydrogen or C 1-6 alkyl; R represents hydrogen or C 1-4 alkyl? and n is an integer of 0 or 1, R4 is (2) - N) V (E) m 4 6 6 where R represents -C00R, where R represents hydrogen or C1-6 alkyl, each R represents independently of each other hydrogen or C 1, n-alkyl, and m is an integer of 1 or 2? R 4 is substituted at the 2- or 3-position and R 3 is substituted at the 2-, 3-, 4-, 5-and / or 6-position, O) coog 2. . . > p where p is an integer 1 or 2? COOH (4) -NO >1> -t or and and 150521 Ar represents phenyl substituted by at least one substituent selected from the class consisting of amino, C1-alkylamino, C1-10-alkanoylamino, C1-hydroxyalkyl, phenyl, phenylalkyl and C1-10 hydroxyalkoxy; phenyl substituted by at least one substituent selected from the class consisting of hydroxy, C1-6 alkyl and C1-6 alkoxy, and at least one substituent selected from the class consisting of C7-8 -alkylcarbon, C2-6 alkylcarbonyl and phenyl; a phenoxy-phenyl, dibenzothienyl, 9,9-dioxodibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl group, each of which is unsubstituted or substituted by one or more groups selected from the class consisting of hydroxy, C1-10 alkoxy and C1-6 alkyl; a Cg_ g cycloalkylphenyl, fluorenyl, thioxanthenyl or 2H-chromenyl group each unsubstituted or substituted by one or more groups selected from the class consisting of hydroxy, C1_1 () - alkyl, C1_1 () - alkoxy, C2_1 () -alkoxycarbonyl and oxo; 3-cyclohexyl-4-ethoxycarbonyloxyphenyl; or a phenyl group substituted by at least one substituent selected from the class consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkoxy and alkoxycarbonylalkoxy, said substituents containing 3-7 carbon atoms and said substituted phenyl group being optionally further substituted by at least one substituent selected from the class consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halogen, or pharmaceutically acceptable salts thereof, characterized in that Q a) the guanidino protecting group (s) of an N -substituted N1-arylsulfonyl-L-argininamide having the general formula XX HN \ C - N - CHoCH0CHoCHCOR ^ 2 2 2 | XX HN R "HNSOo I. r R 'Ar wherein R and Ar are as defined above, wherein R3 in R may also be replaced by benzyl and R1 and R" represent hydrogen or protecting groups for the guanidino group, at least one of R and Ru is a protecting group for the guanidino group, is cleaved by acid hydrolysis or hydrogenolysis and, if necessary, the reaction product obtained is hydrolyzed or esterified; or