CS228103B2 - Production of n-2-arylsulphonyl-l-arginiamides and their salts - Google Patents

Abstract

PURPOSE:N<2>-Arylsulfonyl-L-arginingmides and their salts expressed by the formula I: [R is-NR1(CH2)nCOOR2 (R1 is alkyl, etc.; R2 is H, alkyl, etc.; n is 1,2 or 3), the formula II: (R3 is H, aralkyl, etc.; R4 is alkyl, etc.; R5 is H, aryl, etc.; m is 0.1 or 2), the formula III: (R6 is -COOR8, wherein R8 is H, etc.; R7 is H, phenyl, etc.; p is 1,2,3,4 or 5), the formula IV: (R9 is H, alkyl, etc.; r is 1,2,3 or 4), the formula V: (R10 is H, alkyl, etc.; Z is O, S, etc.; q is 0 or 1), the formula VI: (R11 is H, aryl, etc.; i and j are 0,1 or 2); Ar is naphthyl, phenyl, etc.]. For example, N<2>-(6,7dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine.

Description

The invention relates to a process for the preparation of N2-arylsulfonyl-L-argininamides and their non-toxic acid salts which can be used as anti-thrombosis agents because of their very low toxicity.

A variety of similar compounds are known to be useful in the treatment of thrombosis, for example, N2- (p-tolyisulfonyl) -L-arginine esters are agents that effectively dissolve blood clots, as described in U.S. Patent No. 3,622,615 .

A special class of compounds which are highly specific thrombin inhibitors and are therefore suitable for preventing thrombosis are the N2-dahsyl-L-arginine esters or amides.

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

It has now been found that N -aryl-sulfonyl-L-arginine amides have both antithrombotic activity and very low toxicity with the same relative activity as N2-dansyl-L-arginine esters or amides.

Accordingly, the present invention provides a process for the preparation of the N2-arylsulfonyl-L-arginine amides and their salts of formula I

HN

X

C — N — CH2CH2CH2CHCOR Z 1 · H2N H

AND

HNSO2

Ar (I) where

R is

1.

Ri

Z —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 100 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 w- ·· '·

C 2 -C 10 carboxyalkyl, C 3 -C 10 alkoxycarbonylalkyl. carbon, alkylcarbonylalkyl of 3 to 10 carbon atoms, haloalkyl of 1 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, α-carboxyalkyl of 8. to 15. carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, respectively. 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 C 1 -C 5 alkyl and / or or an alkoxy radical of 1. up to 5 carbon atoms, tetrahydro-2- [3- or -4-pyranylmethyl, optionally substituted with at least one alkyl group having 1 to 5 carbon atoms and / or an alkoxy group having 1 to 5 carbon atoms, 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 alkyl ol to ol 5 'carbon atoms and / or (C 1 -C 5) alkoxy radical and -tetrahydro-dihydro-3-thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical. carbon.

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

2. ......

..... R ³

Z —N \

CH- (CH ₂ ) mCOOR ₅ wherein

R 1 is hydrogen, C 1 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 2 -C 10 alkoxyalkyl, C 2 -C 10 alkylthioalkyl, C 2 -C 10 alkylsulfinylalkyl C 10 -C 10 hydroxyalkyl, C 1 -C 10 hydroxyalkyl, C 2 -C 10 carboxyalkyl. C 10 -C 10 alkoxycarbonylalkyl, C 3 -C 10 alkylcarbonylalkyl; 10 carbon atoms, haloalkyl of 1 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, α-carboxyaralkyl of 8 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tet rahydrofurfuryl, - 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 C 1 -C 5 alkyl and / or alkoxy. a radical of 1 to 5 atoms. carbon,. tetrahydro-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 radical, 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 alkyl radical; C 1 to C 5 and / or C 1 to C 5 alkoxy and tetrahydro-3-thenyl, optionally substituted with at least one C 1 to C 5 alkyl and / or C 1 to C 5 alkoxy. 5 carbon atoms,

R a is alkyl of 1 to 10 carbon atoms; carboxyl, C 2 -C 10 alkoxycarbonyl, phenyl, optionally substituted with at least one C 1-5 alkyl group. atoms. a carbon and / or alkoxy radical having 1 to 5 carbon atoms, aralkyl having 6 to 12 carbon atoms and a substituted benzyl on the nucleus, the substituent being an alkyl having 1 to 5 carbon atoms or an alkoxy having 1 to 5 carbon atoms,

R 5 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms. aralkyl o. 7 to 12 .atom. carbon, or. 5-indanyl a

m. represents an integer of 0, 1 or 2;

where .... · '

R6 is. group '—GOORs, who. Ra means. atom. 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, alkoxy. of 1 to 5 carbon atoms or carboxy, p is an integer of 1 to 5,

Re is substituted in the 2 or 3 position,

R7. it may be substituted at the 2-position. 3, 4, 5. or 6,

COORg

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:

R9 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,

C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, phenyl, optionally substituted with at least one of halogen, nitro, cyano, hydroxy, C 1 -C 10 alkyl Furthermore, Ar may be aralkyl of 7 to 12 carbon atoms, or a moiety of the group consisting of C uhlíku-C alko alko, C alko-C alko alko alkoxy and C dial-C dial dial dialkylamino;

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,

where

R 11 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, i is an integer of 0, 1 or 2, j is an integer of 0, 1 or 2, the sum of i + j is equal to 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 C 1 -C 5 alkoxy, naphthyl optionally substituted with at least one halogen atom, nitro, cyano-

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

R12 is hydrogen, alkyl of 1 to 10 carbon atoms or alkoxy of 1 to 10 carbon atoms, and pharmaceutically acceptable salts thereof, to remove the N-substituent of ^G N ^G -substituted-N ² -arylsulfonyl-L--argininamide of formulas

HN \.

C — N — CH2CH2CH2CHCOR,

Z I I

HN R 'HNSO2

I 'R * Ar where

R and Ar have. as defined above; and

R 'and R "are hydrogen or a protecting group for the guanidino group, wherein at least one of the substituents is such a protecting group such that they contacted the N ^G -substituted-N ² -arylsulfonyl-L-arglninamid acid or hydrolysing N ^G -substituted-N ² -arylsulfonyl-L-argininamide a catalyst activating hydrogen in a hydrogen atmosphere and then optionally the reaction mixture is hydrolysed.

A suitable meaning of R 1 in formula I is 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, alkylthioalkyl of 2 to 6 carbon atoms such as 2-ethylthioethyl and

2-methylthioethyl, alkylsulfinylalkyl of 2 to 6 carbon atoms, such as 2-hydroxyethyl, hydroxyalkyl of 1 to 6 carbon atoms, such as 2-hydroxyethyl and 3-hydroxybutyl, carbonyl of 2 to 6 carbon atoms; 7 carbon atoms such as 1-carboxybutyl, alkoxycarbonylalkyl of 3 to 8 carbon atoms such as 2-ethoxycarbonylethyl, aralkyl of 7 to 10 carbon atoms such as benzyl and phenethyl, α-carboxyaralkyl of 8 to 12 carbon atoms such as α-carboxyphenethyl C 3 -C 10 cycloalkyl such as cyclopropyl, cyclohexyl and cycloheptyl, C 3 -C 10 cycloalkyl such as cyclohexylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl,

2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl.

Preferred R 3 in formula I is hydrogen, C 1 -C 10 alkyl such as methyl, propyl, butyl, isobutyl, pentyl, hexyl and octyl, C 3 -C 6 alkenyl such as allyl, C 3 -C 3 alkynyl C 6-6 atoms, such as 2-propynyl, C 2-6 alkoxyalkyl such as 2-methoxyethyl, 2-methoxypropyl, 2-methoxyethyl, and 3-methoxypropyl, C 2-6 alkylthioalkyl such as C 1-6 alkyl; 1-thioethyl and 2-methylthioethyl, alkylsulfinylalkyl of 2 to 6 carbon atoms, such as 2-methylsulfanyl 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 8 carbon atoms, such as t-ethoxycarbonelethyl, aralkyl of 7 to 10 carbon atoms, such as benzyl and phenethyl, α-carboxyalkynyl of 8 up to 12 carbon atoms such as α-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, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-4-furylmethyl , 2-thenyl, 3-thenyl, tetrahydro-4-thenyl and tetrahydro-3-thenyl.

A suitable value for R 4 in formula I is an 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 on the nucleus substituted benzyl, wherein the substituent is alkoxy of 1 to 3 carbon atoms, such as 4 ^: ethoxybenzyl.

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

Suitable ccow groups

are 3-carboxy-4-morpholine, 3-carboxy-4-thlomorpholine, 1-oxo-3-carboxy-4-thiomorpholine and 4-carboxy-4-thiazolidinyl.

Suitable groups

COOW

they are 2-carboxy-1,2,3,4-trichloro-ceinolyl,

3-carboxy-1,3,3,4-tetrahydro-o-2-isocninolyl, 1-carboxy-1,2,3,4-tetraeydro-2-isoquinolyl, 2-carboxy-1-indolinyl and 1-carboxy- 2-isoindolinyl.

Suitably R 2, R 5, R 6, R 9, R 10 and R 11 in formula Ϊ 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 R, N, -terahydro. naphthyl, naphthyl substituted with at least one substituent selected from the group 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, dialkylamino o 2 to 10 ato228103

a carbon atom such as dimethylamino and dlethylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halogen, such as chlorine, alkyl of 1 to 5 carbon atoms such as methyl, ethyl and isopropyl, and alkoxy of 1 to 5 carbon atoms such as methoxy, (C 7 -C 10) aralkyl such as phenethyl;

as

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,

6,7-dimethoxy-2-naphthyl, 6,7-dethoxy-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 with sufficient activity are:

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

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

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

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

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

N ² (2-naphthylsulfonyl) -L-arginyl-N-butylglycine, N ^{2 -} (2-naphthylsulfonyl) -1-L-arginyl-N-butylglycine ethyl ester, N ^{2 -} (2-naphthylsulfonyl) -L-arginyl-N- benzyl ester butylglycine,

N ^2- (2-naphthylsulfonyl) -L-arginyl-N-butyl- [3-alanine],

N2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-butylglycine,

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

N2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-butyl- _1,3 -alanine,

N2- (6-bromo-1-naphthylsulfonyl) -L-arginy 1-N-butylglycine,

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

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

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

N2- (6,7-thiophenyl-η3-phthylullonyl) -L-arginyl-N-allylglycine,

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-propynyl) glycine,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl- N- (2-methoxyethyljglycinu, octyl N ² - (6,7-dimethoxy-2-naftylsulf) -L-arginyl-N- (2-methoxyethyl Jglycinu,

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- [2-methoxyethyl] glycine as the benzyl ester,

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine 3-methylphenyl ester,

N ² - (6,7-Dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine 5-indanyl ester,

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl] - / --- daNm, ethyl N ² - (6,7-dimethoxy-2-ones naftyllsulf 1] -L-arginyl-N- (2-methoxyethyl) -? 8111 ^,

N ² - (6,7- (d-y-2-naphthosulfonyl) -N-

- () - N - (- carboxypropyl) -L-argininamide,

N2- [6,7-7ηηθΐΙιοχ7-2-η3Π713ΐιΗοη71) -N-

- [2-methoxyethyl] -N- (- tert-butoxycarbonyl-1-propyl) -L-argininamide,

N ^2- (6,7-di-methoxy-2-naphthylsulfonyl) -N-

- (3-Methoxypropyl) glycine,

N2- (6,7-dimethoxy-2-ethoxyphenylsulfonyl) -L-arginyl-N- (ethoxyethyl) -β-alanine,

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

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

N2- [4,6-dimethoxy-2-naphthylsulfonyl] -L-arginyl-N- (2-methoxyethyl) glycine,

N2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as the ethyl ester,

N2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N- [2-methoxyethyl] glycine,

N2- (5-methoxy-1-naphthylsulfonyl) -L-arnyl-N- (2-meteoxyeteyl) glycine,

N2- (7-Methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, N2- (7-Methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2- meteGxyeteyl) glycine

N2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) - a-aanine,

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

N2- (5,6,7,8-tetraeydro-1-naphthylsulphonyl) -L-arginyl-N- (2-nitro-glycine) glycine,

N2- (5-chloro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N2- (6-chloro-2-naphthylsulfonyl) -L-arginyl-N- [2-methoxyethyl] glycine,

N2- [7-chloro-1-2-η 3,7-sulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N2- (7-methyl-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

N2- (6,7-Dimethyl-11-naphthylsulfinyl) -L-arginyl -N- (2-methoxyethyl) glycine,

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

N2- (7-hydroxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxy-ethyl) glycine,

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) glycine,

N2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,

N2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylsulfinylethyl) glycine,

N2- [6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-hydroxyethyl) glycine,

N2- (6,7-dimethoxy-2-naphthylsulphinyl) -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-naphthylsulphonyl) -L-arginyl-N- (2-ethoxycarbonylethyl) glycine,

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzyiglycine, tert-butyl ester N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl 1-N- benzylgly of the act,

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

N- ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzyl-1-alanine, tert-butyl 4- (Bdimethoxy-4-naphthylsulfonyl) -L-arginyl-N- benzyl- / 3-amine,

N ² (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethy-3-amine,

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

N2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine,

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

N2- (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 - (S-methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzylglycine,

N ² - (2-naphthylsulfonyl) -L-arginyl-N-benzyl-11-alanine,

N2- (2-naphthylsulfonyl) -L-arginyl-N-benzylglycine,

N2- (5'6'7'8-tetrahydro-1-naphthylisulfonyl) -L-arginyl-N-phenethylglycine,

N2- (S, bB-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-benzylglycine,

N2- (5,6,7,8-Ietrahydro-2-naphthylisulfonyl) -L-arginyl-N-benzyl-5-alanine,

N2- [7-methyl-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine,

N2- (N-dimethoxy-6-naphthylsulphonyl) -L-arginyl-N- [α-carboxyphenethyl-glycine,

N2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexylmethylglycine, N2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-tert-butyl ester -cyclohexylmethylglycine,

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cycloheptylglycine,

N2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexyiglycine,

N2- (7-methoxy-2-naphthylsulphonyl) -Lallyl-N-cyclohexyliglycine,

N2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexyimethylglycine,

N2- (5-methoxy-1-naphthylsulphonyl) -L-arginyl-N-cyclohexylmethyl-3-alanine tert-butyl ester

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -Larginyl-N-cyclohexyiglycine

N2- (6'7-dimethoxy-2-naítylsulí) -L-aI'ginyl NIcyklohexyI- _1-3-alanine, 'tert-N2- (6,7-dimethoxy-2-naftylsulíonyl] -L-argmyl-NIcyklohexyl - (- alanine,

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -N-cyclopropyl-N- (2-carboxypropyl) -L-argininamide,

N2- (1-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,

N2- (5,6,7,8-tetrahydro-1-naphthylsulphonyl) -L-arginyl-N-cyclohexyigiycin,

N2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine,

226103

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

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

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

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

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

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

N-- (5-chloro-1-naphthylsulfonyl) -L-arginyl-N-etrahydrofurfurylglycine,

N-- (1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,

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

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

N - (N, N-methoxy-4-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine;

', ·

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine, tert-N-- (6,7-dimethoxy-2-naftylsulf) -L-alanine methyl ester Arginy ---- -Butyl ,

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

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

N-- (6,7-dimethoxy-2- and phthylsulfonyl) -L-arginyl-N-phenethylalanine,

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

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

N2- (7-methoxy-2-naphthylsulfonyl) -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-arginyl-norvaline, N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylasparagic acid, diethyl ester N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylaseparic acid, N ² - (6,7-d (inethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylaseparic acid , N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylaseparic acid diethyl ester,

N2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-methyl-Menylalanine,

N- ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- [methyl-4- (4-methoxyphenyl) alanine, 1- [N2- (6,7-dimethoxy- 2-naphthylsulfonyl) -L-arginyl) -2-piperidinecarboxylic acid, ethyl 1- (N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl) -2-piperidinecarboxylate, 1- [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-ethoxy-2-naphthylsulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid 1- [N ² - (5-methoxy-1- naphthylsulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylate, ethyl 1- [N2- (5-methyl-1-naphthylsulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylate 1- [N2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid 1- [N2- (6,7-diethoxy-2-naphthylsulfonyl)] -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N2- (6,7-dimethoxy-2-naphthylsulfonyl)] -L-arginyl) -4-ethyl-2-piperidinecarboxylic acid 1- [N ^2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl) -4-ethyl-2-piperidinecarboxylic acid and 1- [N ² - [6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-propyl-2-piperidinecarboxylic acid 1- [N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L 1- [N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -6-methyl-2-piperidinecarboxylic acid-1- (2-piperidinecarboxylic acid) -arginyl] -4-isopropyl [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-piperidinedicarboxylic acid 1- [N ^2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-phenyl-2-pi peridinecarboxylic acid 1- [N ² - (1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid ethyl-1- [N ² - [1-naphthylsulfonyl] -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] -4-isopropyl-2-piperidinecarboxylate 1- [N ² - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4-methyl acid 1-2-piperidinecarboxylic acid, ethyl 1- [N ² - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4-methyl 1-2-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-naphthylsulphonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N ² - [7-methyl-2-naphthylsulphonyl] )

-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-hexamethylenimine carboxylic acid 4- [N ² - (7-methoxy-2) -naphthylsulfonyl) -L-arginyl] -3-thiomorpholinecarboxylic acid,

4- [N ² - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -3-carboxythiomorpholine-1-oxide, 4- [N ² - [6,7-dimethoxy-2-naphthylsulfonyl) -L-acid -arginyl] -3-morpholinecarboxylic acid, 4- [N ² - (7-methoxy-2-naphthylsulphonyl) -L-arginyl] -3-morpholinecarboxylic acid, 3- [N ² - [7-methoxy-2-naphthylsulphonyl] acid 1-L-arginyl] -4-thiazolidinecarboxylic acid 2- [N ² - (8,7-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 - [3,4,5-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

Ν ^2- (1,4-benzodioxan-6-sulfonyl) -L-arginy1-N- (2-methoxyethyl) glycine,

N2- (6,7-ethylenedioxy-2-naphthylsulfonyl) -L-arginyl-N- [2-methoxyethyl] glycine and 1- [N2- (2-dibenzofuranyl) -L-arginyl] -2-piperidinecarboxylic acid .

Among the compounds of the invention, the following compounds are particularly preferred because of their high antithrombotic activity and low toxicity:

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,

N2- [7-Methoxy-2-naphthylsulfonyl) -L '- [-] - 4-rinyl-N-biphenylglycine,

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

N2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,

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

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

N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginy 1-N-tetrahydrofurfurylglycine.

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

N2- (6,7-dimethoxy-2-phthylsulfonyl) -L-arginyl-N-tetrahydroturylglycine, 1- [N2- [6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4 -methyl-2-piperidinecarboxylic acid, 1- [N2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid and 1- [N2- (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 ester group is attached may be asymmetric so that optically active isomers are formed, namely the DaL-diastereoisomers and their racemic mixture.

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

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

The reaction products can be isolated. in free form or in the form of their salts. . In addition, these compounds can be obtained in the form of pharmaceutically acceptable addition salts by reacting the free compounds with an acid such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, glucone, 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 formula I and their salts have a high specific thrombin inhibitory activity and at the same time 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 N2-arylsulfonyl-L-argininamide according to the invention was compared with that of the known antithrombotic substance, the N2- (p-tolylsulfonyl) -L-arginine methyl ester by determining the clotting time influenced by fibrinogen. This determination was carried out as follows:

0.8 ml of a 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 for control. solution or with a sample in the same buffer, 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. Coagulation time - is measured as the time from transfer to a bath at 25 ° C until the first appearance of fibrin substances. If no active substance was added, the period was 50-55 seconds. The experimental results are shown in Table I. The term "concentration" required to double the "coagulation" twice means the concentration of the active substance which prolongs the coagulation time from 50 to 55 seconds to 100 to 110 seconds.

This coagulation time is achieved using a known antithrombotic agent, i.e. N ² - (p-tolylsulfonyl) -L-arginine methyl ester in an amount of 1100 μιηοΐ. Inhibitors according to the invention are compared in this respect in Table I, listing R and Ar substituents and addition groups.

When the solution of the compound of the invention is administered intravenously, high antithrombotic activity is maintained in the circulation for 1 to 3 hours. The blood half-life of the antithrombotic compound of the invention is about 60 minutes. There was no violation of other physiological processes in experimental animals, such as rat, rabbit, 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:

LD 50 Compound (mg / kg)

N2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-butylglycine> 1500

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-

- (2-methoxyethyl) glycine 1900 2400

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-

- (2-ethoxyethyl) -js-alanine G60-1000

N2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine2000

N2- (5,6,7,8--6,77,7.ro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine> 1500

N2- (6,7-di-6-ethyl-11-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine> 1500

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) glycine> 1000

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine> 1000

Compound

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

N2- (5-Methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzylglycine

N2- [6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine

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

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine

N2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine

N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofuran-4-ylglycine

N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine

N2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylalanine 1- [N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid ethyl [1-N ^2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate

1- | NM L sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1: [N2- [1-naphthylisulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N ² - ( 5-dimethylamino-1-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid 4- [N2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -3-morpholinecarboxylic acid

LD 50 (mg / kg)> 1000> 1000> 1500> 1500> 1500

600

620> 1500> 1500

1500

670—1000

670—1000

700—1000

700—1000> 1000 'LD 50

Compound (mg / kg) ^2- [N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-4-ynyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid> 1000 and

2- [N2t (6,7-dimethoxyl) acid

-2-naphthylsulfonyl) -L-arginyl] -1-isoiridolinecarboxylic acid> 1000

Acute toxicity was determined by intraperitoneal administration of compounds of Formula I to male mice weighing 20 g in the range of 1,000 to 10,000 mg / kg body weight.

On the other hand, the LD 50 values for N ² -dansyl-N-butyl-L-argininamide and N ² -dansyl-N-methyl-N-butyl-L-argininamide are 75 to 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 compound 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.

The invention will be illustrated in the examples below.

Example 1

A. N ^G -nitro-N2- (tert-butoxycarbonyl) -L-arginyl-N- (2-methoxyethyl) glycine as ethyl ester

To a stirred solution of 28.3 g of N ^G -nitro-N2- (tert-butoxycarbonyl JL-arginine in 450 ml of anhydrous tetrahydrofuran was added 12.4 ml of triethylamine at once, and 12.4 ml of isobutyl chloroformate while maintaining the temperature at -5 ° C. After 15 minutes, 14.2 g of N- (2-methoxyethyl) -glycine ethyl ester was added and the mixture was stirred at -5 ° C for 15 minutes, then warmed to room temperature, the solvent was evaporated and the residue dissolved in 400 ml. The solution is washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of - 10% citric acid and 200 ml of water, and the ethyl acetate solution is dried over anhydrous sodium sulfate. in - 20 ml of chloroform - and the solution is applied to a column - measuring 80 X 6 cm containing 500 g of silica gel in chloroform, and the column is eluted first with chloroform and then with 3% - methanol in chloroform. the second type The solvents were evaporated to dryness to give 25.8 g of NG-nitro-N2- (tert-butoxycarbonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester as a syrup in 63% yield.

Infrared spectrum in KBr having the following peaks at 3300, 1740, 1690 ^cm-first

B. NG-nitro-L-arginyl-N- (2-methoxyethyl) glycine as ethyl ester hydrochloride

To a stirred solution of 29.8 g of NG-nitro-N ² - (t-butoxycarbonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester in 50 mL of ethyl acetate was added 80 mL of a 10% anhydrous solution of hydrochloric acid in ethyl acetate at at 0 DEG C. After 3 hours, 200 ml of anhydrous ethyl ether was added to this solution to give a viscous oil.

The product was collected by filtration and washed with anhydrous ethyl ether to an amorphous solid yielded - ethyl N ^G -nitro-L-arginyl-N- (2-methoxyethyl Jglycinu in an amount of 24.1 g.

C. NG-Nitro-N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester

To a stirred solution of 4.0 g of ethyl _n NGT it -LtarginyltNt _Γ0 (2-methoxyethyl Jglycinu in 20 ml water and 20 ml dioxane was added in one portion 2.5 g of sodium bicarbonate and 3.5 g of 6,7-d.imethoxy- Of 2-naphthalenesulfonyl chloride in 30 ml of dioxane at 5 [deg.] C. The reaction mixture is further stirred at room temperature for 3 hours, at which time the solvent is evaporated and the residue is dissolved in 40 ml of chloroform and washed with 10 ml of hydrochloric acid solution. with a concentration of 1 N and 20 ml of water.

The chloroform solution was dried over anhydrous sodium sulfate - and the solvent was evaporated. The residue is chromatographed on 50 g of silica gel in chloroform, the column is washed with chloroform and eluted with a 3% solution of methanol in chloroform. The thus obtained fraction was evaporated to an amorphous solid in 87% yield, 5.3 g of N ^G -nitrotN2t (6,7-dimethoxy-2-onyl naftylsulf J -L-arginyl-N- (2-methoxyethyl ) glycine.

Infrared spectrum has maximum KBr - at 3240, 1740, 1630 cm -1.

D. ² Ethyl N - (6,7-dimethoxy-2-naftylsult) -L-arginyl-N- (2-methoxyethyljglycinu

To a solution of 3.00 g of .alpha.-nitro-N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester in 50 ml of ethanol and 0.5 ml of acetic acid 0.5 g of platinum black is added and the mixture is shaken under a hydrogen atmosphere at room temperature for 100 hours. At the end of this time, the ethanol solution was filtered to remove the catalyst and evaporated to an oily product. Further precipitation of the ethanol-ethyl ether mixture yielded 2.53 g of N ² - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester in 91% yield.

For analytical purposes, part of the product was converted to a flavianate with a melting point of 185 ° C.

The infrared spectrum in KBr had peaks at 3375, 3200, 1740 cm -1

Analysis for

C25H37N5O8S. C10H6N2O8S:

calculated:

% C, 47.67;% H, 4.92;% N, 11.12.

% C, 47.64;% H, 4.81;

Ε. N ^2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-Nb-methoxyethylene glycol

A solution of 2.5 g of ethyl ^2- (6,7-dimethoxy-6-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine in 5 ml of ethanol and 7 ml of 1 N sodium hydroxide is stirred at room temperature for 30 hours. At the end of this time, the solution is concentrated to a volume of 5 ml and chromatographed on 80 ml of 200-300 mesh (Daiaion® SK 102 in H + form) ion exchange resin in water, the column is washed with water and eluted with 3% w / w. The fractions thus obtained were evaporated to dryness and the residue was purified by further precipitation with a mixture of ethanol and ethyl ether to give 1.32 g of N ² - (6,7-dimethoxy-2-naphthylsulfonyl) as an amorphous solid in 72% yield. onyl) -L-arginyl-N- (2-methoxyethyl) glycine.

The infrared spectrum in KBr has peaks at 3380, 3180, 1630 cm @ -1.

Analysis for

C23H33N5O8S:

calculated:

% C, 51.20;% H, 6.17;% N, 12.98.

% C, 50.93;% H, 6.02;% N, 12.63.

The following compounds can be prepared accordingly:

N ² - (5,6,7,8-tetr ahydro-2-naphthylsulphonyl) -L-arginyl-N- (2-ethoxyethyl) glycine,

N2- [5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N- [2-methoxyethyl] glycine,

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

N ² - (^^ j j et et et et et ^ ^ ^ x ^ ^ ^ ^----------fl fl fl fl fl fl fl fl fl fl flulfulfulfulfulf on on]]]--LLLLLLLLLLLLLLLLLLLL)

N ² - (7-Methoxy- ² -naphthylsulfonyl) -L-arginyl-N-4-cyclohexypropylglycine, 2- [N ² - (7-nitrophenyl) -L-arginyl] -1,2, 3,4-Etrahydroisoquinoline-2-carboxylic acid 2- [N ² - (7-methyl-2-iodo-1-piperidin) -L-arginyl] isoidazole-1-carboxylic acid 2- [N ² - (6,7-Dimethyl-2-naphthylsulfonyl) -L-arginyl] isoindol-1-carboxylic acid 2- [N ^2- (2-naphthylsulfonyl) -L-arginyl] isoidol-1-carboxylic acid, 2- [N ² - (5,6,7, -tetahydro-2-naphthylsulfonyl) -L-arginyl] -1,2,2,4,4-tetrahydroisoquinoline-3-carboxylic acid, 2- [N ² - ( 5,6,7,8-tetrahydro-1-naphthylsulphonyl] -L-arginyl] isoidoline-1-carboxylic acid 2- [N ^2- (5-chloro-1-naphthylsulphonyl) -L-arginyl] -1, 2,3,4-Etrahydroisoquinoline-3-carboxylic acid 1- [N ^2- (5-hydroxy-1-aaphthylsulfonyl) -L-arginyl] 1,1,2,3,4-tetrahydroquinoline-2-carboxylic acid 2- [ N ² - (Ei ( ¹⁾ - (1-iodo-Nn α: tylsulfonyl) -L-arginyl) isomidol-1-car boxylic acid and 2- [N ² - (-n) -L-arginyl] -1,2,3,4-tetrahydro-isoisoquinoline-3-carboxylic acid.

Example 2

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

NC-nitro-N ² - (6,7-dimethoxy-2-aaphthylsulfonyl) -L-arginyl-N-methylglycine benzyl ester was obtained as described in Example 1 and had a melting point of 133-135 ° C.

To a solution of 3.00 g of N ^G -аitro-N2- (6,7-dimethoxy-2-naftylsult) -L-arginyl-N-tenethylglyciаu in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium black and the mixture was shaken under a hydrogen atmosphere at room temperature for 100 hours. At the end of this time, the ethanol solution was filtered to remove the catalyst and evaporated

, ²⁷ r dry. The residue is washed several times with anhydrous ethyl ether and then chromatographed on 80 ml of 200-300 mesh (Daiaion ^R SK 102 in H + form) ion exchange resin in water, the column is washed with water and then eluted with 3% ammonium hydroxide solution. The fractions thus obtained were evaporated to dryness to give 1.71 g of N2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine in 70% yield as an amorphous solid.

The KBr infrared spectrum has peaks at 3360, 3200, 1590 cm -1.

Analysis for

C28H35N5O7S:

calculated:

% C, 57.42;% H, 6.02;

57.09% C, 6.06%. H,

11.97% N,

11.74% N.

Other 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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Preparation А

Arylsulfonyl chlorides

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

A vigorously stirred solution of 70.8 g

Sodium 6,7-dihydroxy-2-naphthalenesulfonate a

77.2 g of sodium hydroxide in 450 ml of water are added dropwise with 230 ml of dimethyl sulphate at 00 ° C over 1 hour, at the same time the product precipitates. Sodium hydroxide (38.8 g) was added portionwise to the reaction mixture 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 number

The arylsulfonyl chloride 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 1: 1 benzene / n-hexane to give 32 g.

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 that is essentially identical to that of publication Ε. H. Rodd, &quot; Chemistry of Carbon Compounds &quot;, Elsevier Publishing Company, 1954, Vol. III, pp. 441-469.

Melting point (° C)

118-119.5

136.5 to 138.5

137 to 139

Preparation В

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 evaporated in vacuo and the residue was mixed 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 was distilled under reduced pressure to give a yield

90.9% yield of 17.0 g of N-butylglycine tert-butyl ester, b.p. 76 DEG C. at 0.5 mm Hg.

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. Speziale et al., J. Org. Chem. 25, 731 (1960).

Number Amino acid derivative Boiling point ° C / Pa

(CH 2) 2 CH 3 1 OF HN \ CH2CO2-t-C4H0 95/2666 2 CH2CH (CH3) 2 from HN, CH2CO2-t-C4H9 _; 65 / 666.6 3 (CH 2) 4 CH 3 of HN \ CH2CO2 - C4H9 _ 89 to 90 / 333.3 4 (CH 2) 5 CH 3 of HN \ CH2CO2-t-C4H9 83 to 85/200 (CH 2) 7 CH 3 _from 5 HN \ CH2CO2-t-C4H9 ........ 125 to 130 / 533.3 CH2CH2OCH3 of " · 6 ^z . , .Λ-Ζ .... HN \ .......... CH2CO2-t-C4H9 ............... 61 to 62 / 260.6 CH2CH2OCH3 rz in-, 'ΐ ’. · ι 7 /and HN \ CH2CH2CO2-t-C4H9 94/400 8 CH2CH2OCH3 of HN \ CH2CH2CH2CO24-C4H9 60 to 63/400 9 CH2CH2CH2OCH3 of HN \ CH2CO2-t-C4H9 95, to 97 / 666.6 10 CH 2 CH 2 OCH 2 CH 3 from HN 1 CH 2 CH 2 CO 2 H-C 4 H 9 102 / 533.3 11 166 / 1333.2

Number Amino acid derivative Boiling point ° C / Pa CH2CH2SCH2CH3 12 / HN \ CH2CO2-t-C4H9 ........ CH2CH2SCH3 / 106 to 109/200 13 HN \ CH2CO2-t-C4H9 7 97 / 333.3 14 HN 101 / 666.6 15 Dec ^ ch.co.-i-ca and. c 4 J 101 / 666.6 16 ^ CC ^ CCCOU ^ ^ Tc _of 103 / 533.3 17 of HN ? phyCOft-CCHg 129-130 / 1066.6 18 HN ^ Ch _{i I} p CO-CFF 145 / 1999.8 19 Dec ^ ^СН 2 — СУ HN ° ^ CH.CHXOjt- CH 3 (CH 2) 2 CH 3 / 136 / 1333.2 20 May HN CHCO2-t-C4H9 CH3 (CH 2) 3 CH 3 / 93 / 3466.4 21 HN \ CHCO2-t-C4H9 1 CH3 110 / 3599.7

Amino Acid Derivative (CH2) 4CH5

OF

HN \

CHCO2-t-C4H9

СНз

CH2CH2OCH3 z

HN \

CHCO2-t-C4H9

AND

СНз

HN

CHCO-CH ₂ CH ₂

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-h - • Л

HN

CHCO 3 -CH, (CH 2) 3 CH 3

OF

H, N, CH2CH2CO2-t-C4H9

HN-ca-t-cyi,

Boiling point ° C / Pa

124 / 3466.4 to 90/800

116-118 / 266.6

167 / 2133.2

125 / 2133.2

141 / 1999.8

89/400

111 / 133.3 to 92 / 133.3

Number

Amino acid derivative

CH2CH2CO2C2H5

OF

HN \

CH2CO2-t-C4H9

OH

CH2CH2CHCH3 /

HN \

CH2CO2-C1-C4H9

CH2CH2SOCH3

OF

HN \

CH2CO2-C1-C4H9

CH2CH2OH

OF

HN \

CH2CO2-t-C4H9

CH 2 C = CH 2

HN \

CH2CO2-t-C4H9

Boiling point ° C / Pa

115 / 266.6 to 84 / 266.6

150 / 66.7 to 96 / 266.6

B. N- (2-Methoxyethyl) glycine ethyl ester

To a stirred solution of 165.2 g of 2-methoxyethylamine and 202.4 g of triethylamine in 1 liter of benzene was added dropwise a solution of 334.0 g of ethyl bromoacetate in 200 ml of benzene over 1 hour at room temperature. At the end of this time, the mixture was heated at reflux for 2 hours to complete the reaction. After cooling, the triethylamine hydrobromide was collected by filtration and washed with ben Amino Acid zen. After removal of the solvent, the product was distilled under vacuum to yield a yield

75.3% gave 242.8 g of N- (2-methoxyethyl) -glycine ethyl ester, b.p. 73-75 [deg.] C at 5 mm Hg.

The following amino acid ethyl esters not previously described in the literature have been obtained in the same manner which is substantially identical to that of A. J. Speziale et al., J. Org. Chem., 25, 731 (1960).

in the form of melting or boiling point ^c C / Pa (СНг) зСНз

OF

HN \

CH2CO2C2H5 to 58/400

CH2CH2OCH3

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1 HN \

CH2CH2CO2C2H5

HN to 64/400 to 93 / 266.6

Melting or boiling point ° C / Pa

Number

Amino acid in form

HN

СННнСООН HCt>

coch

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AND

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AND

CH2CHCH3 z

HN \

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OF

HN \

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CH2CO2C2H5

101 to 102

113 to 116/400

116-117 / 133.3-80 / 266.6

C. N- (2-methoxy-ethyl) -glycine p-toluenesulfonate · benzyl ester

To a solution of 55.8 g of N- (2-methoxy-ethyl) -glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of p-toluenesulfonic acid. in the form of the monohydrate. The mixture was heated at reflux for 10 hours while removing the water with a Dean-Stark trap. At the end of this time, the solution was evaporated in vacuo. 300 ml of anhydrous ethyl ether was added to the residue. After standing at room temperature for 2 hours, the resulting precipitate was filtered off, washed with anhydrous ethyl ether and recrystallized from ethyl acetate to give 99.2 g of N- (2-methoxyethyl) glycine benzyl ester p-toluenesulfonate at 85% yield. mp 95-96 ° C.

The following amino acid benzyl ester p-toluenesulfonates, not previously described in the literature, can be obtained as described above.

Benzyl ester p-toluenesulfonate number

Melting point ° C

JCH ^ CH *

HN ^х сн ₂ со ^ сн _г '(СНО.СНь HN

CH _{CO 2} CH _i ^ HN CHÍCHJt

СНрХ ^ СН ^ '(CHJC ^ HN

to 99

122 to 124

to 95

to 68 / CH 2 CH

HN ³ \

CH, CO, CH

CH 2 CO 2 CH

101 to 102

140 to 143

154 to 156

133 to 135

133 to 135

CH 2 CO 2 CH

HN

CHCO 2 CH

CH 2

133 to 138

103 to 106

Number benzyl amino acid p-toluenesulfonate Melting point ° C 12 hh 92 to 94 13 ^Х ^ ^со г. ^СН г2У CH $ chco ₂ ch, - ^ J> 123 to 126 14 ch ₃ of HN / - \ 119 to 123 15 Dec МА / __ 130 to 131

Preparation С

2-Piperidinecarboxylic acids and their esters

A. 4-Methyl-2-piperidinecarbonitrile

A solution of 33.6 g (0.21 mol) of 4-methylpiperidine acetate in 10 ml of water is added dropwise to 500 g of a 10% sodium hypochlorite solution cooled in an ice bath over 1 hour. At the end of this time, the reaction product was extracted twice with 500 ml of ether and dried over anhydrous sodium sulfate. After evaporation of the ethyl ether, the residue was added dropwise to a solution of 11.8 g (0.21 mol) of potassium hydroxide in 100 ml of 96% ethanol. The process is carried out at the reflux temperature of the reaction mixture. The mixture was then heated in the same manner for 10 minutes. The ethanol was evaporated and the residue was dissolved in 50 ml of 2M sodium hydroxide solution and then extracted with ether.

The ether layer was dried over anhydrous sodium sulfate and evaporated. The residue was added under ice-cooling to a solution of 27 g (1 mol) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water. The solution was stirred at room temperature for 4 hours and then basified by addition of sodium hydroxide. The reaction product was extracted with ether, dried over anhydrous sodium sulfate and distilled under reduced pressure to give 17 g (66%) of 4-methyl-2-piperidinecarbonitrile, b.p. 96-97 ° C at 1 mm Hg.

In the above manner, the following 2-piperidinecarbonitriles, which have not been described in the chemical literature, can be obtained. This procedure is essentially the same as described in the following publications: Grundon et al., J. Chem. Soc., 1963, 3898, Grundon et al., J. Chem. Soc., 1964, 2448, R. Bonnett et al., J. Chem. Soc. 1959, 2092 and H. Bdhme et al. Ber., 92, 1613 (1959).

Boiling point ° C / Pa

1 4-CH 2 CH 3 105 to 106/1200 2 4-CH 2 CH 2 CH 3 СНз / 106 / 1066.6 3 4-CH \ СНз 104 / 533.3 4 2-СНз

B. 4-Methyl-2-piperidinecarboxylic acid hydrochloride

A solution of 4-methyl-2-piperidinecarbonitrile in 250 ml of 6 N hydrochloric acid was heated at reflux for 6 hours. After evaporation of the solvent, the residue was recrystallized from water to give 4-methyl-2-piperidinecarboxylic acid hydrochloride.

C. Ethyl 4-methyl-2-piperidinecarboxylate

A solution of 13 g (0.072 mol) of 4-methyl-2-piperidinecarboxylic acid as the hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for 4 hours. At the end of this time, the solvent was evaporated under reduced pressure and the residue was extracted with a chloroform solution and a saturated potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate and the chloroform was evaporated. The residue was distilled in 60% yield.

^R ₇ gives 7.4 g of ethyl 4-methyl-2-piperidinecarboxylate, b.p. 76-77 ° C / 400 Pa.

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

A solution of 20 g (0.112 mol) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g (0.224 mol) of benzyl alcohol and 25.6 g (0.134 mol) of p-toluenesulfonic acid monohydrate in 100 ml of benzene is heated to boiling point below. with a reflux condenser for 5 hours while continuously draining water through the Dean-Stark trap. The solvent was distilled off and the residue was washed with ether-n-hexane and recrystallized to give 10 g of benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate in 22% yield, m.p. 160-163 ° C.

In a similar manner, the following 2-piperidinecarboxylates not previously described in the chemical literature can be obtained:

Number

R7

Addition group

Boiling point ° C / Pa

4-CH 2 CH 3

4-CH2CH2CH3 СНз z

4-CH \ СНз 2-СНз to 84/487

HCl to 96 / 266.6

57/400

Morpholine-3-carboxylic acid hydrochloride, m.p. 200 DEG-202 DEG C., was also prepared as described above.

The following starting materials for the preparation of N ² -arylsulfonyl-L-arginmamides can be obtained according to the above publications:

Compound

Literature

СОН,

ИМ $

J. Org. Chem., 29,2203 (1964)

J. Org. Chem., 29,2203 (1964)

CO, H

AND

J. Am. Chem. Soc., 59,200 (1937)

Zh. Obs. Chim., 9, 2245 (1973)

Ber., 44 2034 (1911) (D) or (L) Ber., 65,927 (1932).

The methyl or ethyl esters of these compounds can be prepared in a conventional manner. Ethylthiomorpholine-3-carboxylate has a boiling point of 108 DEG C. at 0.5 mm Hg.

Diethylpiperidine-2,6-dicarboxylate hydrochloride can be obtained by conventional esterification of piperidine-2,6-dicarboxylic acid. This ester has a melting point of 184-186 ° C. Isoindoline-1-carboxylic acid can be prepared in a manner similar to isoquinoline-3-carboxylic acid. This procedure was described in Ber., 44, 2034 (1911). Ethylisolndoline-1-carboxylate hydrochloride was prepared by conventional esterification of isoindoline-1-carboxylic acid and has a melting point of 139-140.5 ° C.

While the process of the invention has been described in detail, it will be apparent to one skilled in the art that many other changes and modifications may be made to the invention.

Claims (11)

Process for the preparation of N ² -arylsulfonyl-L-argininamides and their salts of the general formula I HN C — N — CH2CH2CH2CHCOR, III H2N H and HNSO2 Ar (I) where R is 1. Rj Z —N \ (CH ₂ ) _n COOR ₂ where R 1 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, alkylthloalkyl 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, ια- carboxyaralkyl of 8 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl and the like; 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 C 1 -C 5 alkyl and / or alkoxy C 1 -C 5 radical, 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 alkyl radical C 1 -C 5 and / or C 1 -C 5 alkoxy and tetrahydro-3-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or alkoxy 1 to 5 carbon atoms R2 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 / —N \ CH (CH ₂ ) _m COOR ₅ R ⁴ where R3 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, alkylsulfonynylalkyl 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 C 4 -C 10 furfuryl, tetrahydrofurfuryl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical 5-carbon atoms of 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with at least one alkyl group of 1 to 5 carbon atoms and / or an alkoxy group 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 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 and / or C 1 -C 5 alkoxy and tetrahydro-3-thenyl optionally substituted with at least one C 1 -C 5 alkyl radical carbon atoms and / or (C 1 -C 5) alkoxy radical, R 1 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 radical, 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, 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 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 is hydrogen, C 1 -C 10 alkyl, phenyl, C 1 -C 5 alkoxy or carboxy, 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, 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: R 8 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, C 7 -C 12 aralkyl, and 5-indanyl; and g is an integer of 1, 2, 3, or 4, wherein: 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 oxycyclic group, a thio group or a sulfinyl group and q represents an integer of 0 or 1, 6. COOR ^ where R 11 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 equal to 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 C 1 -C 5 alkoxy, naphthyl optionally substituted with at least one halogen atom, nitro, cyano, hydroxyl, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, dialkylamino of 2 to 20 carbon atoms, phenyl, optionally substituted with at least one of halogen, nitro, cyano, hydroxy, alkyl o C 1 -C 10, C 1 -C 10 alkoxy, and C 2 -C 20 dialkylamino, furthermore Ar may be C 7 -C 12 aralkyl, or optionally substituted by at least one C 1 -C 5 alkyl radical and / or or an alkoxy radical of 1 to 5 carbon atoms, wherein R12 is hydrogen, alkyl of 1 to 10 carbon atoms or alkoxy of 1 to 10 carbon atoms, and pharmaceutically acceptable salts thereof, characterized by removing the N-substituent of ^{G-substituovavaného} № N ² -arylsulfonyl-L an arginine amide of formula HN C — N — CH2CH2CH2CHCOR From 1 HN R " AND HNSO2 1 / R ‘ Ar where R and Ar are as defined above and R 'and R' represent a hydrogen atom or a protecting group on a guanidine group, at least one of said substituents being a protecting group, contacting N ^G -substituted-N ² -arylsulfonyl-L-argininamide with an acid or hydrolyzing N- ^G- substituted-N ² -arylsulfonyl-L-argininamide in the presence of a hydrogen activating catalyst under a hydrogen atmosphere and then optionally hydrolyzing the reaction mixture. 2. The process of item 1 for the preparation of compounds of the general formula HN HRl \ Iz C — N — CH2CH2CH2CHCON ZI \ H2N HNSO2 (CH2) n — COOR2 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 general formula are used in which Ar, R 'and R' are as defined above and R is a radical of formula Rl Z —N \ (CH2) _n —COOR2 wherein R1, R2 and n are as defined above. 3. The process of item 1 for the preparation of compounds of the general formula HN HRi X Iz C — N — CH 2 Cl 2 H 2 CH 2 CHCON ZI X H2N HNSO2 (CH2) n — COOR2 AND Ar kde 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 process according to claim 1, wherein the starting materials of the above general formula are used, in which Ar, R 'and R' are as defined above and R is a group of the general formula Ri Z —N \ (CH 2) n —COOR 2 where R1, R2. and n are as defined above. 4. The process of item 1 for producing compounds of the general formula HN H X I C — N — CH2CH2CH2CHCON HNSO2 Ar \ (CH 2 ') n —COOR 2 wherein 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 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 which Ar, R 'and R' are as defined above and R is a group of the general formula Ri Z —N \ (CH2n - COOR2 where R1, R2 and n are as defined above. 5. The process of item 1 'for producing compounds of formula HN 'CN- СН ^ СН ^ СН ^ СН CON ^H of ^N HNSO ^ _ AR *. Ar * where Ar represents naphthyl substituted by at least one alkoxy having 1 to 5 carbon atoms, R 7 represents a hydrogen atom or an alkyl of 1 to 10 carbon atoms, ...... R e represents a group -COOR 5 in which R e represents an alkyl of 1 to 10 carbon atoms, an aryl of 6 to 10 carbon atoms or an arylalkyl of 7 to 12 atoms being substituted in carbon, wherein R 2 may be 2, 3, 4, 5 or 6 Rl Z OF H2N HN H \ I. C — N — CH2CH2CH2CHCON I ' HNSO2 AND Ar and Re at the 2 or 3 position as well as 1 pharmaceutically acceptable salts thereof, characterized in that the starting materials of the above general formula are used, in which Ar, R 'and R' are as defined above and R is represents a group of formula * ⁷ wherein R 6 and R 2 are as defined above. 6. The process of item 1 for the preparation of compounds of the general formula: (CH 2) n —COOR 2 where 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, 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; in respect of acceptable salts thereof, characterized in that the starting materials of the above general formula are used, in which Ar, R 'and R' are as defined above and R represents a group of the general formula ...... R1 From —N '· \ (CH2) _n —COOR2 where R1, R2 and n are as defined above. 7. The process of item 1 for producing compounds of the general formula HN H Rz \ I Z C — N — CH 2 CH 2 CH 2 CHCON z · · ·. · S ·. z. r · \ ·. ·. H2N HNSO2 CHCOORj I I Ar R3. where Ar is naphthyl substituted with at least one C 1 -C 5 alkoxy group, R2 is 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 and R4 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 of these compounds, characterized in that starting materials are used above wherein Ar, R 'and R' are as defined above and R is a group of the formula Rž Z —N \ CHCOOR4 AND R3 where 8. The process of item 1, wherein R 2, R 3, and R 1 are as defined above. of the general formula HNH \ I / C — N — CH2CH2CH2CHCON ZI \ H2N HNSO2 AND Ar kde Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent selected from the group consisting of halogen, hydroxy, alkyl of 1 to 10 carbon atoms or dialkylamino of 2 to 20 carbon atoms, 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, R2 is hydrogen, alkyl of 1 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or aryl of 6 to 10 carbon atoms, and R 1 (CH 2) _n —CODR 2 n represents an integer of 1, 2 or 3 as well as pharmaceutically acceptable salts of these compounds, characterized in that starting materials of the above general formula are used in which Ar, R 'and R "have and R is a radical of formula Rl From —N (CH2) nCOOR2 wherein R 1, R 2 - and n are as defined above. 9. The process of item 1 for producing compounds of the general formula HN H R3 X I / C — N — CH2CH2CH2CHCON OF 1 \ H2N HNSO2 CH- (CH 2) n COOR 5 AND Ar 1 Ri where Ar represents naphthyl, 5,6,7,8- [3-31-yl] -tyl or naphthyl substituted by 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 a dialkylamino group of 2 to 20 carbon atoms, R3-represents furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro-3-furylmethyl, R1 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 pharmaceutically acceptable salts thereof; The process of claim 1, wherein the starting materials of the above general formula are used in which Ar, R 'and R' are as defined above and R is a radical of formula R3 Z —N \ CH- (CH 2) _n COOR 5 R4 where R 1, R 5, R 5 and n are as defined above. 10. The method according to claim 1 for the production of the ^compounds: n of Formula У _from C - N - CCCH _Z CH _Z CHCON HNSO, Ar kde Ar is naphthyl, 5,6,7,8-trtrahydrononyl or naphthyl substituted with at least one 22810Э substituent - from the group halogen, nitro, cyano, hydroxy, alkyl of 1 to 10 carbon atoms or dialkylamino of 2 to 20 carbon atoms, R 7 represents a hydrogen atom or an alkyl of 1 to 10 carbon atoms, Re represents a group —COORe in which Re 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, wherein R7 is substituted in the 2, 3, 4, 5 position. - or 6 and Re in position 2 or 3, characterized in that the starting materials of the above general formula are used, in which Ar, R * and R 'are as defined above and R represents a group of the formula: R6 and R7 are as defined above. ’ H. Method according to item 1 for the preparation of compounds of the general formula HN ( H ^ N 'η' C-N-CH2CH2Cl-lHCO3COOHNSO3 Ar Ί Z (сн ₂ ) з where Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or dialkylamino; 2 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 represents an oxy group, - a thio group or a sulfinyl group, and q represents an integer of 0 or - 1, as well as pharmaceutically acceptable salts of these compounds, characterized in that - starting materials of the above general formula are used - Ar, R 'and R' 'are as defined above, and R - is -. a group of the general formula wherein R 10, Z and q are as defined above. 12. The method according to claim 1 for the manufacture of compounds of general formula sldu COORh ^ ⁽⁷ ^ снну H ^ N H 'C-n ~ н с ^ ^ ^ с H NS NS Ar represents - aftyl, 5,6,7,8-tetrahydronaphthyl or - naphthyl substituted by at least one of halogen, nitro, cyano, - hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or a C 2 -C 20 dialkylamino group, 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 j is 1 or 2 as well as pharmaceutically acceptable salts of these compounds, - characterized in that the starting materials of the above general formula are used, - in which Ar, - R 'and R' are as defined above and R is - represents a group of the general formula COOR 4 - (CH ₂ ) i -N 4 - (CH ₂ ) j where R 1, i and j are as defined above.