NO145379B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE N2-ARYLSULPHONYL-L-ARGININAMIDES - Google Patents

Description

The present invention regrets

new and useful N 2-ar<y>lsulfon<y>l-L-ar<g>inamides and pharmaceutically acceptable salts thereof, which compounds are of particular value in view of their excellent antithrombotic properties and low toxicity.

Furthermore, many attempts have been made to

achieve new and improved agents for the treatment of thrombosis. N 2- -

(p-tolylsulfonyl)-L-arginine esters have been found to be a type of agent that can be used and these have been found to be effective in dissolving clotted blood (US Patent No. 3-622,615).

A family connections that are found to be

particularly useful as strong specific inhibitors of thrombin for the control of thrombosis are N 2 -dansyl-L-arginine esters or

-amides.

However, there is a continuous need for one

strong specific inhibitor of thrombin for the control of thrombosis with low toxicity.

It has now been discovered that N <2->arylsulfonyl-L-arginine-

amides show antithrombotic activity and also lower levels of toxicity with the same relative activity compared to N 2 -dansyl-L-

arginine ester or -amide. ■ The compounds according to the invention can be represented by the formula. I:

where R is selected blue

there is C^-C1Q alkyl, c^~ cj_ q alkenyl, C3~cxo alkynyl, C2-C10 alkylthioalkyl., c2~cio<a>lkoxyalkyl, C3~cio alkoxycarbonylalkyl, alkylsulfinylalkyl,•C^-Cl0 cycloalkylalkyl, furyl or oxolyl] R 1 is hydrogen, C 1 -C 10 alkyl, C 1 -C 12 phenylalkyl or 5-indanyl;

n is 1, 2 or 3:

where R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 phenylalkyl, C 1 -C 4 cycloalkyl or C 1 -C 10 cycloalkylalkyl; R 1 is C 1 -C 10 alkyl, C 2 -C 10 alkoxycarbonyl, benzyl or ring-substituted benzyl wherein the substituent is C 1 -C 4 alkoxy; R 1 - is hydrogen or C 1 -C 10 alkyl;

m is 0, 1 or 2:

wherein R 8 is -COOR 8 wherein R 8 is hydrogen, or C 1 -C 4 alkyl; R 1 is hydrogen, C 1 -C 6 -alkyl, phenyl or carboxy; • • where R1Q is hydrogen or C1~C10 alkyl, q is 1 or 2 and Z is 0, S or SO where is hydrogen or C-^-C^q alkyl; i is 0 or 1 or 2; and Ar is naphthyl, 5, 6, 7, 8-tetrahydronaphthyl, naphthyl-substituted with at least one halogen, nitro, cyano, hydroxy, C-^-C-^q alkyl, C-L-C10 alkoxy or C2-C20 dialkylaminoi phenyl, phenyl-substituted with at least one halogen, C₁-C₋ alkyl or C₋-C₋ alkoxy,

The invention also encompasses pharmaceutically acceptable salts of the above compounds.

As indicated above, the invention comprises a group of N 2 -arylsulfonyl-L-arginine amides of the formula (I): where R is selected from

where R^ is selected from C^-C1Q alkyl, such as propyl, butyl-,

isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl with 3-10 and preferably 3-6 carbon atoms, such as allyl, 2-, butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl with 3-10 and preferably 3-6 carbon atoms like this sorr. 2-propynyl, 2-butynyl, 3-butynyl and the like, .<a>lkok<y>alk<y>l with 2-10 and preferably 2-6

. carbon atoms such as methoxymethyl, ethoxymethyl-,-;propoxymethyl, 2- methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-netoxypropyl, 3- methoxypropyl, 3~ethoxypropyl, 3-propoxypropyl, ^i-methoxybutyl, 4- ethoxybutyl, 4 -butoxybutyl, 5-butoxypentyl^or the like'/alkylthioalkyl with 2-10 and preferably. 2-6 carbon atoms such as

methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4-methylthiobutyl, .4-ethylthio-butyl, 4-butylthiobutyl, 5 ~butylthiopentyl or the like, alkylsulfinylalkyl with 2-10 and preferably 2-6 carbon atoms such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like, alkoxycarbonylalkyl with 3- 10 and preferably 3-8 carbon atoms such as methoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or the like, C^-C10 cycloalkylalkyl such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, phenyl or oxolyl; R2 is selected from hydrogen, C^-C^q alkyl such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, phenylalkyl with 7-12 and preferably 7-10 carbon atoms such as benzyl, phenethyl or the like or 5-indanyl; and n is an integer equal to 1, 2 or 3

where R^ is selected from hydrogen, c-]_"c-|_q alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, phenylalkyl with 7-15 and preferably 7-10 carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl or the like, C^-C^, cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, C^-C-^q cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like; R^ is selected from alkyl with 1-10 and preferably 1-5 carbon atoms such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, alkoxycarbonyl with 2-10 and preferably 2-5 carbon atoms such as methoxycarbcnyl, ethoxycarbcnyl, prcpoknycarbnyi or the like, benzyl',: "optionally substituted with at least .on C-^-C- alkoxy, R^ is

selected from hydrogen, c1~c1q a-11^1 such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like; and m is an integer equal to 0, 1 or 2,

where Rg is -COORg wherein Rg is selected from hydrogen, C 1 -C 4 alkyl such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like; R^ is hydrogen, alkyl with 1-10 and preferably 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl, carboxy, in which R- is selected from hydrogen, C^ -G 1 -q alkyl such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like; Z is selected from oxy (-0-1, thio (-S-1) and sulfinyl (-S0-); q is an integer equal to 1 or 2, and

wherein R-q is selected from hydrogen, C₁-C₂ alkyl such as methyl,

ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like; i is an integer equal to 0 or 1; and

Ar is selected from naphthyl such as 1-naphthyl and 2-naphthyl, 5>6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from halogen such as fluorine, chlorine, bromine and iodine, nitro, cyano, hydroxy, alkyl with 1-10 and preferably 1-5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like, alkoxy with 1-10 and preferably 1-5 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the like, and dialkylamino with 2-20 and preferably 2-10 carbon atoms such as dimethylamino, diethylamino, N-methyl-N-ethylamino or the like, phenyl, phenyl substituted with at least one substituent selected from halogen such as fluorine, chlorine, bromine and iodine, alkyl with 1-10 and preferably 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like, alkoxy with 1-10 and preferably 1-5 carbon atoms , such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or l appropriate

The pharmaceutically acceptable salts of the above-mentioned compounds are of course also covered by the scope of the invention.

As the person skilled in the art will readily understand, the carbamate can

2. • ..

in the N-ary 1 sulfony 1- L-arginamides to which the carboxyl group or its ester is bound, be asymmetric and thus allow the existence of two optically active isomers, namely the D- and L-diastereoisomers, as well as the racemate, DL- the mixture.

According to what has been found with regard to antithrombotic activity for such compounds with an asymmetric carbon atom, the compounds according to the invention with D- . configuration more active erm those with L configuration, and they are the preferred compounds, although the L and DL forms of them. present compounds also fall within the scope of the invention.

Por preparation of the compounds

different methods can be used depending on the particular starting material and/or intermediates involved.

the production of these compounds is possible by various synthesis routes which will be indicated below. a) Condensation of an L-argininamide with an arylsulfonyl halide.

This process can be illustrated" as follows:

In the above formulas R and Ar are as above; X is halogen; R"' is a protecting group for the α-amino group, such as beryloxycarbonyl or tert-butoxycarbonyl; R' and R" are selected from hydrogen and protecting groups

for the guariidine group such as nitro, tosyl, trityl, oxycarbonyl

and such; .at least one of R' and R" is a protecting group for the guanidine group.

■ ' • ■ N 2-arylsulfonyl-L-argininamide (I) is prepared by condensation: of an L-argininamide (VI) with an essentially equimolar amount of an arylsulfonyl halide (VII), preferably a chloride.\

The condensation reaction is usually carried out

in a suitable reaction-inert solvent in the presence of an excess of a base such as an organic base (triethylamine,

' pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate), and at a temperature between 0°C and the boiling temperature of the solvent for a period of 10 minutes to 15 hours.

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

After the reaction is finished, the formed salt is extracted with water and the solvent is removed in the usual way, e.g. evaporation under reduced pressure to obtain N -arylsulfonyl-L-argininamide (I) which can then be purified by trituration or recrystallization from a suitable solvent, such as diethyl ether-tetrahydrofuran} diethyl ether-methanol and water-methanol, or chromatographed on silica gel. The L-argininamide (VI) starting materials necessary for the condensation reaction can be prepared by protection of the guanidino and α-amino groups in L-arginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation , tert-butoxycarbonylation or tri-tylation, after which the condensation is carried out by the formed N G -substituted-N 2 -substituted-L-arginine (III) with a corresponding amino acid derivative (IV) in the usual way such as the acid chloride method, the azide method, the mixed anhydride method, the activated ester method or the carbodiimide method, after which protective groups are selectively removed from the formed N Q -substituted-N 2 -substituted-L-argininamide (V).

The amino acid derivatives (IV) which are starting materials for the preparation of N G -substituted-N 2 -substituted-L-arginine amides (V) are represented by the following formulas:

In the formulas given above, R^, Rg, R-j, R^, R^, Rg, Ry, <R>10' Rll5 Z' n> m> r'^' ^ as defined above.

The amino acid derivatives with those indicated above

formulas (VIII) or (EX) can be prepared by condensation of a haloacetate, 3-halopropionate or 4-halobutyrate with a suitable amine of the formula R-^NHp or R-jNHg. (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 from 0-80°C and for a period of time from 10 minutes to 20 hours. After the reaction is finished, the amino acid derivatives formed are separated in the usual way, such as extraction with a suitable solvent or evaporation of the reaction solvent and then purification by distillation under reduced pressure.

Among the amino acid derivatives, the amino acid tert-butyl ester derivatives are preferred because they are easily converted into other ester derivatives by acidolysis in the presence of a corresponding alcohol using an inorganic acid (HCl, H"2SO^, etc.) or an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc. .).

According to the method used for the production of the 2-piperidine carboxylic acid derivatives (X), the following reaction scheme is illustrative:

In the first reaction of this scheme, a suitable substituted piperidine (XIV) is contacted with an aqueous sodium hypochlorite solution at a temperature of -5 to 0°C. The resulting product (XV) is isolated by extraction with a solvent, e.g. diethyl ether, and then treated with potassium hydroxide in a lower alkanol solvent to obtain 1,2-dehydropiperidine (XVI). The effect of cyanogenic agents, e.g. hydrogen cyanide or sodium cyanide, converts the 1,2-dehydropiperidines (XVI) into the corresponding 2-cyano analogues (XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to obtain 2-piperidine carboxylic acids (XVIII) is carried out by treating the 2-cyanopiperidines (XVII) with an inorganic acid such as hydrochloric or sulfuric acid.

The arylsulfonyl halides (VII) which are starting materials in the preparation of the N p-arylsulfonyl-L-argininamides (I) can be prepared by halogenation of the suitable arylsulfonic acids or their salts, e.g. sodium salts, by conventional methods well known to those skilled in the art.

In practice, the halogenation is carried out without a solvent or in a suitable solvent, e.g. halogenated hydrocarbons or DMF in the presence of a halogenating agent, e.g. phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, at a temperature from

-10 to 200°C for a period of 5 minutes to 5 hours. After the reaction is finished, the reaction product is completely immersed in 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 re-, ■ crystallization from a suitable solvent such as hexane, benzene or the like. b) Removal of the N G -substituent from an N G -substituted-N 2 -ar<y>lsulfon<y>l -L-ar<g>inamide.

This process can be illustrated as follows:

In the formulas given above, R, Ar, X,

R', R" and R"' as defined above.

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

The acidolysis is usually carried out by bringing

the N G -substituted-N 2 -arylsulfonyl-L-argininamide (XX) in contact with an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or with a solvent such as an ether (tetrahydrofuran , dioxane), an alcohol (methanol, ethanol) or acetic acid at a temperature from -10 to 100°C, and preferably at room temperature for a period of 30 minutes to 2H hours.

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

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

The removal of the nitro group and the oxycarbonyl group, e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is easily carried out by hydrogeriolysis.

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

The hydrogenolysis is carried out in a reaction-inert solvent, e.g. methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g. Raney nickel, palladium or platinum, in a hydrogen atmosphere

at a temperature of 0°C to the boiling point of the solvent for a period of 2-120 hours.

The hydrogen pressure; is not significant and atmospheric pressure is sufficient. 2 • " *" •

The N -arylsulfonyl-L-arginine amides (I) are isolated

by filtering the catalyst followed by evaporation of the solvent.

The N 2 -arylsulfonyl-L-arginine amides can be purified in the same way as described above.

The G -substituted-N 2 -arylsulfonyl-L-arginine amides (XX) starting materials can be prepared, by corresensing a N G -substituted-N P -substituted-L-arginine (III) (generally, is The N G -substituent nitro or acyl and the N 2 -substituent a protecting group for the amino group such as benzyloxycarbonyl, tert-butoxycarbonyl or the like) and a corresponding amino acid derivative (IV), selective removal of only the N P -substituent in the N G -substituted-N 2 -substituted L-argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then condensation of the N G-substituted-L-argininamide (XIX) with an arylsulfonyl halide (VII), preferably a chloride, in the presence of a base in a solvent. These reaction conditions are as described above in connection with the condensation of an L-argininamide with an arylsulfonyl halide, and removal of

G G ?

The N -substituent from an N -substituted- N -arylsulfonyl-L-argininamide. c) Condensation of an N-arylsulfonyl-L-arginyl halide with an amino acid derivative.

This process can be illustrated as follows:

In the above formulas, R, Ar and X are as above.

The N 2-arylsulfonyl-L-argininamide (I) is prepared by condensation of an N 2-arylsulfonyl-L-arginyl halide (XXII), preferably a chloride, with at least an equimolar amount of an amino acid derivative (IV). The condensation reaction can be carried out without any added solvent in the presence of a base. However, satisfactory results will be obtained using a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).

The amount of solvent used is not essential and can vary from 5 to 100 times the weight of • N 2-arylsulfonyl-L-arginyl halide (XXII).

The preferred condensation temperatures are

in the range from -10°C to room temperature. The reaction time is not significant, but varies with the amino acid derivative (IV) used. In general, time periods from 5 minutes to 10 hours are used. The obtained N-arylsulfonyl-L-argininamide can be isolated and purified in the same way as described above.

N 2-arylsulfonyl-L-arginyl halide (XXII) starting materials required for the condensation reaction can be prepared by reacting an N 2-arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorus oxychloride , phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide. The halogenation can be carried out with or without added solvent. The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of solvent used is not essential and can vary from 5 to 100 times the weight of N -■ arylsulfonyl-L-arginine (XXI).

The preferred reaction temperature is within the range of -10°C to room temperature. The reaction time is not significant, but varies with the halogenating agent and with the reaction temperature. In general, 15 minutes to 5 hours can be specified.

The N<2->arylsulfonyl-L-arginines (XXI) which are starting materials for the preparation of the N p-arylsulfonyl-L-argmyl halides (XXII) can be prepared by condensation of L-arginine (II) with an essentially equimolar amount arylsulfonyl halides (VII) by a method similar to that described for the condensation of an L-argininamide with an arylsulfonyl halide.

It is well known in the state of the art that an ester derivative of N 2 -arylsulfonyl-L-argininamide (I) where R2, R^,

Rg, Rgt R10 or R13 is alkyl, aralkyl, aryl or 5-indanyl,

can be prepared from a carboxylic acid derivative of N<2->arylsulfonyl-L-argininamide in which R2, R^, Rg, Rg, R1Q or R-^ is hydrogen,

by conventional esterification. It is also recognized that the carboxylic acid derivative can be prepared from the ester derivative by conventional hydrolysis or acidolysis. The conditions under which esterification, hydrolysis or acidolysis are carried out will be obvious to the person skilled in the art.

The N 2-arylsulfonyl-L-argininamide (I) according to the invention forms acid addition salts with a large number of inorganic and organic acids. Some of the N 2 -arylsulfonyl-L-arginine amides containing a free carboxyl group, and in which R 2 , R 1 -, R 8 , R 1 , R 1 Q or is hydrogen, form salts with a large number of inorganic or organic bases.

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

In the same way, treatment of the salts with a

base or acid result in a regeneration of the free amide.

As indicated above, the N 2 -arylsulfonyl-L-arginine amides and their salts according to the invention are characterized by the

high specific inhibitory effect against thrombin as well as the almost total lack of toxicity, and therefore these compounds are useful for the determination of thrombin in the blood as a diagnostic reagent, and/or for the medical control or prevention of thrombosis.

The compounds according to the invention are also use-

only as an inhibitor against platelet aggregation.

The antithrombotic effect of the N 2 -arylsulfonyl-L-argininamide according to the invention was compared with that of a known antithrombotic agent, N 2-(p-tolylsulfonyl)-L-arginine methyl ester, by determining the fibrinogen coagulation time. The fibrinogen coagulation time measurements were carried out as follows:

A 0.8 ml amount of a fibrinogen solution was prepared

by dissolving 150 mg of bovine fibrinogen (Cohn fraction I),

in 40 ml of a borate salt buffer (pH 7, H) was mixed with 0.1 ml of a borate salt buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a thrombin solution (5 units/ml) was added to the solutions in an ice bath.

Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 25°C. The coagulation time was taken as the time between the time of transfer to the bath at 25°C and the time of the first appearance of fibrin threads. In the cases where no preparation sample was added, the coagulation time was 50-55 seconds. The test results are shown in Table 1. The expression "concentration necessary to prolong the coagulation time by a factor of two" is the concentration of an active ingredient which is necessary to prolong the normal coagulation time of 50-55 seconds to 100-110 seconds.

The concentration required to prolong the clotting time by a factor of two for the known antithrombotic agent, N -(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100 µm. The inhibitors are shown in Table 1 by indicating R and Ar i

the formula (I) and the addition part.

When a solution containing etl 2-arylsulfonyl-L-argininamide according to the invention was administered intravenously to animals, the high antithrombotic effect in the circulating blood was maintained from one to three hours. The half-life for the decay of the antithrombotic compounds according to the invention in circulating blood was shown to be approximately 60 minutes; the physiological conditions for each animal (rat, rabbit, dog and chimpanzee) were well maintained. The experimental reduction of fibrinogen in the animals caused by infusion of thrombin was satisfactorily controlled by simultaneous infusion of the compounds, according to the invention.

The values for acute toxicity (LDcn) determined by intraperitoneal administration of substances of the formula (I) in male mice. with a weight. of 20 g, was in the range 1000 to 10000 mg/kg body weight.

Representative LD^„ values of the compounds

• 50

according to the invention is shown in the following table.

On the other hand, the LD^ values for N 2-

2 50

dansyl-N-butyl-L-argininamide and N-dansyl-N-methyl-N-butyl-L-argininamide 75 and 70 mg/kg, respectively.

The therapeutic agents according to the invention can be administered alone or in combination with pharmaceutically acceptable carriers, the amount of which is determined by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice. E.g. the compounds can be injected parenterally, i.e. intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds can be used in the form of sterile solutions containing other solutes, e.g. sufficient salt or glucose to make the solution isotonic. "The compounds can be administered orally in the form of tablets, capsules or granules containing suitable extenders such as starch, lactose, sugar and the like. The compounds can be administered sublingually in the form of drugs or the like in which each active ingredient is mixed with sugar or corn syrup, flavorings and colorants, and then sufficiently dehydrated to render the mixture suitable for pressing into solid form.The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents.

The doctor determines the dosage of the available therapeutic substances and the dosage varies with the method of administration and the chosen compound. In addition, the dose will of course vary with the particular patient. When the compound is administered orally, a larger amount of the active ingredient will usually be necessary to produce the same effect as a smaller amount administered parenterally. The therapeutic dose is usually 10-50 mg/kg of active ingredients parenterally, 10-500 mg/kg orally per day..

The invention will now be explained in more detail with reference to the further illustrative examples.

Example 1

(A) N 2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine: To a well-stirred solution of 83.6 g of L-arginine in 800 ml of 1052 potassium carbonate solution was added 114.7 g of 6.7 -dimethoxy^aphthalensulfonyl chloride in 800 ml of benzene. The reaction mixture was stirred at 60°C for 5 hours during which time the product precipitated. After one hour at room temperature, the precipitated product was filtered and washed successively with benzene and water and 129 g or 765? N -(6,7~ dimethoxy-2-naphthylsulfonyl)-L-arginine with melting point 252-255°C.

(B) N 2-(6,7_dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride:

A suspension of 2.00 g of N o -(6,7_dimethoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N 2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride. (C) N 2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester: To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20 ml of chloroform was carefully added N 2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand. room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness.

The residue was triturated with a small amount of water and a crystalline substance was obtained. This was collected by filtration and recrystallized from ethanol-ethyl ether and 2.28 g or 82$ of N<2->(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester were obtained with melting point 164-166°C: I.R. (KBr): 3.390, 3.165, 1-735, 1-370 cm"<1.>

Analysis - calculated for C2gH1| ^ j^^ S • SfH^SO^ {%) :

C, 52.98; H, 7.00; N, 11.04 Found (%) : C, 52.69; H, 6.98; N, 10.86. (D) N 2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine: To a solution of 2.00 g of N 2-(6,7-dimethoxy-2-naphthylsulfonyl)-L -arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform, 50 ml of 15% HCl-ethyl acetate was added. The reaction mixture was stirred for 5 hours at room temperature.

At the end of this time, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml "Daiaion" SK 102" ion exchange resin (200-300 mesh, H+<-> form) packed in water, washed with water and eluted with 3% ammonium hydroxide solution.

The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness and 1.43 g or 19% of N 2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine was obtained as an amorphous solid: I.R. (KBr): 3.360, 3.140, 1.622 cm"<1>.

Analysis:

Calculated for C^H^N^S {%) : C 53.62; H 6.56; N 13.03

Found {%) : C 53.48; H 6.43; N 12.98.

Example 2

(A) N -(6-Methoxy-2-naphthylsulfonyl)-L-arginyl chloride:

A suspension of 2.5 g of N 2-(6-methoxy-2-naphthyl-sulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. The addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride. (B) Ethyl 1-(N<2->(6-methoxy-2-naphthylsulfonyl)-L-arginyl 7-2-piperidinecarboxylate).

o To a stirred solution of 2.2 g of ethyl 2-piperidine carboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, the above obtained N 2-(6- methoxy-2-naphthylsulfonyl)-L-arginyl chloride. The reaction mixture was stirred overnight at room temperature.

At the end of this time, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The oily residue was washed with ethyl ether and 2.9 g of powdered ethyl 1-(N_2-(6-methoxy-2-naphthylsulfonyl)-L-arginyl 7-2-piperidinecarboxylate were obtained.

Upon analysis of the product, part of it was converted to the flavianate with a melting point of 192-193°C. I.R. (KBr): 3•210 , ' 1.747 , I.638 cm"<1>.

Analysis:

Calculated for C^H^OgN^. Cl0HgO8N2S (%): C 49.58; H 4.87; N 11.56. Found (%) : C 49.24; H 4.70; N 11.85. (C) 1-/N_2-(6-methoxy-2-naphthylsulfonyl)-L-arginyl_/-2-piperidinecarboxylic acid: A solution of 2.8 g of ethyl 1-/N-(6-methoxy-2 -naphthylsulfonyl)-L-arginyl7-2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2N-NaOH solution was heated to 60°C and held at this temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200-ml "Daiaion SK 102" ion exchange resin (200-300 mesh, H+ form;) , packed in water, washed with ethanol-water (1:4)' and eluted' with ethanol-water-NH^OH (10: 9:1). The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of 1-(6-methoxy-2-naphthylsulfonyl)-L-arginyl-(2-piperidinecarboxylic acid) as an amorphous solid.

I.R. (KBr): 3-200 (wide), 1,620, 1,150 cm"<1>

Analysis:

Calculated for C^H^OgN^S (%): C 54.64; H 6.18; N. 13.85

Found (%) : C 56.88; H 6.31; N 13.83.

Example 3

(A) N -nitro-N -(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine ethyl ester: To a stirred solution of 28.3 g of N G -ni•tro-N 2- (tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran, 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate while maintaining the temperature at -5°C.. After 15 minutes, 14.2 g of n-(2-methoxyethyl)glycine ethyl ester was added to this, and the mixture was stirred for 15 minutes at -5°C . At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate and washed successively with 200 ml of water, 100 ml of a 5% sodium bicarbonate solution, and 100 ml of a 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate.

After evaporation of the solvent, the residue was dissolved in 20

ml of chloroform and the solution was added to a column (80 cm x 6 cm) with 500 g of silica gel packed in chloroform. The product was eluted first with chloroform and then with 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to dryness and 25>8 g or 63% N Q-nitro-N o-(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl) was obtained )glyein ethyl ester in the form of a syrup.

"i.R. (KBr): 3-300, 1,740, 1,690 cm"<1>.

(B) N -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride: To a stirred solution of 29.8 g of N G -nitro-N 2-(tert-butoxycarbonyl)-L-arginyl-N-( 2-methoxyethyl)glycein ethyl ester in 50 ml of ethyl acetate, 80 ml of 103S-ig dry HCl-ethyl acetate was added at 0°C. After 3 hours, 200 ml of dry ethyl ether was added to this solution to precipitate a viscous oily product.

This was filtered and washed with dry ethyl ether

and 24.1 g of N G-nitro-L-arginyl-N-(2-methoxyethyl)-glycine ethyl ester hydrochloride was obtained as an amorphous solid.

(C) N r -nitro-N"n-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glyein ethyl ester: To a stirred solution of 4.0 g of N c- nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 20 ml of water and 20 ml of dioxane, 2.5 g of sodium bicarbonate and 3.5 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride were added in sequence in 30 ml of dioxane at 5°C, and stirring was continued for 3 hours at room temperature.At the end of this time,

the solvent evaporated and the residue dissolved in 40 ml of chloroform and washed with 10 ml of 1N hydrochloric acid solution and 20 ml of water.

The chloroform solution was dried over anhydrous sodium sulfate. By evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3% methanol-chloroform.

The fraction eluted from 3% methanol-chloroform was

evaporated and one obtained 5.3 g or 87% N G -nitro-N 2-(6,7-di-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glyein ethyl ester in the form of an amorphous solid.

I.R. (KBr): 3-240, 1,740, 1,630 cm"<1>. (D) N<2->(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester : To a solution of 3.00 g of NG<->nitro-N<2->(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glyein ethyl ester in 50 ml of ethanol and To 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature.At the end of this time the ethanol solution was filtered to remove the catalyst and it was evaporated to obtain an oily product.Reprecipitation with ethanol-ethyl ether gave 2.53 g or 91% of N<2->(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester.

For analysis of the product, a portion was converted

to the Flavianate; melting point l85°C, I.R. (KBr):

3,375, 3-200, 1,740 cm"<1>.

Analysis:

Calculated for C^H^N^gS. C₂H₂N₂₂S (%): C 47.67; H. 4.92; N 11.12 Found (%): C 47.64; H 4.81; N 11,12 (E) N<2->(6,7~dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine: A solution of 2.5 g of N 2-(6, 7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 5 ml of ethanol and 7 ml of 1N sodium hydroxide solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml "Daiaion SK 102" ion exchange resin (200-300 mesh, H+<-> form) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness and the residue was purified by reprecipitation from ethanol-ethyl ether and 1.32 g or 72% of N2-(6,7~dimethoxy-2-naphthylsulfonyl)- L-arginyl-N-(2-methoxyethyl)glycine as an amorphous solid. 'I.R. (KBr): 3-380, 3-180, 1,630 cm<-1.>

Analysis:

Calculated for C^H^I^<Og>S (%) : C 51.20; H 6.17] N 12.98 Found {%) : C 50.93; H 6.02; N 12.63-

Example 4

(A) L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride:

To a solution of 4.0 g of N -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 50 ml of ethanol was added 0.5 g of palladium black and then the mixture was shaken in a hydrogen atmosphere for 150 hours at room temperature. At the end of this time, the ethanol solution was filtered to remove the catalyst and evaporated to obtain an oily product. Reprecipitation from ethanol-ethyl ether gave 3.0 g or 81% of L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride as a powder. (B) N2-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester: To a well-stirred solution of 2.00 g of L-arginyl-N-(2- methoxyethyl)glycine ethyl ester hydrochloride and 1.95 g of K2C0^ in 20 ml of water and 10 ml of dioxane, a solution of 2.17 g of 4,6-dimethoxy-2-naphthalenesulfonyl chloride in 30 ml of dioxane was added dropwise over the course of 30 minutes while the temperature was kept at 0°C. The reaction mixture was stirred for an additional 5 hours at room temperature. At the end of this time, the solvent was evaporated and the residue taken up in 50 ml of chloroform. The chloroform solution was filtered to remove insolubles and dried over anhydrous sodium sulfate. addition,

of 150 ml of ethyl ether to the chloroform solution resulted in a precipitate which was separated by decantation and purified by reprecipitation from ethanol-ethyl ether to give 2.31 g or .7255 N2-(4,6-dimethoxy-2-naphthylsulfonyl)-L- arginyl-N-(2-methoxyethyl)glycine ethyl ester.

For analysis of the product, a portion was converted

- to the flavianate with melting point 225-227°C.

I.R. (KBr): 3-375, 3-200, 1,742 cm<-1>.

Analysis:

Calculated for C^H^N^OgS. C10H6N2OgS C 47.67; H 4.92; N 11.12 Found (%) : C 47.62; H 4.84; N 11,18.' (B) N<2->(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glyein: N 2-(4,6-dimethoxy-2-naphthylsulfonyl)-L- arginyl-N-(2-methoxyethyl)glyein was obtained in the form of an amorphous solid in a manner similar to that described under Example 3 (E). I.R. (KBr): 3-360, 3-180, 1,610 cm<-1>.

Example 5'

(A) N p-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethyl-glycine: NG<->nitro-N<2->(6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine benzyl ester was prepared by the method described in example 3 and had a melting point of 133-135°C.

To a solution of 3.00 g of N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine benzyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g palladium-blaek and then the mixture was shaken in one hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove catalyst and then evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml "Daiaion SK 102" ion exchange resin (200-300 mesh, H+<->form), packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness and 1.71 g or 70% of N<2->(6,7~ dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine was obtained in the form of an amorphous solid. I.R. (KBr): 3-360, 3-200, 1,590 cm<-1>.

Analysis:

Calculated for C^gH^N^<S> (%) : C 57.42; H 6.02; N 11.97

Found {%) : C 57.09; H 6.06; N 11,7.4.

Example 6

(A) N<2->(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride: A suspension of 2.00 g of N -(6,7-dimethoxy- 2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycyl chloride hydrochloride. (B) N<2->(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glyein m-tolyl ester hydrochloride: A mixture of 2.00 g of m-cresol' and N - (6,7-Dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride as obtained above was heated to 90°C for 50 minutes. At the end of this period was reaction the mixture cooled, washed several times with dry ethyl ether and then dissolved in 10 ml of dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a precipitate which was washed several times with dry ethyl ether and 2.12 g or 86% of N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-( 2-Methoxyethyl)-glycine m-tolyl ester hydrochloride in the form of a powder. I.R. (KBr): 3-250, 3,100, 1,740, 1,640 cm"1.

Various other N 2 -arylsulfonyl-L-arginine amides or salts thereof were synthesized according to the procedure of the above examples, and the test results are shown in Table 1.

Example 7

Tablets suitable for oral administration.

Tables containing the ingredients listed below can be prepared by common techniques.

Example 8

Capsules for oral administration.

Capsules of the ingredients listed below were made by thoroughly mixing the ingredients and filling hard gelatin capsules with the mixture.

Example 9

Sterile solution for infusion.

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

Preparation A

Arylsulfonyl chlorides.

(A) Sodium 6,7_dimethoxy-2-naphthalene sulfonate.

To a well-stirred solution of 70.8 g of sodium

6,7-dihydroxy-2-naphthalenesulfonate and 77.2 g of sodium hydroxide in 450 ml of water are added dropwise to 230 ml of dimethyl sulphate at 60°C over the course of one hour, during which time the product precipitated. To this reaction mixture, 38.8 g of sodium hydroxide are added in portions and the stirring is continued for one hour.

After one hour at room temperature, the precipitate was filtered, washed with ethanol and dried and 50 g of sodium 6,7-dimethoxy-2-naphthalene sulphonate was obtained.

(B) 6,7-dimethoxy-2-naphthalenesulfonyl chloride.

To a stirred suspension of 50 g finely divided

sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide, 62.2 ml of thionyl chloride were added dropwise at room temperature. After 30 minutes, the reaction mixture was poured into 1 liter of ice water, and the precipitate was filtered and then dissolved in 250 ml of benzene. The benzene solution was repeatedly washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo and the residue was recrystallized from benzene-n-hexane (1:1) and 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride with melting point 127.5-129.5° was obtained C.

Analysis:

Calculated for C-^H^C^SCl C 50.26; H 3.87; Cl 12.37 Found (%): C 50.45; H 4.00; Cl 12,33-The following arylsulfonyl chlorides which have not previously been reported in the chemical literature were synthesized by the above-mentioned method which is essentially as described by E.H. Rodd in "Chemistry of Carbon Compounds", Elsevier Publishing Company, 1954, Vol III, pages 441-469-

Preparation B

Amino acid derivatives.

(A) N-butylglycine tert-butyl ester.

It is added to 36.5 g of butylamine while stirring

15.05 g of tert-butyl chloroacetate during 30 minutes while maintaining the temperature at 30-70°C. The reaction mixture is kept at 70°C for a further hour. At the end of this period, excess butylamine is evaporated under vacuum and the residue is taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred to a separatory funnel and shaken well. The benzene solution is separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of the benzene, the residue is distilled under a reduced

pressure and 17.0 g or 90.9% of N-butylglycine tert-butyl ester with boiling point 76°CM mm Hg is obtained.

The following amino acid tert-butyl esters which have not previously been reported in the chemical literature were synthesized by the above-mentioned method which corresponds substantially to that described by A.J. Speziale et al., in "J.' Org. Chem., 25 731 (1960).

(B) N-(2-methoxyethyl)glyein ethyl ester.

To a stirred solution of 165.2 g of 2-methoxy-γ-ethylamine and 202.4 g of triethylamine in 1 liter of benzene, a solution of 334.0 g of ethyl bromoacetate in

200 ml of benzene during one hour at room temperature. At the end of this time, the mixture was heated under reflux for 2 hours to complete the reaction. After cooling, the triethylamine hydrobromide was removed by filtration and washed with benzene.' After removal of the solvent, the product was distilled under vacuum and 242.8 g or 75.3% of N-(2-methoxyethyl)glycine ethyl ester with a boiling point of 73~75°C/4 mmHg was obtained.

The following amino acid ethyl esters, which are not described in the chemical literature, were synthesized by the above-mentioned method, which corresponds substantially to that described by A.J. Speziale et al., in "J. Org. Chem.", 25 731 (1960).

(G) N-(2-Methoxyethyl)glyene benzyl ester p-toluenesulfonate. To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene, 63.8 g of benzyl alcohol and 72.9 g of p-toluenesulfonic acid monohydrate are added. The mixture was heated under reflux for 10 hours with simultaneous removal of water using a Dean-Stark water trap. At the end of this period, the solution was concentrated under vacuum and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the precipitate formed was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate and 99.2 g or 85% of N-(2-methoxyethyl) glycine benzyl ester p-toluenesulfonate with a melting point of 95- 96°C. The following amino acid benzyl ester p-toluenesulfonates which have not previously been reported in the chemical literature were synthesized by the method indicated above.

Preparation C

2-piperidine carboxylic acids and their esters.

(A) M-methyl-2-piperidinecarbonitrile.

A solution of 33.6 g is added dropwise to 500 g of 10/S sodium hypochlorite solution cooled in an ice bath

■ or 0.21 mol of 4-methylpiperidine acetate in 10 ml of water over the course of 1 hour. At the end of this period, the reaction product was

extracted twice into 500 ml of ethyl ether and dried over anhydrous sodium sulfate. After evaporation of ethyl ether, the residue was added dropwise to a solution of 11.8 g or 0.21 mol of potassium hydroxide in 100 ml of 96% ethanol under reflux. Reflux heating was continued for a further 10 minutes. Ethanol was evaporated and the residue dissolved in 50 ml of 2N sodium hydroxide solution and then extracted with ether.

The ether layer was dried over anhydrous sodium sulfate after which the ether was evaporated. The residue was added to an ice-cooled solution of 27 g or 1 mole of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water. The solution was stirred at a temperature of 10 to 20°C for 4 hours and then made basic by the addition of solid sodium hydroxide. The reaction product was extracted with ether, dried over anhydrous sodium sulfate and then distilled under reduced pressure and 17 g or 66% of 4-methyl-2-piperidinecarbonitrile with a boiling point of 96-97°C/10 mmHg was obtained.

The following 2-piperidinecarbonitriles which have not previously been described in the literature were synthesized by the above method which is substantially as described by Grundon et al., in "J. Chém. Soc", 1963, 3898, Grundon et al. , "J. Chem. Soc", 1964, 2448, R. Bonnett et al., "J. Chem. Soc", 1959, 2092 and H. Bohme et al. in "Ber.", 92 1613 (1959).

(B) 4-Methyl-2-piperidinecarboxylic acid hydrochloride.

A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 ml of 6N hydrochloric acid was refluxed for 6 hours. After evaporation of the solvent, the residue was recrystallized from water and 13 g of 4-methyl-2-piperidinecarboxylic acid hydrochloride was obtained.

(C) Ethyl 4-methyl-2-piperidinecarboxylate.

A solution of 13 g or 0.072 mol of 4-methyl-2-piperidinecarboxylic acid hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for 4 hours. After this, the solvent was evaporated under reduced pressure and the residue was extracted with a solution of chloroform and saturated potassium carbonate solution.

The chloroform layer was dried over anhydrous sodium sulfate and then the chloroform was evaporated. Distillation of the residue gave 7.4 g or 60% ethyl 4-methyl-2-piperidine carboxylate with boiling point 76-77°C73 mmHg.

(D) Benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate.

A solution of 20 g or 0.112 mol of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g or 0.224 mol of benzyl alcohol and 25.6 g or 0.134 mol of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours while continuously removing water using a Dean-Stark apparatus. At the end of this period the solvent was distilled off and the residue was washed with ether-n-hexane and recrystallized to give 10 g or 22% of benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate with a melting point of 160-163° C

The following 2-piperidine carboxylates which have not previously been described in the literature were synthesized by the method indicated above.

N CO„C-,HI-

Morpholine-3-carboxylic acid hydrochloride was prepared by the above procedure and had a melting point of 200-202°C.

. The following starting materials for the production of N-arylsulfonyl-L-argininamides were prepared by the methods described in the literature listed below:

The methyl or ethyl ester of the above compounds was prepared by conventional esterification. Ethyl thiomorpholine-3-carboxylate has a boiling point of 108°C74 mmHg.

Diethylpiperidine-2,6-dicarboxylate hydrochloride was prepared by the usual esterification of piperidine-2,6-dicarboxylic acid and has a melting point of 184-186°C.

Isoindoline-1-carboxylic acid was prepared by a method similar to that for the preparation of isoquinoline-3-carboxylic acid described in "Ber.", HH 2034 (1911). Ethyl iso-indoline-1-carboxylate hydrochloride was prepared by conventional esterification of isoindoline-1-carboxylic acid and has a melting point of 139-140.5°C.

Claims (1)

Analogous process for the preparation of therapeutically active N-arylsulfonyl-L-argininamide with the formula (I): or pharmaceutically acceptable salts thereof, wherein: R is where R1 is C^-C^ alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkylthioalkyl, C2-C10 alkoxyalkyl, C-^- C^ alkoxycarbonylalkyl, alkylsulfinylalkyl, C 1 -C 10 cycloalkylalkyl, furyl or oxolyl; R 2 is hydrogen, C 1 -C 4 alkyl, C 1 -C 12 phenylalkyl or 5-indanyl; n is 1, 2 or 3: where R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 phenylalkyl, C 1 -C 1 cycloalkyl or C 4 -C 10 cycloalkylalkyl; R 1 is C 1 -C 10 alkyl, C 2 -C 10 alkoxycarbonyl, benzyl or ring-substituted benzyl wherein the substituent is C 1 -C 4 alkoxy; R 1 - is hydrogen or C 1 -C 4 alkyl; m is 0, 1 or 2: wherein R 8 is -COOR 8 wherein R 8 is hydrogen, or C 1 -C 4 alkyl; R 1 is hydrogen, C 1 -C 1 alkyl, phenyl or carboxy; where R1Q is hydrogen or C1-C4 alkyl, q is 1 or 2 and Z is 0, S or SO where R-^ is hydrogen or Cj-C^Q alkvli i is 0 or 1 or 2; and Ar is naphthyl, 5, 6, 7, 8-tetrahydronaphthyl, naphthyl substituted with at least one halogen, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy or C2-C20 dialkylamino; phenyl, phenyl-substituted by at least one halogen, C₁-C₁₋ alkyl or C₁-C₋₋₋ alkoxy, characterized in that a) an L-arginine of the formula where R is as indicated above, is reacted with an arylsulfonyl halide of the formula: where Ar is as indicated above and X is halogen, b) the N G -substituent is removed from an N G -substituted-N 2 -arylsulfonyl-L-argininamide of the formula: ' . where R and Ar are as indicated above, R' and R" are selected from hydrogen and protecting groups for the guanidine group, and at least one of R' and R" are protecting' groups' for the guanidine group, c) an N -arylsulfonyl-L- arginyl halide with the formula: where Ar is as stated above and X is halogen, is reacted with a compound of the formula: where R is as indicated above.