NO762744L - - Google Patents

Description

N -substituted L-arginine derivatives

The present invention relates to new and therapeutically usable N 2 -substituted L-arginine derivatives, as well as pharmaceutically acceptable acid addition salts thereof, which derivatives have an outstanding antithrombotic effect.

In the past, many attempts have been made to obtain new and improved agents for the treatment of thrombosis.

Of these, N 2-(p-tolylsulfonyl)-L-arginine esters have been known for their clot-dissolving activity (US Patent No. 3,622,615).

However, there is still a need for highly specific inhibitors of thrombin for the control of thrombosis. N p-substituted L-arginine derivatives have now been discovered which show a distinct anti-thrombosis effect.

The compounds according to the invention can be represented by the formula (I):

where R is selected from 1) -OR-^, R-^ is selected from C-^-C^qa]<_>k<y>i C^-C-^Qcyclqalkyl, C-^-C-^q haloalkyl, C 8 -C 10 alkoxyalkyl, <C>2<-C>10 alkenyl, C 2 -C 10 alkynyl and C 1 -C 10 aralkyl; 2) -N^-<R>2 where and R^ is selected from hydrogen, ^3<G>1"<C>10alkyl'C7"C15 aralkyl, and C]_-C10alkyl substituted with a group selected from C^ -C 1 -C 6 alkoxy, C 8 -C 6 -C 6 alkoxycarbonyl and carboxy; and 3) ~? C ^ Z, where Z is a divalent group consisting of two or more groups selected from methylene-CHg- and

monosubstituted methylene

alkyl and

(where<R>^ is selected from C-^-C^g

Gl~^10a^oxy)>°S none or one or more groups selected from oxy -O-, thio -S-, alkyl substituted imino^5 (where

-N-

R^ is G-^-G-^q alkyl) and acyl-substituted amino

OC-R5

-N- (wherein Rg is C-j^-C^q alkyl), which are combined in any order and the number of the combined groups is up to 20;2 and R» is selected from the group

where R" and R<Mt> considered separately are C-^-C^q alkyl, or R" and R"' taken together are C-^-C^q alkyl en; where R"<»>is C 1 -C 4 alkoxy;

The invention also relates to pharmaceutically acceptable acid addition salts. The invention also relates to a method for inhibiting the activity and suppressing the activation of thrombin in vivo, comprising administration to a living body of a pharmaceutically effective action of an N p-substituted L-arginine ester or an amide or pharmaceutically acceptable acid addition salts thereof.

As indicated above, the invention relates to a group of N 2 -substituted L-arginine esters and amides with the formula Jl):

where R is represented by the formula (l)-OR-^, (3)-N Z , which shall be described in.

or

details below.

1) When R is -OR-^, R^ is selected from straight or branched C-^-C-^Q alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl or the like; G3~C10cycloalkyl such as cyclopropyl, cyclopentyl or

cyclohexyl or the like; C 1 -C 4 haloalkyl such as 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl: or the like; ^"^lO alkoxyalkyl such as 2-methoxyethyl, 2-ethoxyethyl or the like; G2~G10alkenyl such as allyl, 2-butenyl or the like; C8-C^ alkynyl such as 3-^utynyl or the like; and C^-C^ aralkyl such as benzyl, phenethyl or the like.

2) When R is

R 8 and R 8 are selected from hydrogen; straight or branched G1~G10α alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl or the like; C 1 -C 14 aralkyl such as benzyl, phenethyl, 3-phenylpropyl or the like; and C-^-G-^Q alkyl substituted with a group selected from G^-C-^q alkoxy, C 8-10 alkoxycarbonyl and carboxy such as 2-methoxy-ethyl, 3-methoxypropyl, 2-ethoxyethyl, ethoxycarbonylmethyl, 2-met -oxycarbonylethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, carboxymethyl, 2-carboxyethyl or the like.

is Z a divalent group consisting of two or more groups

selected from methylene -CHg- and monosubstituted methylene where R^ is selected from C^-C^q alkyl and

C 1 -C 10 alkoxy; and none or one or more

groups selected from oxy -O-, thio -S-, alkyl-

substituted imino R 5 where R 5 is C -C -C -C alkyl, and acyl substituted

-N-

imino where Rg is ci~ G10^^ yl, which are combined i

-N-

indifferent order, and the number of combined groups usually

is up to 20. Thus indicates the group

a ring with up to

21 paragraphs.

More particularly, R includes 1-polyethyleneiminyl groups or derivatives thereof, such as 1-aziridinyl, 1-azetidinyl, 3-methoxy-1-azetidinyl, 3-ethoxy-1-azetidinyl, 1-pyrrolidinyl, piperidino, 4-methylpiperidine: -en » 4-ethylpiperidino, 4_ProPyl-piperidino, 4-is°ProPylP:i-Per:3-dino, 2-methylpiperidino, 3"methyl~piperidino, 4~methoxypiperidino, 1-hexamethyleneiminyl, 1-octame-tyleneiminyl and the like; an oxazole or thiazole compound such as 3-oxazolidinyl, 3*thiaz°lidinyl and the like; an isoxazole or isothiazole compounds such as 2-isoxazolidinyl, 2-isothiazolidinyl and the like; an oxazine compound such as morpholine, 2,6-dimethylmorpholine, tetrahydro-1,3-oxazin-3-yl, and the like, a thiazine compound such as tetrahydro-1,4-thiazin-4-yl and the like; 4-methyl-1-piperazinyl, 4-acetyl-1-piperazinyl, and the like.

The preferred groups R are the following:

1) When R is -OR^:

C1"<G>8alkyloxy>cyclohexyloxy, Gg-Cg omega-chloral-oxy, Gg-Cg omega-alkoxyalkoxy, C^-Cg alkenyloxy, Gg-<C>g alkynyloxy, Gy-Cg aralkyloxy 2) When R is C1~ G9alkylamino°jG2~G6omega-Alkoxyalkylaminoy C^-Gg omega-Alkoxycarbonylalkylamino, Gy-C-^Q aralkylamino, G^-C^q dialkylamino 3) When R "is -N^Z: G3~<G>10N>N-P° lymethyleneiminyl; G3"G10N>N-polymethylene-iminyl substituted with a group selected from C-^-C^alkyl and C-^-C^ alkoxy. tetrahydro-1, n-oxazin-n-yl (n=2,3 or 4 ); tetrahydro-1,n-thiazin-n-yl (n= 2,3 or 4)in 1-piperazinyl substituted with a group selected from C-pC-4 alkyl and G-1-C-4 acyl.

The most preferred groups represented by R are the following: 1) When R is -OR-^ propoxy, butoxy, pentyloxy, hexyloxy, cyclohexyloxy, 3-chloropropoxy, 2-methoxyethoxy, 2-butenyloxy, 3-butynyloxy»benzyloxy. 2) When R is

butylamino, 2-methoxyethylamine, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino, benzylamino, N-methyl-N-butylamino.. 3) When R is

piperidine, hexamethyleneiminyl, 4-^tylpiperidine > 4-ethylpiperidine, 4~methoxypiperidine, morpholine, tetrahydro-1,4-thiazin-4~ylj4-roethyl-1-piperazinyl, 4-acetyl-1-piperazinyl.

In the formula (I) stated above, R' is selected from

a) substituted naphthyl

where R" and R,,<f>when seen separately are respectively G1-C-L0 (preferably G-j^-C^) alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or the like ; or R" and R™ when taken together are G]__C2.o^preferably O^-O^) alkylene such as methylene, ethylene, trimethylene or the like; alkoxy (-0R", -0R"<f>) or alkylenedioxy (-0R"-R"'0-) and the sulfonyl group can be in any of the positions 1-8 of the naphthalene nucleus; where the sulfonyl group is usually in the 1- or 2-position and the alkylenedioxy group is a 6,7-alkylenedioxy group; d) 2H-3,4-dihydro-1,5-benzodioxepin-7~yl e) derivatives of d) with a substituent in the 3"Position

, where R"" is C-^-G^q(preferably

G1~G5)Alkoxy,

f) 2-dibenzofuranyl

g) 4-dibenzofuranyl h) 2-xanthenyl i) dibenzo-p-dioxin-2-yl

Typical groups represented by R' are the following:

Illustrative of the typical N 2-substituted L-arginine esters and amides according to the invention are the following: 1) Ester derivatives: N p-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine propyl ester N -(6,7 ~dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester N p-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine benzyl ester N p-(6,7-dimethoxy-2-naphthalenesulfonyl)-L- arginine-3"chloropropyl ester N p-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine-2-methoxyethyl ester N -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine-2-butynyl ester N - (6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine-2-butenyl ester 2) Amide derivatives where R is

N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methoxyethyl)-L-argininamide

N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-N-benzyl-L-argininamide

N p-(2-xanthenesulfonyl)-N-methyl-N-butyl-L-argininamide

3) Amide derivatives where R is -N Z: 4-methyl-1-[2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginy3,/piperidine

4-ethyl-1/N2-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl7piperidine

1-/N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl7 hexamethyleneimine

4-/N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl7" morpholine

4-Methoxy-1-(N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl piperidine

4-methyl-1-(N<2->(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl7piperidine

4-ethyl-1-(N<2->(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl)piperidine

4-ethyl-1-[N<2->(2H-3,4-dihydro-1,5-benzodioxepin-7-sulfonyl)-L-arginyl-7piperidine

4-methyl-1-(N<2->(2H-3,4-dihydro-1,5-benzodioxepin-7-sulfonyl)-L-arginyl-7piperidine

4-ethyl-1-ZN<2->(3-methoxy-(2H-3,4-dihydro-1,5-benzo-dioxepine)-7-sulfonyl)-L-arginyl7piperidine 4-ethyl-1-^N2 -(2-xanthenesulfonyl)-L-arginyl/piperidine

4-ethyl-1-^J<2->(2-dibenzofuransulfonyl)-L-arginyl/ piperidine

4-ethyl*1-/N<2->(4-dibenzofuransulfonyl)-L-arginyl/ piperidine

4-Ethyl-1-N2-(dibenzo-p-dioxin-2-sulfonyl)-L-arginyl piperidine

1-^/N 2 -(4-dibenzofuransulfonyl)-L-arginyl/hexamethyleneimine.

The following compounds are the most preferred because of the high level of antithrombotic activity.

N -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester

N2-(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methoxyethyl)-L-argininamide

4-methyl-1-(N<2->(6,7~dimethoxy-2-naphthalenesulfonyl)-L-arginyl/piperidine

4-Ethyl-1-(Tj2-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl7piperidine

4-methoxy-1-/N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl/piperidine

4-methyl-1-/N<2->(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl/piperidine

4-ethyl-1-(N<2->(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl/piperidine 4-ethyl-1-£ft<2->(2-xanthenesulfonyl)-L-arginyl /piperidine

4-ethyl-1-(N<2->(4-dibenzofuransulfonyl)-L-arginyl) piperidine

4-ethyl-1-N p-(dibenzo-p-dioxin-2-sulfonyl)-L-arginyl/piperidine

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

The above-mentioned inventions shall only illustrate the structural variation possibilities that can be used in the method according to the invention, and this summary shall not be limiting of the invention.

These typical compounds are very effective in antithrombotic activity.

For the preparation of the compounds according to the invention, different methods can be used depending on the particular starting materials and/or intermediates involved. Successful preparation of the compounds is possible by means of various synthetic routes to be outlined below.

k 2

1) Preparation of N-substituted L-arginine esters:

a) Esterification of an N 2 -substituted L-arginine I) Reaction between an N -substituted Largining and

an alcohol:

This procedure can be illustrated as follows:

In the above formulas, R is -OR-^, wherein R^ is as indicated above and RA o is as indicated above.

The N p-substituted L-arginine ester (I) is prepared by esterification of an N p-substituted L-arginine (II) with an alcohol (III).

The esterification can be effected by reacting N p -substituted L-arginine, preferably with at least 5 equivalents of alcohol in the presence of at least an equimolar amount of an acid catalyst such as hydrogen chloride, sulfuric acid, toluenesulfonic acid and the like. The reaction is generally carried out without an added solvent or in a suitable reaction-inert solvent at a temperature of 0°C and up to the boiling temperature of the alcohol or solvent for a period of 10 minutes to 15 hours. The preferred solvents are those which form an azeotropic mixture with water and which facilitate the removal of water formed during the reaction.

Examples of such solvents are benzene, toluene, xylene, cyclohexane, carbon tetrachloride and dichloromethane.

After the reaction is finished, the alcohol and/or solvent is distilled off to obtain the N p -substituted L-arginine ester (I) or an acid addition salt thereof, which can be purified by recrystallization from a combination of solvents such as ethyl ethers, alcohols and acetone or by refilling by adding ether to the alcohol solution.

The acid addition salt of the N p -substituted L-arginine ester can be easily converted into the corresponding ester by adjusting the pH value of the solution.

II) Reaction between an N P-substituted L-arginine, an alcohol and a thionyl halide.

The N p -substituted L-arginine ester (I) can be prepared by reacting an N -substituted L-arginine (II), an alcohol (III) and a thionyl halide such as thionyl chloride or thionyl bromide.

Thionyl halide is preferably used in an amount of not less than 2 mol per mol N 2 -substituted L-arginine.

The other reaction conditions such as reaction temperature, reaction time, amount of alcohol used, as well as the procedures for separating and purifying the product are as described above in connection with esterification with an acid catalyst.

According to this process, the product is usually a halo" monoacid salt of the N 2 -substituted L-arginine-. ester.

The N<2->substituted L-arginine (II) can be etherified

by many other methods.

The N p-substituted L-arginine (II) starting material is easily obtained by reacting arginine and a sulfonyl halide (preferably a chloride) with the formula (IV):

where R' is as defined above and X is halogen, in the presence of a base such as KgCO^, KOH, NaOH,

triethylamine or pyridine.

b) Condensation of an L-arginine ester with a sulfonyl halide.

This process can be illustrated as follows:

In the formulas given above, R is -OR-^ where R-^ is as defined previously, R' is as defined previously and X is halogen.

The N 2 -substituted L-arginine ester (I) is prepared by condensation of an L-arginine ester (V) with an essentially equimolar amount of a sulfonyl halide (IV), preferably a chloride.

The condensation reaction is usually carried out in

a suitable reaction-initiated 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), at a temperature from 0°C to the boiling temperature of the solvent for a period of time in 10 minutes to 15 hours.

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

After the reaction is finished, it is formed

salt extracted with water and the solvent removed by standard aids such as evaporation under reduced pressure to obtain the N -substituted L-arginine ester (I), which

can then be purified by trituration or recrystallization from a suitable solvent, such as diethyl ester-tetrahydrofuran, diethyl ether-methanol and water-methanol, or by chromatography on silica gel. The L-arginine ester (V) starting materials are usually prepared by reacting L-arginine with an alcohol in the presence of an acidic catalyst. 2) Preparation of N p-substituted L-arginine amides. a) Condensation of an L-argininamide with a sulfonyl halide.

This process can be illustrated as follows:

In the formulas given above, R is -N^Z, where R^, Ro and Z are as

or

defined above, R' is as defined above and X is halogen.

The N-substituted L-argininamide (I) is prepared by condensation of an L-argininamide (V) with an essentially equimolar amount of a sulfonyl halide (IV), preferably chloride, in the presence of a base.

The reaction conditions are the same as those described in Method 1) b) (condensation of an L-arginine ester with a sulfonyl halide).

The L-argininamide (V) starting materials which are necessary for the condensation reaction can be prepared by protecting the guanidine and α-amino group in arginine by means of nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then condensation of the formed N c--substituted N p-substituted L-arginine with a corresponding amine by such common methods as the acid chloride method, azide method, mixed anhydride- method, activated ester method or carbodiimide method, and then selectively removing the protecting group. b) Removal of the N -substituent from an N -substituted-N 2 -substituted L-argininamide.

This process can be illustrated as follows:

In the formulas given above, R is equal to or -N Z, where R 1 , R 2 and Z are the same

defined above, R' is as defined above, X is halogen, Y" is a protecting group for the amino group such as benzyloxycarbonyl or tert-butoxycarbonyl, and Y and Y' are hydrogen and protecting groups for the guanidine group such as nitro , tosyl, trityl, oxycarbonyl and the like.

At least one of Y and Y' is a protecting group for the guanidine group.

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

The acidolysis is generally carried out by contacting its N -substituted N -substituted L-argininamide (IX) with an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid without the use of a solvent or in a solvent such as a ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol). or acetic acid at a temperature of between -10°C and 100°C, preferably at room temperature, for a period of 10 minutes to 24 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 an excess of acid, the products are usually the acid addition salts of the N p -substituted L-arginine amides (I), which can easily be converted to a free acid by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is easily carried out 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 between 0°C and the boiling temperature of the solvent and for a period of time from 2 hours to 120 hours.

The hydrogen pot is not substantial and atmospheric

pressure is sufficient.

The N p-substituted L-arginine amides (I) are isolated by filtering the catalyst, followed by evaporation of the solvent.

The N -substituted L-argininamides can be purified in the same way as described above.

N -substituted N -substituted L-argininamides (IX) starting materials can be prepared by condensation of an N G-substituted N p -substituted L-arginine (VI) (usually the N p -substituent is a protecting group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl and the like) and a corresponding amine (III) by means of the azide method, mixed anhydride method, activated ester method, carbodiimide method or the like, selective removal of only the N 2 -substituent in a NG. -substituted N p-L-argininamide (VII) by means of catalytic hydrogenolysis or acidolysis, and then condensation of the thus obtained N -substituted-L-argininamide (VIII) with a sulfonyl halide (IV), preferably a chloride in the presence of a base in a solvent. These reaction conditions are described above for the condensation of an L-argininamide with sulfonyl halide, and the removal of the NG '-substituent from an N G -substituted N 2 -substituted-L-argininamide. c) Condensation of an N p -substituted-L-arginyl halide with an amine.

The process can be illustrated "as follows:

In the formulas given above, where Rp, Ro and Z are as indicated

or -iT^

above, Rf is as above and X is halogen.

The N p-substituted -L-argininamide (I) is prepared by condensation of an N p-substituted L-arginyl halide (X), preferably a chloride with at least an equimolar amount of an amine (III). The condensation reaction can be carried out without the use of a solvent. 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 the N--substituted L-arginyl halide (X).

Preferred reaction temperatures for the condensations lie within the range of -10°C to room temperature. The reaction time is not essential, but varies with the amine (III) used. In general, a period of time from 5 minutes to 10 hours can be used.

The obtained N 2 -substituted L-argininamide can be isolated and purified in the same way as described above.

N -substituted L-arginyl halide (X) starting materials for the condensation reaction can be prepared by reacting an N p -substituted-L-arginine (II) 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 an 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 the N 2 -substituted L-arginine. Preferred reaction temperatures are within the range of -10°C to room temperature. The reaction time is not significant, but varies with the halogenating agent and the reaction temperature. Usually, a period of time from 15 minutes to 5 hours can be used. d) Guanidylation of an N p-substituted L-ornithine amide or an acid addition salt thereof.

This procedure can be illustrated as follows:

In the aforementioned formulas, R is where Rg, Ro and Z are as

or -N*"*Z

indicated above and R' is as indicated above.

The N-substituted L-argininamide (I) is prepared by guanidylation of an N-substituted L-ornithine amide (XI) with a common guanidylation agent such as an O-alkylisourea, S-alkylisothiourea, l-guanyl-3>5-dimethylpyrazole or carbodiimide . The preferred guanidylating agent is O-alkylisourea and S-alkylisothiourea.

The guanidylation of the N p-substituted L-ornithine amide (XI) with O-alkylisourea or S-alkylisothiourea is usually carried out in a solvent in the presence of a base at a temperature from 0°C to the boiling temperature of the solvent for a period of 30 minutes to 50 hours.

Examples of preferred bases are triethylamine, pyridine, sodium hydroxide and sodium methoxide. The base is used in an amount of 0.01 to 0.1 equivalents calculated on N-substituted L-ornithine amide. Examples of preferred solvents are water, water-ethanol and water-dioxane.

After the reaction is finished, the obtained N•-substituted L-argininamide (I) is isolated by evaporation of the solvent, followed by removal of the excess of base, and the formed salt is washed. e) Reaction between an N p-substituted L-arginine ester and a primary amine.

This process can be described as follows:

In the formulas given above, Rg and R<*> have the same meaning as above and Ry is C₁-C₋₋ alkyl.

The N-substituted L-argininamide represented by the formula (XIV) can be prepared by reacting an N-substituted L-arginine ester (XII) and about 2 to 10 equivalents of a primary amine (XIII).

The reaction is usually carried out without application

of solvent or in a solvent such as an alcohol (methanol, ethanol), an ether (ethyl ether, tetrahydrofuran), a hydrocarbon (benzene, toluene), a' halogenated. hydrocarbon (chloroform, dichloromethane) or water at room temperature for a period from a few hours to days.

To accelerate the reaction, the reaction mixture can be mixed up to a temperature up to the boiling point of the amine or solvent. Alternatively, a basic catalyst such as sodium methoxide or pyridine can be added to the reaction mixture.

After the reaction is finished, the N p-substituted L-argininamide (XIV) formed is isolated by filtration

or by evaporation of the excess of amine and/or solvent, washed with water and then purified by recrystallization from a suitable solvent such as water-methanol.

The N-substituted L-arginine esters or amides (I) according to the invention form acid addition salts with any of a number of inorganic and organic acids. The product of the reactions described above can be isolated in free form, or in the form of acid addition salts. In addition, the product can be obtained as a pharmaceutically acceptable acid addition salt 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 and the like. The treatment of acid addition salts results in the same way

with a base in a regeneration of the free compound in the form of amide or ester..

As stated above, the N 2 -substituted L-arginine esters and amides, as well as the salts thereof, according to the invention are characterized by a strong specific inhibitory effect against thrombin and therefore these compounds are useful for determining thrombin in the blood as diagnostic agents, and/or for medical checks or prevention of thrombosis. The antithrombotic effects of the N 2 -substituted L-arginine esters and amides according to the invention were compared with that of a known antithrombotic agent, N 2 -(p-tolyls'sulfonyl)-L-arginine methyl ester, by determining the coagulation time for fibrinogen. The fibrinogen coagulation time measurements were carried out as follows: A 0.8 ml portion of a fibrinogen solution prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) in 40 ml of a borate salt buffer (pH 7>4) >was mixed with 0.1 mol of a borate salt buffer, .pH 7j4>(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. Coagulation times were measured as the time between the time of transfer to the 25°C bath and the time of the first appearance of fibrin strands. In the cases where no drug dosage was added, the coagulation time was 50-55 seconds.

The test results are summarized in Table 1. The expression "concentration necessary to extend the coagulation time by a factor of two* is the concentration of an active ingredient which is necessary to extend the usual 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 R' in formula (I) as well as the addition parts.

When a solution containing an N 2 -substituted-L-arginine ester or amide according to the invention was administered intravenously to an animal, the high lantithrombotic effect in the circulating blood was maintained from one to three hours.

The half-life of the antithrombotic compound of the invention in circulating blood was determined to be approximately 30 minutes; the physiological conditions of the host animal (rats, rabbits, dogs and chimpanzees) were well maintained. The experimental reduction of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by simultaneous infusion of compounds according to the invention.

The acute toxicity values (LD^q) determined by oral administration of substances of formula (I) in mice (male mice, 20 g) ranged from approximately 1,000 to 10,000 mg/kg body weight.

The therapeutic agents according to the invention can be administered alone or combined with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, the chosen form of administration and standard pharmaceutical practice.

E.g. can the compounds be injected parenterally,

that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds can be used in the form of sterile solutions containing other dissolved substances, 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, white sugar and the like. The compounds may be administered sublingually in the form of lozenges or tablets in which each of twenty ingredients is mixed with sugar or syrup, flavorings and coloring agents, and then dehydrated sufficiently to render the mixture suitable for pressing into a solid form. The compounds can be administered orally in the form of solutions which may contain coloring agents and flavourings.

The doctor determines in each case the dosage of the available therapeutic agents, so that the amount is as appropriate as possible, and the dosages vary with the method of administration and the particular compound. In addition, the dosage will of course vary with the particular patient being treated.

When the compound is administered orally, a larger amount of active ingredient will be necessary to achieve the same effect as caused by a smaller amount given parenterally. The therapeutic dose is generally 10-50 mg/kg active ingredient for parenteral administration, 10-500 mg/kg for oral administration, all per day.

The following illustrative examples will illuminate the invention in more detail.

Example 1

To 1.0 g (0.0018 mol) 4-ethyl-1-(/NG-nitro-<N>2-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl/piperidine was added 5> 7 g (0.0053 mol) anisole and 3 ml of hydrogen fluoride below

■cooling■with dry ice/acetone and the mixture was stirred for 30 minutes in an ice bath. Anisole and excess hydrogen fluoride were evaporated under reduced pressure with cooling to give an oil-like product, which was slurried with 100 ml of dry ethyl ether. The ether layer was separated by decantation and the powder obtained was dissolved in methanol, re-precipitated with ethyl ether, and then filtered. 4"ethyl-1~ ^N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl/piperidine hydrofluoride was obtained in powder form in a yield of 75$*

Elemental analysis: as Cp^H^yO^N^S .HF

Example 2

A suspension of 1.0 g (0.00186 mol) 4-(NG-nitro-N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl/morpholine and

0.1 g of palladium catalyst in 30 ml of ethanol and 10 ml of acetic acid was bubbled with hydrogen gas for 60 hours at room temperature. When the reaction was complete, the catalyst was filtered off and the solvent was evaporated under reduced pressure, and a viscous oil-like residue was obtained which was taken up in methanol and reprecipitated with ether and 4-^N2~(6,7-dimethoxy-2 -naphthalenesulfonyl)-L-arginyl/myrfolin acetate in powder form in a yield of 82%.

Elemental analysis: as C^H^OgN^S .CH^COOH

Example. 3

Through a suspension of 2.0 g (0.0027. mol)

N p , N ri -dibenzyloxy-carbonyl-N p -(6,7-dimethoxy-2-naphthalene-sulfonyl)-N-butyl-L-argininamide and 0.2 g of 20% palladium-carbon in 50 ml of ethanol and 10 ml of acetic acid, hydrogen gas was bubbled through for 10 hours at room temperature. After the reaction was complete, the catalyst was filtered off and the solvent was evaporated under reduced pressure and an oil-like residue was obtained which was reprecipitated with methanol-ether and N p-(6,7-dimethoxy-2-naphthalenesulfonyl)-N-butyl-L -argininamide acetate in powder form in a yield of ^ 8%.

Elementary analysis: as CgoH^oO^N^S.CH^COOH

Example 4

To 5.0 ml (0.069 mo1) of cold thionyl chloride, 1.0 g (0.00236 mol) N<2->(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine was added with vigorous stirring, and the reaction mixture was allowed to react at room temperature for 1 hour.

After the reaction was complete, 100 ml of dry ether was added to the reaction mixture and the precipitate formed was collected and washed well with 50 ml of dry ether.

The N -(6,7-dimethoxy-2-naphthalene-sulfonyl)-L-arginyl chloride dihydrochloride thus obtained was added with stirring to a solution of 1.2 g (0.012 mol) of 4-methyl -piPeridine in 10 ml of chloroform, and the mixture was left for 3 hours at room temperature. After the reaction was complete, the solvent and excess 4-methylpiperidine were distilled off under reduced pressure, and the residue was dissolved in 20 ml of chloroform. The chloroform layer was washed well with a saturated aqueous NaCl solution and dried over sodium sulfate, after which the chloroform was distilled off under reduced pressure. Addition of 10 ml of acetic acid and 100 ml of dry ether to the residue resulted in the deposition of an oil-like product. The ether was removed by decantation and the oily product was washed well with dry ether and powdery 4-methyl-1-(N<2->(6,7-dimethoxy-2-naphthalene-sulfonyl)-L-arginyl) was obtained. piperidine monoacetate, in a yield of

<!>»<1>g (84%).

Elemental analysis: as C^H^N^O^S . GH^COOH

Example 5

To a suspension of 1.00 g (0.00236 mol) N<2->(6,7~dimethoxy-2-naphthalenesulfonyl)-L-arginine in 20 ml of tetrahydrofuran there was. eventually added 0.98 g (0.0047 mol) phosphorus pentachloride while cooling with ice water. The mixture was stirred for 1 hour at 0-5°C, and then for 2 hours at room temperature.

100 ml of dry ether was added to this reaction mixture, and the supernatant liquid was removed by decantation. The obtained oil-like product was washed with 50 ml of dry ether and powdery N -(6-,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride dihydrochloride was obtained, to which, with stirring, was added a solution of 1, 31 g (0.015 mol) of N-methyl-N-butylamine in 10 ml of chloroform. Then, following the same procedure as in Example 1, I -(6,7-di-methoxy-2-naphthalenesulfonyl)-N-methyl-N-butyl-L-argininamide mono-acetate was obtained in a yield of 0.76 g (58%).

Elemental analysis: as O^Ho^N^S.CH^COOH

Example 6

1.14 g (0.004 mol) of 4,6-di- methoxy-2-naphthalenesulfonyl chloride with stirring at room temperature.

After stirring for 5 hours at room temperature, the reaction mixture was washed with water to remove the formed triethylamine hydrochloride. After the solution was dried over sodium sulfate, dichloromethane was evaporated under reduced pressure and N p -(4>6-dimethoxy-2-naphthalenesulfonyl)-L-arginine ethyl ester was obtained.

Ethyl ether was added to this product and the hydrogen chloride was then bubbled through. The precipitate formed was filtered and N p-(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginine ethyl ester hydrochloride in powder form was also obtained in a yield of 84$.

Elemental analysis: as Cp^HggOgN^SCl

Example 7

To a suspension of 1.50 g (0.005 mol) of L-arginine butyl ester dihydrochloride in a solution consisting of 1.4 g of potassium carbonate and 10 ml of water, which solution had been cooled to 0-5°C, was added dropwise added a solution of 1.43 g (0.005 mol) of 6,7-dimethoxy-2-naphthalenesulfonyl chloride in 10 ml of ethyl ether with vigorous stirring over a period of 30 minutes.

The mixture was further stirred for 10 minutes

and a viscous deposit was obtained. The solvent was removed by decantation and the residue was washed with water and ether.

To a suspension of the resulting product in 20 ml of ethyl ether, 2 g of p-toluenesulfonic acid monohydrate was added with stirring, and a crystalline product was obtained which was filtered and washed several times with ethyl ether, after which N p-(6 ,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine-butyl-ester-p-toluenesulfonate.in a yield of 92%, and with a melting point of 113-115°G.

Elemental analysis: as C29H40°9<N>4<S2>

Example 8

To a mixture of 1.00 g (0.0037 mol) 4-ethyl-1-

(L-arginyl)piperidine and 0.6l. g (0.0044 mol) of potassium carbonate in 10 ml of water, which solution had been cooled to 0°C, a solution of 1.25 g (0.0044 mol) of 6,7-dimethoxy-2-naphthalenesulfonyl- chloride in 30 ml of dioxane with vigorous stirring over a period of 30 minutes.

The reaction mixture was stirred for a further 5 hours at room temperature and the precipitate formed was removed by filtration. The solvent was evaporated under reduced pressure, and 50 ml of chloroform was added to the residue. Undissolved substances were filtered off and the solution was dried over sodium sulfate. Addition of 10 ml of acetic acid to this solution, followed by evaporation of the solvent gave a viscous oil-like product which was reprecipitated with methanol-ethyl ether to give 4-ethyl-1-^N<2->(6,7~dimethoxy- 2-naphthalenesulfonyl)-L-arginyl-7-piperidine-acetate in a yield of 62%.

Elemental analysis: as Cg^H^<OyN>^<S>

Example 9

1.48 g (0.00.52 mol) 6,7-dimethoxy-2-naphthalenesulfonyl chloride with stirring at room temperature.

After stirring for 5 hours at room temperature, the reaction mixture was slurried with 10 ml of water.

The aqueous layer was separated and the remaining chloroform layer was dried over sodium sulfate. Addition of 2 ml of acetic acid to the chloroform layer followed by evaporation of the chloroform gave a viscous oily residue, which was reprecipitated with methanol-ethyl ether to give 4~Z^ -(6,7-dimethoxy-2-naphthalenesulfonyl)-L- arginyl7morpholine acetate in a yield of 66%. Elemental analysis: as Cp^H<g>^<OgN>^S

Example 10

To a suspension of 1.0 g of N p-(4>6-dimethoxy-2-naphthalenesulfonyl)-L-arginine in 30 ml of ethanol, 1 ml of thionyl chloride was gradually added with stirring. The suspension quickly became a clear resolution. After the solution was refluxed with stirring for 4 h, ethanol was distilled off under reduced pressure, and a viscous oil-like residue was obtained, which was washed well three times with 20 mL of ethyl ether to obtain a colorless and powdery N -( 4>6-dimethoxy-2-naphthalenesulfonyl)-L-arginine ethyl ester hydrochloride in a yield of 9,695.

Elemental analysis:' as Cp^H<ggO>gN^SCl

Example 11

A mixture of 1.0 g of N p-(6,7-dimethoxy-2-naphthalene-sulfonyl)-L-arginine and 1.0 g of p-toluenesulfonic acid monohydrate in 5 ml of butyl alcohol and 30 ml of benzene was refluxed for 5 hours while simultaneously removing formed water of reaction. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl ether to obtain a crystalline substance which was filtered off, washed several times with ethyl ether, and there was obtained N -(6,7-dimethoxy-2-naphthalenesulfonyl)- L-arginine-butyl ester-p-toluenesulfonate in a yield of 92% 5 m.p. 113-H5°C.

Elemental analysis: as CggH^QO^N^Sg

Example 12

To 1.2 g (0.0020.mol) of 4-ethyl-1-/NG-nitro-N2-(6-chromansulfonyl)-L-arginyl/piperidine was added 0.64 g (0.0060) of anisole and 3 ml of hydrogen fluoride under simultaneous cooling with dry ice and acetone, and the mixture was stirred for 30 min. in an ice bath. Excess hydrogen fluoride was evaporated under reduced pressure with simultaneous cooling to obtain an oil-like product which was slurried with 100 ml of dry ethyl ether. The ether layer was separated by decantation and the powder obtained was dissolved in methanol, re-precipitated with ethyl ether and then filtered to give 4-ethyl-1-(R-(6-chromanesulfonyl)-L-arginyl/piperidine hydrochloride in powder form in a yield of 63%.

Elementary analysis: as Cp^H^gO^N^S «HF

Example 13»

Through a suspension of 1.2 g (0.0020 mol) /\.-ethyl-1-^N G -nitro-N 2 -(1,4-benzodioxane-6-sulfonyl)-L-arginyl/-piperidine and 0.1 g of palladium catalyst in 30 ml of ethanol and 10 ml of acetic acid was bubbled with hydrogen for 30 hours at room temperature. After the reaction was complete, the catalyst was filtered off and the solvent was evaporated under reduced pressure, and a viscous oily residue was obtained which was taken up in methanol and reprecipitated with ethyl ether, whereby 4-ethyl-1-ZN -(1, 4-benzodioxane-6-sulfonyl)-L-arginyl-7-piperidine-acetate in powder form in a yield of 85%.

Elemental analysis: as Cp^H^oO^N^S.CH^COOH

Example 14

Through a suspension of 2.0 g (0.0026 mol) /\.-ethyl-1-^NG,NG-dibenzyloxycarbonyl-N2-(2H-3,4-dihydro-1,5-benzo-dioxepin-7- sulfonyl)-L-ar<g>in<y>17piperidine and 0.2 g of 10% palladium carbon in 50 ml of ethanol and 10 ml of acetic acid, hydrogen gas was passed for 10 hours at room temperature. After the reaction was complete, the catalyst was filtered off and the solvent was evaporated under reduced pressure and a viscous oily residue was obtained which was reprecipitated with methanol-ether and 4-ethyl-1-^N2-(2H-3,4- dihydro-1,5-benzodioxapine~7-sulfonyl)-L-arginyl-7piperidine acetate in powder form in a yield of 81%.

Elemental analysis: as Cg^Ho^O^N^S.CH^COOH

Various other N0--substituted<e>L-arginine esters and ■-amides were synthesized according to the above examples. The results, including the results from the above examples, are listed in Table 1.

In Table 1, the N p-substituted L-arginine esters and amides are represented by the general formula (I) by indicating R and R' in the formula, as well as the addition part.

Claims (22)

1. N p-substituted L-arginine esters and amides and pharmaceutically acceptable acid addition salts thereof, characterized by the general formula: where R is selected from 1) -OR-^ , where R-^ is selected from C]_-C]_o alkyl, G^ -C^ q cycloalkyl, ' C-j^-C^q haloalkyl, Cg-C-^ alkoxyalkyl, G2~G10 alkenyl, C2~C10 alkynyl° S C7~C15 aralkyl; , where R^ and R^ are selected from hydrogen, G^ -C^ q alkyl, C7 ~ <C>15a ralkyl and G-^ -C^ alkyl substituted with a group selected from C^-C-j^q alko<ksy>, ^ 2~ C10 alkoxycarbonyl and carboxy; and 3) -ff^Z, where Z is a divalent group consisting of two or more groups selected from methylene -OHo - and monosubstituted the methylene c where R^ is -selected from G-^-C^q alkyl and G-^-C-^ alkoxy, and zero, one or more groups selected from oxy -O-, thio -S-, alkyl substituted imino R,5 > where R^ is G-^ -C-^ q alkyl, 0=C-R5 and acyl substituted imino ' ' where R r is C--C, n alkyl, -N- which are combined in any order, and the number of combined groups is up to 20; and R' is selected from where R" and R"', when considered separately is C-^ -G-j^Q alkyl, or R" and R"', when taken together are G^-C^q alkylene, where R"" is C-L-C10 alkoxy) 2. Compounds according to claim 1, characterized in that R is -OR-^ , where R-^ is selected from G-^-C-^q alkyl, G3~ C10 cycloalkyl, C^ -C-^ q haloalkyl, C2~ G10 Alkoxyalkyl, C2-C10 Alkenyl, C2-C10 Alkyny1° S G7-C15 Aralkyl; andR; is where R'" and R"', when considered separately is C-^-C-^Q alkyl, or R" and R"', when considered together are Gi~Gio aikyien*;3. Compounds according to claim 2, characterized in that R is selected from C--Cg alkyloxy, cyclohexyloxy, Cg-Cg omega-4 alkyloxy, C-Cg omega-alkyloxy, Co-Cg alkenyloxy, V-Cg alkynyloxy and Cy -C 6 aralkyloxy; and R' is where R" and R"', when be considered separately, C-j^ -G^ is alkyl and R" and R"', when considered together, is Gi~ G5 alkylien* 4. Compounds according to claim 3, characterized in that R is selected from propoxy, butoxy, hexyloxy, cyclohexyloxy, 3-chloropropoxy, 2-methoxyethoxy, 2-butenyloxy, 3-butynyloxy and benzyloxy; and R' is selected from 5. Compounds according to claim 1, where R is • characterized in that <R>2 and R^ are selected from hydrogen, C^-C-^ q alkyl, C^-C-^ aralkyl, and C^-C-^ q alkyl, substituted with a group selected from C-^ -C-^ q alkoxy, ^ 2~^ 10 alk° oxycarbonyl and carboxy. 6. Compounds according to claim 5j, characterized in that R is selected from C-C-C alkylamino, Cg-Cg omega-Alkoxyalkylamino, C-Cg omega-Alkoxycarbonylalkylamino, Cy-CiQ aralkylamino and Cg-Cg 10 dialkylamino; and R' is selected from where R" and R"' considered separately are G-^-G^ alkyl, or R" and R,<M> considered together are G1~G5 Skylen; where R"" is C₁-C₁ alkoxy, 7- Compounds according to claim 6, characterized in that R is selected from butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is selected from 8. Compounds according to claim 1, where R is -N Z, characterized by atZer divalent group consisting of two or more groups selected from methylene -CH0 - and monosubstituted methylene where R^ is selected from G-^ -C-^ q alkyl and C-j^ -C^ q alkoxy, and zero or one or more groups selected from oxy -O-, thio -S-, alkyl substituted^5 where R^ is G1~ G10 alkyl and acyl substituted imino -N- where Rg is C-^ -C-^ q alkyl, which are combined in any order and the number of combined groups is up to 20. 9. Compounds according to claim 8, characterized in that R is selected from G^ -C-^ q N,N-polymethylene-iminyl, C^-C^C1 N,N-polymethyleneiminyl substituted with a group , selected from G-^ -C₁ alkyl and C₁₂ -C₁ alkoxy, tetrahydro-1, n-oxa-zin-n-yl, where n is an integer 2, 3 or 4» tetrahydro-1, n-thiazin-n-yl , where n is an integer 2, 3 or 4j 1-piperazinyl substituted with a group selected from C-^-C^ alkyl and C-^-C^ acyl, and R' is selected from where R" and R'!' considered separately, G1~ is alkyl or R" and R"' considered together is C1 -C3 alkylene. R"" where R"" is C 1 - C 6 alkoxy, 10. Compounds according to claim 9, characterized in that -R is selected from piperidine, hexamethyleneiminyl, 4-methylpiperidine, 4-ethylpiperidine, 4-methoxypiperidine, morpholine, tetrahydro-1,4-thiazinp-4-yl, 4-methyl-1 -piperazinyl and 4-acetyl-1-piperazinyl; and R' is selected from 11. Compound according to claim 4> characterized in that it is N -(6,7-dimethoxy-2-naphthalene-sulfonyl)-L-arginine-butyl ester. 12. Compound according to claim 7> characterized in that it is N p-(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methoxyethyl)-L-argininamide. 13. Compound according to claim 10, characterized in that it is 4-methyl-1-(N-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-7-piperidine). 14. Compound according to claim 10, characterized in that it is 4-ethyl-1-(N 2 -(6,7-dimethoxy-2-'naphthalenesulfonyl)-L-arginyl/piperidine). 15. Compound according to claim 10, characterized in that it is 4-methoxy-1-</N <2-> (6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-7-piperidine. 16. A compound according to claim 10, characterized in that it is 4-methyl-1-N--(4-6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-7-piperidine. 17. Compound according to claim 10, characterized in that it is /\.-ethjl-1JTi^-(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl/piperidine. 18. Compound according to claim 10, characterized in that it is 4-ethyl-1-Z^~ (2-xanthenesulfonyl)-L-arginyl/piperidine. 19. Compound according to claim 10, characterized in that it is 4-ethyl-1-N<2-> (4-dibenzofuransulfonyl)-L-arginyl/piperidine. 20. Compound according to claim 10, characterized in that it is 4" ethyl-1_Z^-(dibenzo-p-dioxin-2-sulfonyl)-L- is ginyl piperidine. 21. Method for liberating the effect and suppressing the activation of thrombin in vivo, characterized in that a pharmaceutically effective amount of an N 2 -substituted L-arginine ester or amine is added to a living body, with the formula or a pharmaceutically acceptable acid addition salt thereof, in which formula R is selected from 1) -OR^ , where R^ is selected from C^ -C^ q alkyl, C^ -C^ q cycloalkyl, C^ -C^ q haloalkyl, <G> 2~ <C > 10 alkoxyalkyl > G 2 ~ C 10 alkenyl, ^^'^ 10 alkynyl and G 7 ~ C 15 aralkyl; R 2 ) m -N-"-' , where RD and RQ are selected from hydro-R^ ^Ji- gene, G <->^ -C^Q alkyl, Cy-C^ aralkyl and C^ -C^ q alkyl substituted with a group selected from C-^-C-^q alkoxy, ^ 2~^ 10 alkoxy carbonyl and carboxy; 3)~ N 2, where Z is a divalent group consisting of two or more groups selected from methylene-GH?- and monosubstituted the methylene where R^ is selected from G^-C-^q alkyl and C^-C-^q alkoxy, and zero or one or more groups selected from oxy -O-, thio -S-, alkyl substituted imino Rt , j--N-wherein R^ is C-^-C^q alkyl and alkyl substituted imino wherein R 8 is C 1 -G 2 alkyl, which are combined in any order, and the number of combined groups is up to 20; and R' is selected from where R" and R"' considered separately is C-^-C^Q alkyl or R" and R"' taken together is G-^-C-^q alkylene, where R"" is 0-20-4 alkoxy; 22. Process for the preparation of compounds according to claim 1, characterized in that for the preparation of the ester either) an N-substituted L-arginine is reacted with the gene real formula II with an alcohol of the general formula III where R' and R have the above meaning, in the presence of an acidic catalyst, or b) reacts the N -substituted L-arginine of the general formula II with the alcohol of the general formula III and a thiohalide, or c) reacts an L-arginine ester of the general formula V: with a sulfonyl halide of the general formula IV where R and R' have the meaning given above and X denotes a halogen atom, in the presence of a base, and to produce the N 2 -substituted L-argininamide d) reacts an L-argininamide of the general formula V, where R denotes a group of the general formula where R 2 , R 1 and Z have the meaning given above, with sulfonyl halide of the general formula IV in the presence of a base, or e) subject to an N-substituted N-substituted L-argininamide of the general formula IX where R' has the meaning mentioned above, R has the meaning given under d) and Y and Y' denote hydrogen atoms or guanidine protecting groups, where at least one of the residues Y and Y' is a guanidine protecting group, an acidolysis or hydrogenolysis, or f) reacts an N-substituted L-arginylhadSogenide with the general formula X where R' has the meaning given above and X denotes a halo gene atom, with an amine of the general formula R-H, where R denotes a residue of the general formula where Rg, R^ and Z have the meaning indicated above, or g) reacts an N p-substituted L-ornithine amide or et salt thereof with an acid of the general formula XI where R' has the meaning given above and R has the meaning given under d), with et. O-alkylisourea, S-alkylisothiourea, l-guanyl-3,5-dimethylpyrazole or carbodiimide, or h) reacts an N-substituted L-arginine ester with the general formula XII with an amine of the general formula XIII where Rg and R' have the meaning given above and Ry denotes a G1~G10 alkyl residue, and optionally transfer the compounds obtained according to points a) to h) to a salt by means of an acid.