CS228113B2 - Production of n2-arylsulphonyl-l-argininamides and their salts - Google Patents

Description

OKAMOTO SHOSUKE, ΚΟΒΕ, KIKUMOTO RYOJI, MACHIDA,

TAMAO YOSHIKUNI, YOKOHAMA, OHKUBO KAZU, MICHADA, TEZUKA TOHRU, YOKOHAMA, TONOMURA SHINJI, TOKIO,

HIJIKATA AKIKO, ΚΟΒΕ (Japan)

1. MITSUBISHI CHEMICAL INDUSTRIES LIMITED, TOKIO (Japan)

2. OKAMOTO SHOSUKE, ΚΟΒΕ (Japan) (54) Method for producing N ² -arylsulfonyl-L-argininamides and their salts

The present invention relates to a process for the preparation of N ² -arylsulfonyl-L-arginine amides and their non-toxic acid salts which can be used as anti-thrombosis agents due to their very low toxicity.

A variety of similar compounds are known to be useful in the treatment of thrombosis, for example, N ² - (p-tolylsulfonyl) -L-arginine esters are agents that effectively dissolve blood clots, as described in US Patent No. 3,622,615.

A special class of compounds which are highly specific thrombin inhibitors and are therefore suitable for the prevention of thrombosis are the esters or amides of N ² -dansyl-L-arginine.

However, a greater number of highly specific thrombin inhibitors are needed, especially those having low toxicity.

It has now been found that N ² -arylsulfonyl-L-arginine amides have both antithrombotic activity and very low toxicity at the same relative activity as N ² -dansyl-L-arginine esters or amides. These compounds can be represented by formula (I)

HN \

C — N — CH2CH2CH2CHCOR / 1 I,

HNN H HNSO2

Ar (I) where

R is

1.

R ¹ /

—N \

(CH ₂ ) _n COOR ₂ where

R1 is alkyl of 2 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthio228113 alkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms , C 1 -C 10 hydroxyalkyl, C 2 -C 10 carboxyalkyl, C 3 -C 10 alkoxycarbonylalkyl, C 3 -C 10 alkylcarbonylalkyl, C 1 -C 10 haloalkyl, C 7 -C 15 aralkyl, and -carboxyaralkyl of 8 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, optionally substituted with at least 1 to 5 carbon atoms and / or 1 to 5 alkoxy radicals 5-carbon atoms, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 to 5 carbon atoms, trahydro-2- (3- or -4-) pyranylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical, and / or (C 1 -C 5) alkoxy and tetrahydro-3-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical,

R @ 2 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms and 5-indanyl and n is an integer of 1, 2 or 3,

2.

R ₃

Z —N \

CH - (CH ₂ ) _m COOR ₅ R where

R 5 is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, hydroxyalkyl of 1 to 10 carbon atoms, carboxyalkyl of 2 to 10 carbon atoms, alkoxycarbonylalkyl of 3 to 10 carbon atoms, alkylcarbonylalkyl of 3 to 10 carbon atoms, haloalkyl of 1 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms , ω-carboxyaralkyl of 8 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, optionally substituted by at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 up to 5 carbon atoms, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 to 5 carbon atoms tetrahydro-2- (3- or -4-) pyranylmethyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical, and / or (C 1 -C 5) alkoxy and tetrahydro-3-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical,

R @ 1 represents alkyl of 1 to 10 carbon atoms, carboxyl, alkoxycarbonyl of 2 to 10 carbon atoms, phenyl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 to 5 carbon atoms, aralkyl of 7 up to 12 carbon atoms and benzyl substituted on the nucleus, wherein the substituent is an alkyl of 1 to 5 carbon atoms or an alkoxy of 1 to 5 carbon atoms,

R5 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms or 5-indanyl and m is an integer of 0, 1 or 2,

3.

where

R 6 is -COOR 6 wherein R 5 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and 5-indanyl,

R 7 is hydrogen, C 1 -C 10 alkyl, phenyl, C 1 -C 5 alkoxy or carboxy, p is an integer of 1 to 5,

Re is substituted in the 2 or 3 position,

R 7 may be substituted at the 2, 3, 4, 5 or 6 position,

4.

COOR * carbon, phenyl, optionally substituted with at least one of halogen, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, and C 2 -C 20 dialkylamino; (C až-Calkyl) aralkyl group or group, which group is optionally substituted by at least one C 5-C / alkyl group and / or C alko-Cyl alkoxy group wherein:

R 8 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and

5-indanyl and r is an integer of 1, 2, 3 or 4,

5.

-N Z W (City where

R 10 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and 5-indanyl,

Z represents an oxy group, a thio group or a sulfinyl group and q represents an integer of 0 or 1,

6.

where

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, C 7 -C 12 aralkyl and 5-indanyl; i is an integer of 0, 1 or 2, j is an integer of 0, 1 or 2, the sum of i + j is 1 or 2 and Ar is neiftyl, 5,6,7,8-tetrahydronaphthyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical , naphthyl, optionally substituted with at least one of halogen, nitro, cyano, hydroxyl, alkyl of 1 to 10 atoms; C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino

optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical, wherein:

R 12 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms or an alkoxy of 1 to 10 carbon atoms.

The pharmaceutically acceptable salts of the compounds are equally effective. These agents are useful for inhibiting the activity and activation of thrombin in vivo. This effect is achieved by administering an effective dose of a compound of formula I or a salt thereof.

The invention therefore relates to a process for the preparation of N ² -arylsulfonyl-L-argininamide of the formula I

HN '\

e_N — CH2CH2CH2CHCOR / ZZ11

HzN H HNSOz where R is 1 1 Ar (AND) R ¹ Z -N \

(CH ₂ ) _n COOR ₂ where

R1 is alkyl of 2 to 10 carbon atoms, ethyl, propyl, butyl, isobutyl, pentyl, and the like. hexyl, octyl, decyl, and the like, alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like, alkynyl of 3 to 10 (preferably 3 to 6) carbon atoms such as 2-propynyl, 2-butynyl, 3-butynyl and the like, alkoxyalkyl of 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms) such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, -ethoxyethyl,

2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl and the like, alkylthioalkyl of 2 to 10 (preferably 2 to 6) carbon atoms such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl,

3-methylthiopropyl, 2-methylthlopropyl, 3-ethylthiopropyl, 3-propylthlopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl and the like, alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl,

2-propylsulfinyl ethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl and the like, hydroxyalkyl of 1 to 10 (preferably 1 to 6) carbon atoms such as hydroxymethyl, 2-hydroxyethyl,

3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl and the like, carboxyalkyl of 2 to 10 (preferably 2 to 7) carbon atoms such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3- carboxypropyl, 1-carboxybutyl, 2-carboxybutyl,

4-carboxybutyl and the like, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to 8) carbon atoms, such as methoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl, 4-methoxycarbonylbutyl 3 to 10 carbon atoms, for example methylcarbonylmethyl and the like, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl,

4-chlorobutyl and the like, aralkyl of 7 to 15 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl and the like; carboxyaralkyl of 8 to 15 (preferably 8 to 12) carbon atoms such as α-carboxybenzyl, α-carboxyphenethyl and the like, cycloalkyl of 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl , C 4 -C 10 cycloalkylalkyl such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl and the like, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical carbon, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, tetrahydro-2- (3- or -4-) pyranylmethyl, eventually substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or alkoxy C 1 -C 5 radical, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, and tetrahydro-3 -thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, or substituted with pyranyl, R 2 represents hydrogen, C 1 -C 10 alkyl such as methyl, ethyl, propyl , butyl, tert-butyl, hexyl, aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl and n are an integer of 1, 2 or 3,

2nd group

R ₃

OF

-N \

CH (CH ₂ ) _m COOR ₅

Rš kde

R 5 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl and the like; alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like, alkynyl of 3 to (preferably 3 to 6) carbon atoms such as 2-propynyl, 2-butynyl, 3-butynyl and the like, alkoxyalkyl of 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms) such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl,

3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl and the like, alkylthioalkyl of 2 to 10 carbon atoms (preferably 2 to 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-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl and the like, alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2- propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl and the like, hydroxyalkyl of 1 to 10 (preferably 1 to 6) carbon atoms such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl and the like, carboxyalkyl of 2 to 10 (preferably 2 to 7) carbon atoms such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl and the like, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to 8) carbon atoms such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxybutyl, 4-methoxybutyl, 4-methoxybutyl, 4-methoxybutyl; 10 atoms carbon atoms such as methylcarbonylmethyl and the like, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloro. propyl, 2-chlorobutyl, 4-chlorobutyl and the like, aralkyl of 7 to 15 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2- phenylpropyl and the like, α-carboxyaralkyl of 8 to 15 (preferably 8 to 12) carbon atoms such as α-carboxybenzyl, α-carboxyphenethyl and the like, cycloalkyl of 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl or cyclodecyl, cycloalkylalkyl of 4 to 10 carbon atoms, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl and the like, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy C 1 -C 5 radical, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted by at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, tetrahydro-210

- (3- or -4-pyranylmethyl) optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one alkyl radical C 1 -C 5 and / or C 1 -C 5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or alkoxy radical; C1-C5 and tetrahydro-3-thenyl optionally substituted by at least one C1-C5 alkyl and / or C1-C5 alkoxy radical, R1 is C1-C10 alkyl (preferably 1-5) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and the like, carboxy, alkoxycarbonyl of 2 to 10 (preferably 2 to 5) carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like; , phenyl optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, aralkyl C 7-12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and on the nucleus substituted benzyl, wherein the substituent is alkyl of 1 to 5 (preferably 1 to 3) carbon atoms such as methyl, ethyl, propyl or isopropyl, or alkoxy of 1 to 5 (preferably 1 to 3) carbon atoms such as methoxy, ethoxy, propoxy or isopropoxy, R 5 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 10 carbon atoms such as phenyl, m -olyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl and m is an integer of 0, 1 or 2,

3.

(R j) p wherein R 6 is -COOR e, wherein R 5 is hydrogen, C 1 -C 10 alkyl such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 6 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl, (R 7) _D is hydrogen, alkyl of 1 to 10 (preferably 1 to 6) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl and the like, phenyl, C 1 -C 5 alkoxy or carboxyl, p is an integer of 1 to 5, R 6 is substituted at the 2 or 3 position and R 2 is optionally substituted at the 2, 3, 4, 5 or 6 position,

4.

COOR 5 optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical wherein R 9 is hydrogen, C 1 -C 10 alkyl such as methyl, ethyl, propyl, butyl, tert. butyl, hexyl, octyl, decyl and the like; aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like; aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like. and 5-indanyl ar is an integer of 1, 2, 3 or 4,

5. '

COOR _1CU

-NZ (CH 2 where

R 10 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl, Z is oxy (-O-), thioscycline (-S-), and sulfinyl ( —SO—), q is an integer of 0 or 1 and

6.

COORn where

R11 represents hydrogen, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like and 5-indanyl, i is an integer of 0, 1 or 2, j is an integer of 0, 1 or 2 and the sum i + j is 1 or 2, and Ar is naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or an alkoxy radical of 1 to 5 carbon atoms, such as 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl, naphthyl, substituted with at least one substituent from the group halogen, such as fluorine, chlorine, bromine and iodine, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, alkoxy of 1 to 10 {s you suitable for 1 to 5) carbon atoms such as methoxy, ethoxy, propoxyl, isopropoxyl, butoxyl, sec-butoxy, tert-butoxyl, pentyloxy and the like and a dialkylamino group of 2 to 20 (preferably 2 to 10) carbon atoms such as dimethylamino , diethylamino, N-methyl-N-ethylamino, and the like, phenyl, phenyl substituted with at least one of halogen, such as fluorine, chlorine, bromine and iodine, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 up to 5) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms such as methoxy, ethoxy, propoxyl, isopropoxyl, butoxyl, sec-butoxyl , t-butoxy, pentyloxy and the like, and a dialkylamino group of 2 to 20 (preferably 2 to 10) carbon atoms such as dimethylamino, diethylamino, N-methyl-N-ethylamino and the like, aralkyl of 7 to 12 (preferably 7 to 12) 10) carbon atoms such as benzyl, phenethyl and the like,

optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical wherein R 8 is hydrogen, C 1 -C 10 alkyl (preferably 1 to 5), such as methyl, ethyl, propyl and the like, or alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms such as methoxy, ethoxy, propoxyl and the like.

A suitable meaning of R 1 in formula I is an alkyl of 2 to 10 carbon atoms such as propyl, butyl, isobutyl, pentyl, hexyl and octyl, alkenyl of 3 to 6 carbon atoms such as allyl, alkynyl of 3 to 6 carbon atoms such as 2-propynyl , (2-6C) alkoxyalkyl such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, (2-6C) alkylthioalkyl such as 2-ethylthioethyl and 2-methylthioethyl, (2-6C) alkylsulfinylalkyl; carbon such as 2-methylsulfinylethyl, hydroxyalkyl of 1 to carbon atoms such as 2-hydroxyethyl and 3-hydroxybutyl, carboxyalkyl of 2 to carbon atoms such as 1-carboxybutyl, alkoxycarbonylalkyl of 3 to 8 carbon atoms such as 2-ethoxycarbonylethyl, aralkyl o From 7 to 10 carbon atoms, such as benzyl and phenethyl, α-carboxyaralkyl of 8 to 12 carbon atoms, such as n-carboxyphenethyl, cycloalkyl of 3 to 10 carbon atoms, such as cyclopropyl, cyclohexyl and cycloheptyl, cycloalkylalkyl of 4 to 10 carbon atoms, such as cyclohexylmethyl, furfuryl, tetrah hydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl.

Preferred R 3 in formula I is hydrogen, alkyl of 1 to 10 carbon atoms such as methyl, propyl, butyl, isobutyl, pentyl, hexyl and octyl, alkenyl of 3 to 6 carbon atoms such as allyl, alkynyl of 3 to 6 atoms carbon such as 2-propynyl, (2-6C) alkoxyalkyl such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, (2-6C) alkylthioalkyl such as 2-ethylthioethyl and 2-methylthioethyl, alkylsulfinylalkyl of 2 to 6 carbon atoms such as 2-methylsulfinyl ethyl, hydroxyalkyl of 1 to 6 carbon atoms such as 2-hydroxyethyl and 3-hydroxybutyl, carboxyalkyl of 2 to 7 carbon atoms such as 1-carboxybutyl, alkoxycarbonylalkyl of 3 to 6 carbon atoms such as 2-ethoxycarbonylethyl, aralkyl of 7 to 10 carbon atoms such as benzyl and phenethyl, N-carboxyaralkyl of 8 to 12 carbon atoms such as α-carboxyphenethyl, cycloalkyl of 3 to 10 carbon atoms such as cyclopropyl, cyclohexyl and cycloheptyl C 4 -C 10 cycloalkylalkyl, such as cyclo xylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl.

A suitable value for R4 in formula I is alkyl of 1 to 5 carbon atoms such as methyl, and propyl, carboxyl, alkoxycarbonyl of 2 to 5 carbon atoms such as ethoxycarbonyl, aralkyl of 7 to 10 carbon atoms such as benzyl and benzyl substituted on the nucleus, wherein the substituent is C 1 -C 3 alkoxy, such as 4-methoxybenzyl.

A suitable value for R 7 is hydrogen, alkyl of 1 to 6 carbon atoms, such as methyl, ethyl, propyl and isopropyl, phenyl and carboxyl, and a suitable position for R 7 is 2, 4 or 6.

Suitable groups

COOH dH ^ _Z ^ is 3-carboxy-4-morfollnový radical, 3-carboxy-4-thiomorpholine, 1-oxo-3-carboxy-4-thiomorpholino and 4-carboxy-3-thiazolidinyl.

Suitable groups

H 3 O are 2-carboxy-1,2,3,4-tetrahydro-1-quinolyl, 3-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, 1-carboxy-1,2,3,4 -tetrahydro-2-isoquinolyl, 2-carboxy-1-indolinyl and 1-carboxy-2-isoindolinyl.

Suitable meanings of R 2, R 5, R 6, R 9, R 10 and R 11 are hydrogen, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, tert-butyl, and octyl, aryl of 6 to 10 carbon atoms such as phenyl and m- tolyl, C7 -C10 aralkyl such as benzyl and 5-indanyl.

A suitable meaning of Ar in formula I is naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8 -tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halogen atom such as chlorine and bromine, hydroxy, alkyl of 1 to 5 carbon atoms such as methyl, ethyl, and isopropyl, alkoxy of 1 to 5 carbon atoms such as methoxy and ethoxy, C 2 -C 10 dialkylamino, such as dimethylamino and diethylamino, phenyl, phenyl substituted with at least one substituent selected from halogen, such as chlorine, C 1 -C 5 alkyl such as methyl, ethyl and isopropyl, and C 1 alkoxy up to 5 carbon atoms, such as methoxy, aralkyl of 7 to 10 carbon atoms, such as phenethyl,

Preferred Ar groups are 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5-chloro-1-naphthyl, 6- chloro-2-naphthyl, 6-bromo-1-naphthyl, 5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-naphthyl, 6-methyl-1-naphthyl, 7-methyl- 1-naphthyl, 7-methyl-2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl, 6,7-dimethyl-2-naphthyl, 6-isopropyl-2-naphthyl-5- methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl, 4,6-dimethoxy-2-naphthyl, 5-dimethylamino-1-naphthyl,

5-dimethylamino-2-naphthyl, 5-diethylamino-1-naphthyl, 6-dimethylamino-1-naphthyl, 6-dimethylamino-2-naphthyl, 4-chlorophenyl, 2,4,5-trichlorophenyl, p-tolyl, anisyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,

Examples of N ² -arylsulfonyl-L-argininamides having sufficient activity are:

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-propylglycine,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-propylglycine as tert-butyl ester,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine, tert-butyl ester N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine ,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-isobutylglycine,

N ^2- (8,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-hexylglycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-octylglycine,

N ² - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N ^2- (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N ² - (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-propylglycine,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-amininyl-N-butylglycine,

N ² - (7-Methyl-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,

N ² - (2-naphthylsulfonyl) -L-arginyl-N-butylglycine, N ² - (2-naphthylsulfonyl) -L-arginyl-N-butylglycine ethyl ester, N ² - (2-naphthylsulfonyl) -L- arginyl -N-butylglycine,

N- ^2- (2-naphthylsulfonyl) -L-arginyl-N-butyl- N-alanine,

N ² - (5,6,7,8-tetrahydro-1-naphthylsulphonyl) -L-arginyl-N-butylglycine,

N ² - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,

N ^2- (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N-butyl-5S-alanine,

N ^2- (6-bromo-1-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N ² - (6-methyl-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,

N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N ² - (5-dimethylamino-1-naphthylsulphonyl) -L-arginyl-N-butylglycine,

N ² - (6,7-dimethoxy-2-maphthylsulfonyl) -L-arginyl-N-allylglycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-propynyl) glycine,

N- ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, ethyl ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl -N- (2-methoxyethyl) glycine, N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine octyl ester,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as the benzyl ester,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine 3-methylphenyl ester,

N ^{; 2-} (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine 5-indanyl ester,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) -1S-alanine, N ² - (6,7-dimethoxy-2-haphtylsulfonyl) -L-arginyl- N- (2-methoxyethyl) -β-alanine,

N ^2- (6,7-Dimethoxy-2-naphthylsulfonyl) -N- (2-methoxyethyl) -N- (3-carboxypropyl) -L-arginine amide

N ^2- (6,7-diethoxy-2-naphthylsulphonyl) -N- (2-methoxyethyl) -N- (3-tert-butoxycarbonylpropyl) -L-argininamide,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -N- (3-methoxypropyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-ethoxyethyl) - β-alanine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxypropyl) glycine,

N ^2- (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ² - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as the ethyl ester,

N ² - (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ² - (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N- ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, ethyl ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N- ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) -alanine,

N ² - (1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ² - (5-chloro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (6-chloro-2-naphthylsulfonyl) -L-arginyl -N- (2-methoxyethyl) glycine,

N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ² - (7-methyl-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (6,7-dimethyl-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (5-dimethylamino-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ² - (7-hydroxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-ethylthloethyl) glycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl -N- (2-methylsulfinylethyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-hydroxyethyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-hydroxybutyl) glycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (1-carboxybutyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethoxycarbonylethyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine, tert-butyl ester N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N -benzylglycine,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl 1-N-phenylethylglycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzyl-1H-alanine, tert-butyl ester N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L- arginyl-N-benzyl- (1-alanine),

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arinyl-N-phenyl-5S-alanine,

N ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-phenylethylglycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-benzyl-5S-alanine,

N ^2- (6-methoxy-2-naphthylsulfonyl) -N-benzyl-N- (3-carboxypropyl) -L-argininamide,

N ^2- (6-methoxy-2-naphthylsulfonyl) -N-benzyl-N- (3-tert-butoxycarbonylpropyl) -L-argininamide,

N ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzylglycine,

N ^2- (2-naphthylsulfonyl) -L-arginyl-N-benzyl-5S-alanine,

N ² - (2-naphthylsulfonyl) -L-arginyl-N-benzylglycine, iW.

N ² - (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-phenethylglycine,

N ² - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine,

N ² - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-argininyl-N-benzyl-5S-alanine,

N ^2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (α-carboxyphenethyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl} -L-arginyl-N-cyklohexylmethylglycin, of N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyklohexylmethylglycinu,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cycloheptylglycine,

N ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,

N ^2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine,

N- ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethyl-5S-alanine, tert-butyl ester N- ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- cyclohexylmethyl-5S-alanine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexyl-4-alanine, tert-butyl ester N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L- arginyl-N-cyclohexyl-3-alanine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -N-cyclopropyl-N- (3-carboxypropyl) -L-argininamide,

N ² - (1-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,

N ^2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,

N ^2- (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -Larginyl-N-cyclohexylmethylglycine,

N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine,

N ^2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-furfurylglycine,

N ^2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-furfurylglycine, N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-furfurylglycine tert-butyl ester,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfuryl glycine,

N ² - (5-dimethylamino-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N ^2- (5-chloro-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

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N ² - (6,7-dimethyl-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N ² - (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine, tert-butyl ester N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine ,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-pentylalanine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylalanine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylalanine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylalanine,

N ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylalanine,

N ^2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-propylalanine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) alanine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginylnorvaline, N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylaparamic acid, N diethyl ester ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylasparagic acid, N - ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -1-arginyl-N-benzylasparagic acid, diethyl ester N ² - (6,7-dimethoxy-2-naphthylsulfonyl) - L-arginyl-N-benzylaparagine,

N ^2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-methyl-β-phenylalanine,

N- ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-methyl-N - (4-methoxyphenyl) alanine, 1- [N ² - (6,7-dimethoxy- 2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid, ethyl 1- [N ^2- (6,7-dixethoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylate, 1- [acid] N ^2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid 1- [N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4 methyl-2-piperidinecarboxylic acid 1- [N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N ² - (5-methoxy-1- naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, ethyl 1- [N ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate, acid 1 - [N ² - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N ² - (6,7-diethoxy-2-naphthylsulfonyl)] -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N ² - (6,7-dimethoxy-2-naphthyl) Ylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1 - [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-propyl-2-piperidinecarboxylic acid 1- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) 1-L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid 1- [N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -6-methyl-2-piperidinecarboxylic acid, acid 1 - [N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-methyl-2-piperidinecarboxylic acid 1- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L -arginyl] -3-piperidinecarboxylic acid methyl 1- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -3-piperidinecarboxylate 1- [N ² - (7-methoxy) 2-naphthylsulfonyl) -L-arginyl] -3-piperidinecarboxylic acid 1- [N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -2,6-piperidinecarboxylic acid 1- [N ^2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl] - 4-phenyl-2-piperidinecarboxylic acid 1- [N ² - (1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid ethyl-1- [N ² - (Imaphthylsulfonyl) - L-arginyl] -4-methyl-2-piperidinecarboxylate, 1- [N ^2- (2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid, ethyl 1- [N ² - (2-naphthylsulfonyl) -L-arginyl] -d-isopropyl-4-piperidinecarboxylate 1- [N ² - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4- Methyl 1-2-piperidinecarboxylic acid, ethyl 1- [N ² - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate, 1- [N ^2- (6-chloro-2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid 1- [N ^2- (5-dimethylamino-1-naphthylsulfonyl) -L-arginyl] - 2-piperidinecarboxylic acid 1- [N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N ² - (7-methyl-2- naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [ N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid, ethyl-1- [N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl] - 4-Isopropyl-2-piperidinecarboxylate, 1- [N ² - (6-methyl-2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid, 1- [N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -2-hexamethylenine-linkarboxylic acid 4- [N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -3-thiomorpholinecarboxylic acid,

4- [N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -3-carboxythiomorpholin-1-oxide, 4- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) acid] -L-arginyl] -3-morpholinecarboxylic acid 4- [N ² - (7-methoxy-2-naphthylsulphonyl) -L-arginyl] -3-morpholinecarboxylic acid 3- [N ² - (7-methoxy) -2-naphthylsulfonyl] -L-arginyl] -4-thiazolidinecarboxylic acid 2- [N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline -3-carboxylic acid 2- [N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] isoindoline-1-carboxylic acid,

N ^2- (4-chlorophenylsulfonyl) -L-arginyl-N-butylglycine,

N ^2- (2,4,5-trichlorophenylsulfonyl) -L-arginyl-N-butylglycine,

N ² -tosyl-L-arginyl-N-butylglycine

N ^2- (4-methoxyphenylsulfonyl) -L-arginyl-N-benzylglycine,

N ^2- (3,4-dimethoxyphenylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (3,4,5-trimethoxyphenylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ² -phenethylsulfonyl-L-arginyl-N-furfurylglycine

N ² - (1,4-benzodioxan-6-sulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (6,7-ethylenedioxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl] glycine, 1- [N ² - (2-dibenzofuranyl) -L-arginyl] - 2-piperidinecarboxylic acid.

Of the compounds of the invention, these compounds are particularly preferred because of their high antithrombotic activity and low toxicity

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N- ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, ethyl ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl -N- (2-methoxyethyl) glycine,

N ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N ² - (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -1-arginyl-N- (2-methoxyethyl) glycine,

N ² - (7-inoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrafluorofurylglycine,

N ^2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N- ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine, acid 1- [N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4- methyl-2-plperidinecarboxylic acid 1- [N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid and 1- [N ² - (7-methoxy-2- naphthylsulfonyl] -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid.

The invention also relates to a process for the preparation of pharmaceutically acceptable salts of these compounds.

It will be appreciated that the carbon atom of the compounds to which the carboxyl group or the ester group is attached may be asymmetric, so that the optically active isomers are formed, namely the D- and L-diastereoisomers and the racemic mixture thereof.

Compounds in the D configuration are more potent with respect to the efficacy of these compounds than the L compounds and the racemates, although these forms also have some antithrombotic activity. The above compounds have only been mentioned in order to show the structural differences of the compounds according to the invention.

The novel derivatives of L-arginine can be obtained by use of starting materials in which Ar is as hereinbefore defined and R represents a group of formula ^{C R} °° »

- r'V;

~ N ^ ( ^CR 12 ^} j where

Ru, i and j are as defined above.

Ar is as defined above and

X represents a halogen atom, with an amino acid derivative of the general formula. RH

where

R is as defined above, whereupon the reaction mixture is optionally hydrolyzed.

The compounds of formula I form addition salts with a variety of inorganic and organic acids. Many of these free carboxyl groups in which the above substituents are hydrogen form salts with a large amount of inorganic and organic bases.

The reaction products may be isolated in the free form or in the form of their salts. In addition, they can be obtained in the form of pharmaceutically acceptable addition salts by reacting the free substances with an acid such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic , benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic and the like. Similarly, the resulting product can be obtained in the form of a pharmaceutically acceptable salt by reacting some of the free carboxylic acids with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, N-ethylpiperidine and the like.

If the salt is treated with a base or an acid, the free amides can be recovered.

As mentioned above, the compounds of the formula I and their salts have a high specific thrombin inhibitory activity and at the same time a low toxicity, so that they can be used as diagnostic agents for the determination of thrombin in blood and / or for preventing and preventing thrombosis.

The compounds of the invention may also be used as platelet aggregation inhibitors.

The antithrombotic activity of N ² -arylsulfonyl-L-argininamide according to the invention was compared with that of the known antithrombotic substance, N ² - (p-tolylsulfonyl) -L-arginine methyl esters by determining the clotting time influenced by fibrinogen.

0.8 ml of the fibrinogen solution prepared by dissolving 150 mg of bovine fibrinogen (Cohn Fraction I) in 40 ml of borate buffer pH 7.4 is mixed with 0.1 ml of borate buffer pH 7.4 in the case of a control solution or sample in the same buffer, and 0.1 ml of 5 units / ml thrombin solution is added to both solutions in the ice bath.

Immediately after mixing, the reaction mixture was transferred from an ice bath to a 25 ° C bath. The coagulation time is measured as the time from transfer to a 25 ^° C bath until the first appearance of fibrin substances. If no drug was added, this was a period of 50 to 55 seconds. The experimental results are given in Table I. The term "concentration", which is required to double the coagulation twice, means the concentration of the active substance; which increases the coagulation time from 50 to 55 seconds to 100 to 110 seconds.

This coagulation time is achieved using the known antithrombotic agent, i.e., N ² - (p-tolylstilphonyl) methyl ester. L-arginine in an amount of 1100 μπιοΚ The inhibitors of the invention are compared in this respect in Table I with the substituents R and Ar and addition groups.

In case the solution of the compound; according to the invention administered intravenously, maintaining high antithrombotic activity in the circulation for 1 to 3 hours. Half-life; The anti-thrombotic compounds of the invention in the bloodstream are approximately 60 minutes. There was no violation of other physiological processes in experimental animals such as rat, dog, and chimpanzee. The experimental decrease in fibrinogen in animals caused by the infusion of thrombin was satisfactorily compensated by the simultaneous infusion of the compounds of the invention.

The LD 50 values for the compounds of the invention are shown in the table:

Compound LD 50 (mg / kg)

N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-butylglycine> 1500

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine 1900-2400

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-ethoxyethyl) -α-alanine 680-1000

N- ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxy ethyl) glycine 860-1000

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginy 1-N- (2-methoxyethyl) glycine 2000

N- ^2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine> 1500

N ² - (6,7-Dimethyl-1-naphthylsulfonyl-L-arginyl-N- (2-methoxyethyl) glycine> 1500

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) glycine> 1000

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine> 1000 s

Compound LD 50 (mg / kg)

N ² - (4,6-dimethoxy-2-naphthylsulfonyl) -1-arginyl-N-benzylglycine> 1000

N ² - (5-methoxy-1-naphthylsulfonyl) - L-arginy 1-N-benzylglycine> 1000

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine> 1500

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine> 1500

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine> 1500

N ^2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine 600

N ² - (6,7-idimethoxyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine 620

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylanine> 1500

N ² - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginy 1-N-cyclohexylmethylalanine> 1500 1- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -1-arginyl} -2 -piperidinecarboxylic acid 1500 ethyl 1- [N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate 670-1000 1- [N ² - (4,6-dimethoxy- 2-naphthyl, sulfonyl-1-L-arginyl] -4-methyl-2-piperidinecarboxylic acid 670-1000 1- [N ² - (1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 700- 1000 1- [N ² - (5-dimethylamino-1-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid 700-1000 4- [N ² - (7-methoxy-2-Biphenylsulfonyl) -L-arginic acid 1} -3-morpholinocarboxylic acid> 1000 (N - [(4-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid> 1000

Compound LD50 (mg / kg) 2- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1-isoindolinecarboxylic acid> 1000

Acute toxicity was determined by intraperitoneal administration of compounds of Formula I to male mice weighing 20 g in the range of 1000 to 10,000 mg / kg body weight.

On the other hand, the LD 50 values for the N ² -dansyl-N-butyl-L-argininamide, and N ² -dansyl-N-methyl-N-butyl-L-argininamide 75 and 70 mg / kg.

The compounds of the invention may be administered as such or together with pharmaceutically acceptable carriers depending on the solubility and chemical nature of the active ingredient, the route of administration and other factors. The compounds of the invention may be administered intramuscularly, intravenously or subcutaneously in the form of sterile solutions containing other ingredients, for example sodium chloride or glucose, to achieve isotonicity of the solution. For oral administration, tablets, capsules or granules containing starch, lactose, sucrose and the like may be used. Sublingual administration is particularly possible when the active ingredient is mixed with sugar or corn syrup, flavorings and colorants, followed by dehydration and compression. When administered orally, these solutions usually contain flavoring and coloring agents. The appropriate dose and route of administration will be determined by the physician. For oral administration, it is usually possible to administer a greater amount or more effective compound to achieve the same effect as parenteral administration. The effective dose is usually 10 to 50 mg / kg parenterally or 10 to 500 mg / kg orally. Suitable dosage forms and dosages are particularly indicated in the Examples.

The invention will be illustrated in the examples below.

Example 1

A. N ^2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginine

To a solution of 83.6 g of L-arginine in 800 ml of 10% potassium carbonate was added 114.7 g of 6,7-dimethoxynaphthalenesulfonyl chloride in 800 ml of benzene with vigorous stirring. The reaction mixture was stirred at RT. at 60 ° C for 5 hours, after which time the precipitate after one hour at room temperature the filtered and washed successively with benzene and water to give in 76% yield gave 129 g of N ² - (6,7-dimethoxy-2-naphthylsulfonyl onyl) -L-arginine, m.p. 252-255 ° C.

Β. N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl chloride

A suspension of 2.00 g of N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginine in 200 ml of thionyl chloride was stirred at room temperature for 2 hours. Addition of cold anhydrous diethyl ether gives a precipitate which is collected by filtration and washed several times with anhydrous diethyl ether to give N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl chloride.

C. tert-Butyl N @ ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine

To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20 mL of chloroform was carefully added the above-obtained N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl chloride. The reaction mixture was allowed to stand at room temperature for one hour and then washed twice with 20 ml of saturated sodium chloride solution and then evaporated to dryness.

The residue was triturated with a small amount of water to give a crystalline material which was collected by filtration and recrystallized from ethanol / ethyl ether to give 2.28 g of N ² - (6,7-dimethoxy-2) tert -butyl ester in 82% yield. 164 DEG-166 DEG C. (naphthylsulfonyl) -L-arginyl-N-butylglycine.

The infrared spectrum in KBr has peaks at 3390, 3165, 1735, 1370 cm ^-1 . Analysis for G28H43O7N5S. V2 H2SO3: calculated:

% H, 7.00%, N 11.04%, found ·

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 as tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% hydrochloric acid in ethyl acetate. The reaction mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was evaporated to dryness, the residue was washed several times with anhydrous diethyl ether and then chromatographed on 80 ml of 200-300 mesh anion-exchange resin (Daiaion ^(R) SK 102 in H ⁺ form) in water. Rinse with water and then elute with 3% ammonium hydroxide solution.

The fractions thus obtained were evaporated to dryness to give 1.43 g of N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine as an amorphous solid in 79% yield.

The infrared spectrum in KBr has peaks at 3360, 3140, 1622 cm ^-1 . Analysis for C24H35N5O7S:

calculated:

% C, 53.62;% H, 6.56;% N, 13.03%.

53.48%, 6.43% Η, 12.98% Ν.

Accordingly, the following compounds can be obtained:

N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-butyl- (3-alanine),

N ^2- (7-methyl-2-naphthylsulfonyl) -N- (2-methoxyethyl) -N- (3-carboxypropyl) -L-argininamide,

N ² - (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,

N ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine as the tert-butyl ester,

N- ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) - N-alanine,

N ² - (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,

N ² - (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -N- (2-methylthioethyl) -N- (3-carboxypropyl) -L-argininamide,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -N- (3-methylthiopropyl) glycine,

N- ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) -N-alanine benzyl ester N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L- arginyl-N-benzylglycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl-N-benzyl-N- (3-tert-butoxycarbonylpropyl) -L-argininamide),

N ² - (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine, 4-N- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl ] -N-cyclohexylaminobutyric,

N- ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethyl- [3-alanine],

N ^2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-phenylpropyl) glycine,

N ² - (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzyl- β-alanine,

N ² - (3-nitro-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N ² - (7-hydroxy-2-naphthylsulfonyl) -1-arginyl-N-tetrahydrofurfurylglycine,

N ^2- (5-cyano-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -1-arginyl-N-tetrahydrofurfuryl-1-alanine,

N ^2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfuryl-5-alanine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylalanine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -N- (3-carboxypropyl) -N-tetrahydrofurfuryl-L-argininamide,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-pentylalanine,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-argin-1-N-isobutyl lalanine,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylalanine,

N ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-butylalanine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-phenylpropyl) alanine,

N ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzylalanine,

N ^2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexylalanine,

N ^2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexylmethylalanine,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-butylbutyrine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-furylmethyl) glycine,

N ² - {6,7-dimethoxy-2-naphthylsulphonyl-L-arginyl-N- {tetrahydro-3-furylmethyl} glycine,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) L-arginyl-N- (2-thenyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) L-arginyl-N- (2-acetylethyl) glycine,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (4-methoxyfuryl) glycine,

N ^2- (7-methyl-2-naphthylsulphonyl) -L-arginyl-N- (5-methylfurfuryl) glycine,

N ^2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (1,4-dioxacyclohexylmethyl) glycine,

1- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-methoxypiperidine-2-carboxylic acid 1- [N ² - (6,7-dimethoxy-2-naphthyl) Tylsulfonyl) -L-arginyl] -3-methylhexamethylenimine-2-carboxylic acid, 1- [N ^2- (3,7-dimethyl-2-dibenzofuranyl) -L-arginyl] -4,4-dimethyl-2-piperidinecarboxylic acid,

N ² - (3-methoxy-3,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N- (tetrahydro-2-pyranylmethyl) glycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-thenyl) glycine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N (tetrahydro-2-thenyl) glycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (tetrahydro-3-thenyl) glycine.

Example 1 a d 2

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

A suspension of 2.5 g of N ² - (6-methoxy-2-naphthylsulfonyl) -L-arginine in 20 ml of thionyl chloride was stirred at room temperature for 2 hours. Addition of anhydrous cold diethyl ether gave a precipitate which was washed on the filter several times with anhydrous ethyl ether to give N ² - (6-methoxy-2-naphthylsulfonyl) -1-arginyl chloride.

B. Ethyl 1- [N ² - [6-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylate

To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform was added portionwise the above-obtained N ² -6-methoxy-2-naphthylsulfonyl) -L- with cooling in an ice bath. arginylchloride. The reaction mixture is stirred overnight at room temperature, then 500 ml of chloroform are added and the chloroform solution is washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 2.9 g of powdery ethyl 1- [N ² - (6-methoxy-2-naphthylsulphonyl) -1-arginyl] -2-piperidinecarboxylate.

For analytical purposes, a portion of this product is converted to a flavinate of m.p. 192-193 ° C.

The infrared spectrum in KBr has maxima at 3210, 1747, 1638 cm ^-1 .

Analysis for C25H36O6N5S. C 10 H 15 O 5 N 2 S: calculated:

% C, 49.58;% H, 4.87;% N, 11.56.

49.24 _0/0 C, 4.70% H, 11.85% N.

C. 1- [N ² - (6-Methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid

A solution of 1.8 g of ethyl 1- [N ² -6-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2 N sodium hydroxide solution is heated to 60 ° C. ° C and held at this temperature for 10 hours. The reaction mixture is concentrated and chromatographed on 200 ml of 200-300 mesh ion exchange resin (Daision ^(R) SK 102 in H + form) in water, washing the column with ethanol / water 1: 4 and then ethanol / water. The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of 1- [N ² - (6-methoxy-2-naphthylsulfulfate) as an amorphous solid. onyl) -L-arginyl] -2-piperidinecarboxylic acid.

The KBr infrared spectrum has peaks at 3200, 1620, 1150 cm ^-1 . Analysis for C23H31O6N5S:

calculated:

% C, 54.64;% H, 6.18%;

% H, 6.31;% N, 13.83.

Accordingly, the following compounds can be obtained:

N ^2- (6-chloro-2-naphthylsulfonyl-L-arginyl-N-butylglycine),

N ⁱ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N- (2-ethoxyethyl J glycine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,

N ² - (4,6-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methylthioethyl) glycine,

N ² - (4,6 * dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethyl-1-alanine,

N ² - (6,7-dimethoxy-2-naphthylsulphonyl) -N-benzyl-N- (3-carboxypropyl) -L-argininamide,

N ^2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexylnorleucine,

N ^2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-butylisoleucine,

3β

Ν ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-pentylbutyrine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine,

N ^2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-cycloheptylalanine,

N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) alanine,

N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethoxyethyl) alanine,

N ² - (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexyl-, S-alanine,

N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) norvaline,

N ^2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylleucine, 1- [N ^2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl] -4-ethyl-2 -piperidinecarboxylic acid 1- [N ² - (6-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N ² - (4,6-dimethoxy-2-naphthylsulfonyl) 1-L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N ^2- (5-ethoxy-1-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [ N- ^2- (7-ethoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N ^2- (6,7-diethoxy-2-naphthylsulfonyl) -L- arginyl] -4-ethyl-2-plperidinecarboxylic acid, 1- [N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-tert-butyl-2-piperidinecarboxylic acid, phenyl-1- [ N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylate, benzyl 1- [N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] - 4-ethyl-2-piperidinecarboxylate, benzyl 1- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-a 4-Methyl-2-piperidinecarboxylate, 1- [N ² - (5-nitro-1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-plperidinecarboxylic acid, 1- [N ² - ( 7-hydroxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-plperidinecarboxylic acid 1- [N ^2- (5-cyano-1-naphthylsulfonyl) -L-arginyl] -4-methyl- 2-Plperidinecarboxylic acid 1- [N ² - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N ² - (5-dimethylamino-1- naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N ^2- (2-iniaphylsulfonyl) -L-arginyl] -4-ethyl-2-plperidinecarboxylic acid 1- [ N ² - (5,8,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N ² - (5-dimethylamino-1-naphthylsulfones) 1-L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N ² - (7-methyl-2-naphthylsulphonyl) -L-arginyl] -6-methyl-2-piperidinecarboxylic acid 1- [N ² - (7-Meithy-2-inaphthylsulfonyl) -L-arig 1- [N ^2- (5-nitro-1-phthylsulfonyl) -L-arginyl] -indoline-2-carboxylic acid, 2- [N ² - (5- cyano-1-naphthylsulfonyl) -L-arginyl] isoindoline-1-carboxylic acid, 1- (N ² - (7-meithyl-2-inaphthylsulfonyl) -L-arginyl Jithiourofoline-3-carboxylic acid, 4 - [ ^with N - (6,7-dim »methyl-2-naphthylsulfonyl) -L-arginyl] morpholin-3-karboixylová,

4- [N ² - (5,6,7,8-tetrahydro-2-naphthylsulphonyl) -L-arginyl] -3-carboxythiomorpholine-1-oxide, 4- [N ² - (7-meithyl-2-naphthylsulfonyl) -acid onyl) -L-arginyl] morpholin-3-carboxylic acid 4- (Kf ^2- (7-chloro-2-naphthylsulfonyl) -L-argininyl) morpholin-3-carboxylic acid 4- [N ^2- (7-hydroxy-2-naphthylsulfonyl) -L-arginyl] morpholin-3-carboxylic acid 4- [N ^2- (5-nitro-2-naphthylsulfonyl) -L-arginyl] thiomorpholinyl-3 -carboxylic acid, 4- [N ² - (5-cyano-1-naphthylsulphonyl) -L-arginyl] thiomorpholine-3-carboxylic acid, 4- [N ² - (5-methoxy-1-naphthylsulfonyl)] -L-arginyl] morpholine-3-carbonyl-ethyl-4- [N ^2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl] morpholine-3-carboxylate, 4- N ^2- (5-ethoxy-1-naphthylsulfonyl) -L-arginyl] morpholine-3-carboxylic acid 4- [N ² -15-dimethyliamino-1-naphthylsulphonyl) -L-airginyl-thiomorpholin-3 -carboxylic acid, 3- [N ² - (1-naphthylsulfonyl) -L-arginyl] thiazolidinyl-4-carboxylic acid 2- [N ^{: 2-} (7-methoxy-2-naphthylsulfomyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid seline, 2- [N ² - (7-methoxy) -2-naphthylisulfonyl 1-L-arginyl] isoindoline-1-carboxylic acid 2- [N ² - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, 2- [N ² -15-methoxy-1-naphthylsulfonyl) -L-arginyl] isoindoline-1-carboxylic acid, and 2- [N ² - (5-ethoxy-1-naphthylsulfonyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Example 3

A. N ^2- (6,7-Dimethoxy-2-inaphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycyl chloride hydrochloride

A suspension of 2.00 g of N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine in 20 ml of thionyl chloride was stirred at room temperature for 2 hours. Addition of cold anhydrous ethyl ether gave a precipitate which was collected by filtration and washed several times with anhydrous ethyl ether to give N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycylchloride hydrochloride.

B. N ² - (6,7-Dimethylthioxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine m-iolylester hydrochloride

Srqěs 2.00 g of m-cresol and N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- [2-methoxyethyl] glycylchlocidhydrochloridu obtained as described above was heated to ^90? C 50 mimt. At the end of this time, the reaction mixture was cooled, washed several times with anhydrous ethyl ether and then dissolved in 10 ml of anhydrous ethyl alcohol. Addition of cold anhydrous ethyl ether gave a precipitate which was washed several times with anhydrous ethyl ether to give a powder (86% yield).

2.12 g of N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as the m-tolyl ester hydrochloride.

The infrared spectrum in KBr has maxima at 3250, 3100, 1740, 1640 cm ^-1 .

The following compounds can be prepared accordingly:

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) glycine as the phenyl ester, N ² - (6,7-dimethoxy-2-ouftylsulfonyl) -L- arginyl-N- (2-ethyithioethyl] glycine fenyleslter N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-íarginyl benzylglycimu N-benzyl N ² - (6,7-dimethoxy-2-naftylsu, 1-Onyl] -L-airginyl-Nf urfurylglycine, N ^2- (6,7-dimethoxy-2-naphthylphenylsulfonyl) -L-arginyl-N-tetrahydrofuranofurylglycine, phenyl-1- [N ² - (7-meithyl- 2-onyl maftylsulf] -L-arginyl] ^{-4-ethyl-2-piperidinyl;} pyridinecarboxylate benzyl-1- [N ² - (7-met hyl-2-naftylsulf) -L-arginyl] -4-ethyl- 2-piperidinecarboxylate, benzyl 1- [N ² - (6-chloro-2-uphthylsulfoinyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate and ethyl 4- [N ² - (7-methyl-2-) methylsulfonyl) -Liarginyl] methyl-3-carboxylate.

Further N ² -arylsulfonyl-L-arginine amides or addition salts thereof were obtained by the method of the previous examples. The results are shown in Table I below:

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N ² - (7-methoxy-2-naphthyl- sulfonyl 1 -L-arginyl-N- - (2-methoxyethyl) glycine 250 lactose maize starch talc 20 Magnesium stearate Total 450 Example 1 a d 5 Capsules for oral administration Capsules for oral administration may be formed from the following mixture so that the components mixed and filled into hard gelatin capsules:. ' Amount Folder on the capsule mg N ² - (7-methoxy-2-naphthylsulfonyl) - N -L-arginyl-N- (2-metho- xyethyl jglycine 250 lactose 250 Total 500 Example 6 Sterile solution for infusion The following components are dissolved in water for intravenous use and the solution is sterilized: Amount Folder in g N ² - (7-methoxy-2-naphthylsulphonyl) - nyl) -L-arginyl-N- (2-metho- xyethyl jglycine 25 buffer as needed glucose 25 distilled water 500

Preparation

Ar ylsulfonyl chlorides

A. Sodium 6,7-dimethoxy-2-naphthalenesulfonate

To an vigorously stirred solution of 70.8 g

Sodium 6,7-dihydroxy-2-naphthalenesulfonate a

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38.8 g of sodium hydroxide and the mixture was further stirred at room temperature for 1 hour. After this time, the precipitate was filtered off, washed with ethanol and dried, yielding 50 g of sodium 6,7-dimethoxy-2-naphthalenesulfonate.

B. 6,7-Dimethoxy-2-naphthalenesulfonyl chloride

To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide was added dropwise 62.2 ml of thionyl chloride at room temperature. After 30 minutes, the reaction mixture was poured into 1 liter of crushed water and the resulting precipitate was collected by filtration and dissolved in 250 ml of benzene. The benzene solution was washed several times with water and then dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo and the residue was recrystallized from benzene / n-hexane (1: 1) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, m.p. 127.5-129.5 ° C. .

Analysis for C12H11O4SCI:

calculated:

% C, 50.26;% H, 3.87;% Cl, 12.37.

% C, 50.45;% H, 4.00;

The following table lists the arylsulfonyl chlorides not previously described in the literature, which are obtained by a process which is essentially identical to that of publication Ε. H. Rood, &quot; Chemistry of Carbon Compounds &quot;, Elsevier Publishing Company, 1954, Vol. III, pp. 441 to 469:

Melting point (° C)

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Preparation

Amino acid derivatives

A. N-Butylglycine tert-butyl ester

To 36.5 g of butylamine is added, with stirring, 15.05 g of tert-butyl chloroacetate over a period of 30 minutes, maintaining the temperature of the mixture between 30 and 70 ° C. The mixture was then heated at 70 ° C for an additional hour. At the end of this time, the excess butylamine was removed in vacuo and the residue was treated with 40 ml of 2 N sodium hydroxide solution and 50 ml of benzene, transferred to a separatory funnel, separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of the benzene fraction, the residue is distilled under reduced pressure to give 17.0 g of N-butylglycine tert-butyl ester of boiling point 76 ^DEG C. (0.5 mm Hg) at 90.9% yield.

In a similar manner, the following tert-butyl amino acid esters were obtained, which have not been described in the literature. The procedure is essentially the same as that of A. J. Special et al., J. Org. Chem. 23, 731 (1960).

Number Amino acid derivative Boiling point ° C / Pa 1 (CH 2) 2 CH 3 / HN 95/2666 \ CH2CO2-t-C4Hfl •• -.- u.-ait ... · ..- 2 CH 2 CH (CH 3) 2 of HN 65 / 666.6 3 \ CH2CO2-t-C4H9 (CH 2) 4 CH 3 of HN 89 to 90 / 333.3 4 \ CH2CO2-t-C4H9 (CH 2) 5 CH 3 / HN 83 to 85/200 5 \ CH2CO2-C1-C4H9 (CH 2) 7 CH 3 of HN 125 to 130 / 533.3 \

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Number Amino acid derivative Boiling point ° C / Pa CH2CH2OCH3 OF 6 HN \ CH2CO2-t-C4H9 CH2CH2OCH3 of 61 to 62 / 266.6 7 HN \ CH2CH2CO2-t-C4H9 CH2CH2OCH3 of 94/400 8 HN \ CH2CH2CH2CO2-t-C4H9 CH2CH2CH2OCH3 of 60 to 63/400 9 HN \ CH 2 CO 2 -t-C 1 H 8 CH2CH2OCH2CH3 OF 95 to 97 / 666.6 10 HN \ CH2CH2CO2-t-C4H9 102 / 533.3 11 CH2CH2SCH2CH3 of 166 / 1333.2 12 HN \ CH2CO2-t-C4H9 CH2CH2SCH3 of 106 to 109/200 13 HN CH2CO2-t-C4H9 97 / 333.3 14 HN CH ^H ^H HC ^ t-C ^ 7 101 / 666.6 15 Dec HN 101 / 666.6

amino acid derivative

Boiling point ° C / Pa

16 HN 105 / 533.3 17 »« P 129-130 / 1066.6 18 ( ^CH X 3 HN? CH? CO? 1? H? / ^CH 2 -O) 145 / 1999.8 19 Dec Η N (CH 2) 2 CH 3 / HN X CHCO2-t-C4He 1 CH3 (CH 2) 3 CH 3 156 / 1333.2 20 May 93 / 3466.4 21 HN 110 / 3599.7 \ \ CHCO2-t-C4.H9 CH3 (CH2) 4CH3]. 22nd HN. . X CHCO2-t-C4Hfl [ CH3 CH2CH2OCH3. . of ' / . 124 / 3566.4 23 HN X CHCO 2 -t-C 4 H 9 CH3 88 to 90/800 24 XcHCOj HN-T-X, CH _3, 116-118 / 266.6

Number Amino acid derivative Boiling point ° C / P aCH ₂ CH _{from -} no

25 HN 167 / 2133.2 CHCO ₂ -t CH ₃ Ό 26 HN ^CHCO ^ tCCHgCH ₃ · ^CH irOO 125 / 2133.2 27 Mar: HN ~ '''' tC CHCO ₂ ^CH ₃ H _LF i (CH2) 3CH3 Z 141 / 1999.8 28 HN \ CH 2 CH 2 CO 2 -t-CuHe / CHjZoJl 89/400 29 HN = CH ₂ CO ₂ -t-C 4 H _s 111 / 133.3 30 HN - CH 2 CO 4 -CH 2 Hg CH2CH2CO2C2H5 / HN \ CH2CO2-t-C6H9 OH CH2CH2CHCH3 OF 91 to 92 / 133.3 31 115 / 266.6 32 HN \ CH2CO2-t-C4H9 CH2CH2SOCH3 of 82 to 84 / 266.6 33 HN 1 -, CH ₂ CO ₂ -t-C ₄ H ₉ 150 / 66.7

Boiling point ° C / Pa

Number Amino acid derivative

CH2CH2OH

OF

HN 95 to 96 / 266.6 \

CH2CO2-t-C4H9

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HN \

CtoCO2-t-CaHg ...........

Claims (12)

SUBJECT 1. R 3 by using the starting materials of the above formulas, wherein Ar and X are as defined above and R is a group of the formula OF. · . Z. R2 '(Z, - <Z). —N \ CHCOOR4 R3 wherein R2, R3 and R4 are as defined above. A process for the preparation of N ² -arylsulfonyl-L-arginine amides and their salts of the general formula I HN C — N — CH2CH2CH2CHCOR From 1 1 HNSO2 Ar H2N H means Rt OF -N \ (CH 2) _n COOR 2 where R 1 represents alkyl of 2 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2. The process of item 1 for the preparation of compounds of the general formula HN H Rl V I Z C — N-CH2CH2CH2CHCON Z I \ H 2 _N HNSO 2 (CH 2) _n -COOR 2 Ar kde Ar is a naphthyl group substituted with an alkoxy group having 1 to 5 carbon atoms, R1 is alkyl of 2 to 10 carbon atoms or alkoxyalkyl of 2 to 10 carbon atoms, R2 represents a hydrogen atom or an alkyl of 1 to 10 carbon atoms and n represents an integer of 1, 2 or 3 as well as pharmaceutically acceptable salts of said compounds, characterized in that starting materials of the above formulas are used in which Ar and X is as defined above and -R represents a group of the general formula Rl ^f Z '—N \ _{(CH2) n} -COOR 2 wherein R, R2 and n are as defined above. 2. R ₃ - Z —N \ CH - (CH ₂ ) _m COOR ₅ R ₄ where R3 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an alkenyl of 3 to 10 carbon atoms, an alkynyl of 3 to 10 carbon atoms, an alkoxyalkyl of 2 to 10 carbon atoms, an alkylthioalkyl of 2 to 10 carbon atoms, an alkylsulfinylalkyl of 2 to 10 carbon atoms, hydroxyalkyl of 1 to 10 carbon atoms, carboxyalkyl of 2 to 10 carbon atoms, alkoxycarbonylalkyl of 3 to 10 carbon atoms, alkylcarbonylalkyl of 3 to 10 carbon atoms, haloalkyl of 1 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms , .alpha.-carboxyaralkyl of 8 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, optionally substituted by at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 up to 5 carbon atoms, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally 45 »substituted by at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, tetrahydro-2- (3- or -4- (pyranylmethyl), optionally substituted by at least one C 1 -C 5 alkyl radical carbon and / or C 1 -C 5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, 2-ethyl 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy and tetrahydro-3-thenyl optionally substituted with at least one C 1 -C 5 alkyl radical 5 carbon atoms and / or (C 1 -C 5) alkoxy radical, R a is C 1 -C 10 alkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, phenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, and C 7 -C 8 aralkyl. 12 carbon atoms and benzyl substituted on the core, wherein the substituent is an alkyl of 1 to 5 carbon atoms or an alkoxy of 1 to 5 carbon atoms, R 5 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, or 5-indanyl and m is an integer of 0, 1 or 2, 2 to 10 carbon atoms, 2 to 10 carbon atoms alkylsulfinylalkyl, 1 to 10 carbon atoms hydroxyalkyl, 2 to 10 carbon atoms carboxyalkyl, alkoxycarbonylalkyl groups 3. The process of item 1 for producing compounds of formula HN H Ri \ I Z C — N — CH2CH2CH2CHCON Z I \ H2N HNSO2 (CH2) _n —COOR2 Ar 491 where Ar is naphthyl substituted with at least one C 1 -C 5 alkoxy group, R1 represents arylalkyl of 7 to 15 carbon atoms, R2 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an aryl of 6 to 10 carbon atoms or an arylalkyl of 7 to 12 carbon atoms and n is an integer of 1, 2 or 3 as well as pharmaceutically acceptable salts thereof; The method according to claim 1, wherein the starting materials of the above formulas are used, in which Ar and X are as defined above and R is a group of the formula Ri / —N \ (CH 2 '- COOR 2 wherein R 1, R 1 and n are as defined above). 3. (R ^ p where R 6 is -COOR 6 wherein R 8 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and 5-indanyl, R 7 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, phenyl, an alkoxy group of 1 to 5 carbon atoms or a carboxy group, p is an integer of 1 to 5, R 6 is substituted in the 2 or 3 position, R 7 may be substituted at the 2, 3, 4, 5 or 6 position, C 3 -C 10 alkylcarbonylalkyl, C 1 -C 10 haloalkyl, C 7 -C 15 aralkyl, C 8 -C 15 aralkylcarboxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl C 4 -C 10 furfuryl, tetrahydrofurfuryl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one alkyl radical C 1 -C 5 and / or C 1 -C 5 alkoxy, tetrahydro-2- (3 or -4-pyranylmethyl), optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical carbon atoms, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted by at least one alkyl radical of 1 to 5 carbon atoms and / or an alkoxy radical of 1 to 5 atoms carbon, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, and tetrahydro-3-thenyl optionally substituted at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical, R2 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an aryl of 6 to 10 carbon atoms, an aralkyl of 7 to 12 carbon atoms, and 4. The process of item 1 for producing compounds of formula HN H R 1 \ _M ^Z C - N - CH 2 Cl 2 CH 2 CHCON HzN HNSO2 Ar kde Ar is naphthyl substituted with at least one C 1 -C 5 alkoxy group, R 1 represents alkylthioalkyl of 2 to 10 carbon atoms, R2 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an aryl of 6 to 10 carbon atoms or an arylalkyl of 7 to 12 carbon atoms and n is an integer of 1, 2 or 3 as well as pharmaceutically acceptable salts thereof; in that Ar and X are as defined above and R is a group of the general formula R 1 (CH ₂ ) _{n -} COOR 2 wherein Ar represents naphthyl substituted by at least one alkoxy of 1 to 5 carbon atoms, R 7 represents a hydrogen atom or an alkyl of 1 to 10 carbon atoms, R e is -COOR 6 wherein R e is C 1 -C 10 alkyl, C 6 -C 10 aryl or C 7 -C 12 arylalkyl, wherein R 7 may be substituted at the 2, 3, 4, 5 or 6 position and Re at position 2 or 3, as well as pharmaceutically acceptable salts thereof, characterized in that the starting materials of the above formulas are used, in which Ar and X are as defined above and R is a group of the formula (CH 2 - COOR 2) wherein R1, R2 and n are as defined above. 4. wherein said group is optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical wherein the C 1 -C 5 alkyl radical wherein R 9 is hydrogen, C 1 -C 10 alkyl aryl, C 6 -C 10 aryl, C 7 -C 12 aralkyl, and 5. The process of item 1 for producing compounds of formula ¹⁴ HN H / -R d1-C ^CH ^CWCON ^J HNSO- T Ar ¹ wherein R 6 and R 7 are as defined above. 5. where R 10 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and 5-indanyl, Z represents an oxy group, a thio group or a sulfinyl group and q represents an integer of 0 or 1, 5-indanyl, r is an integer of 1, 2, 3 or 4, 5-indanyl and n is an integer of 1, 2 or 3, 6. The process of item 1 for producing compounds of formula Sl Η Rl HN \ I V. C — N — CH2CH2CH2CHCON Z I H2N HNSO2 AND Ar kde Ar is naphthyl substituted with at least one C 1 -C 5 alkoxy group, R 1 represents cycloalkyl of 3 to 10 carbon atoms or cycloalkylalkyl of 4 to 10 carbon atoms, R @ 5 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms or arylalkyl of 7 to 12 carbon atoms and n is an integer of 1, 2 or 3 as well as pharmaceutically acceptable salts thereof; in that (CH2) _n —COOR2 is used starting materials of the above formulas, in which Ar and X are as defined above and R is a group of the general formula Ri Z —N \ (CH 2) _{n -} COOR 2 wherein R 1, R 2 and _n are as defined above. 6. where Ru represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an aryl of 6 to 10 carbon atoms, an aralkyl of 7 to 12 carbon atoms and 5-indanyl, _v 1 being an integer of 0, 1 or 2, | is an integer of 0, 1 or 2, the sum of i + j is 1 or 2, and Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally substituted with at least one C 1 -C 5 alkyl and / or alkoxy radical C 1 -C 5 naphthyl, optionally substituted with at least one substituent selected from halogen, nitro, cyano, hydroxyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, phenyl optionally substituted with at least one substituent selected from halogen, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy and C 2 -C 20 dialkylamino, further Ar may be 7 to 12 aralkyl carbon atoms or groups optionally substituted by at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical, wherein: R1a represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms or an alkoxy of 1 to 10 carbon atoms, and a pharmaceutically acceptable salt thereof, characterized in that it reacts with N ² -arylsulfonyl-L-arginyl halide of the formula HN C — N — CH2CH2CH2CHCOX H2N H HNSO2 Ar kde Ar is as defined above and X represents a halogen atom, an amino acid derivative of the general formula RH where R is as defined above, whereupon the reaction mixture is optionally hydrolyzed. 7. The process of item 1 for the preparation of compounds of the general formula HN H · \ I z C — N — CH2CH2CH2CHCON Z I \ H2N HNSO2 AND Ar kde Ar is naphthyl substituted with at least one C 1 -C 5 alkoxy group, R 12 represents alkyl of 1 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, arylalkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms or cycloalkylalkyl of 4 to 10 carbon atoms , R 3 represents alkyl of 1 to 5 carbon atoms, R 1 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an arylalkyl of 7 to 12 carbon atoms or an aryl of 6 to 10 carbon atoms, as well as pharmaceutically acceptable salts thereof, characterized by: R2 CHCOOR4 8. The process of item 1 for producing compounds of formula HN H Ri \ I / C — N — CH2CH2CH2CHCON Z I \ H2N HNSO2 (CH2) n — COOR2 Ar kde Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl or C 2 -C 20 dialkylamino, R1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, arylalkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms or cycloalkylalkyl of 4 to 10 carbon atoms, Ra represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an arylalkyl of 7 to 12 carbon atoms or an aryl of 6 to 10 carbon atoms and n is an integer of 1, 2 or 3 as well as pharmaceutically acceptable salts thereof; The method according to claim 1, wherein the starting materials of the above formulas are used, in which Ar and X are as defined above and R is a group of the formula Ri Z —N \ (CH2j _n —COOR2 wherein R1, Re and _n are as defined above). 9. The process of item 1 for producing compounds of the general formula H2N HNSO2 AND Ar HN H R3 C — N — CH2CH2CH2CHCON Z I \ CH - (CH 2) _n COOR 5 I R4 where Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or dialkylamino of 2 up to 20 carbon atoms, R3 is furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro-3-furylmethyl, R4 represents a hydrogen atom or an alkyl of 1 to 5 carbon atoms, R 5 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an arylalkyl of 7 to 12 carbon atoms or an aryl of 6 to 10 carbon atoms and n is an integer of 1, 2 or 0 as well as 1 pharmaceutically acceptable salts thereof; by using the starting materials of the above formulas in which Ar and X are as defined above and R is a group of the general formula Rs Z —N \ CH- (CH 2) n COOR 5 AND R 4 wherein R 4, R 1, R 5 and n are as defined above. 10. The method according to claim 1 for preparing compounds of the formula II / H / ^N 4R hihso _the second II wherein R Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent selected from halogen, nitro, cyano, hydroxy, C 1 -C 10 alkyl or C 2 -C 20 dialkylamino, R 7 represents a hydrogen atom or an alkyl of 1 to 10 carbon atoms, R 6 is -COOR 5 wherein R 5 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, or C 7 -C 12 arylalkyl, wherein R 7 is substituted at the 2, 3, 4, 5 position or 6 and R e in the 2 or 3 position, characterized in that starting materials of the above formulas are used, in which Ar and X are as defined above and R is a group of the formula wherein R 6 and R 7 are as defined above. 11. The process of item 1 for producing compounds of the formula wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent selected from halogen, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy or C 2 dialkylamino up to 20 carbon atoms, R 10 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, an aryl of 6 to 10 carbon atoms or an arylalkyl of 7 to 12 carbon atoms, and Z is oxy, thio or sulfinyl; and q is an integer of 0 or 1, as well as pharmaceutically acceptable salts thereof, wherein the starting materials of the above formulas are used, wherein Ar and X are as defined above, and R is represents a group 0 of the general formula COOR _1o V x -N z wherein R 10, Z and q are as defined above. 12. The process of item 1 for producing compounds of formula COOR. ^HI Í y T-N-CHCl3 CH ₉ CH CON. Ar kde Ar is naphthyl, 5,6,7,8-tetrahydro-naphthyl, naphthyl or naphthyl substituted with at least one substituent selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy or C 2 -C 20 dialkylamino, R11 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms or arylalkyl of 7 to 12 carbon atoms, j is an integer of 0, 1 or 2, i is an integer of 0, 1 or 2 and i plus j is 1 or 2, as well as pharmaceutically acceptable salts thereof, characterized in that the starting materials of the above formulas are used, in which Ar and X are as defined above and R is a group of the formula: R 11, i and j are as defined above.