CH633773A5 - N(2)-Arylsulphonyl-L-arginamides, process for their preparation and medicaments containing them - Google Patents

Description

The invention relates to N2-arylsulfonyl-L-argininamides with a therapeutic effect and their pharmaceutically acceptable salts, which are of particular value owing to their excellent antithrombotic effects and their low toxicity, to processes for the preparation of these compounds and to medicaments containing these substances as active ingredients.

Many attempts have been made in the past to provide new and better means of treating thrombosis. The N2- (p-tolylsulfonyl) -L-arginine esters have been shown to be suitable agents for this purpose which are effective for the dissolution of blood clots (see US Pat. No. 3,622, issued November 23, 1971 615). A family of compounds which have been found to be particularly effective as a highly specific thrombin inhibitor for combating thrombosis are the N2-dansyl-L-arginine esters or amides (see US Patent Application No. Applicant's 496,939, which resulted in U.S. Patent 3,978,045). For the treatment of thrombosis, however, there is a continuing need for an extremely specific thrombin inhibitor that has a lower toxicity.

It has now been found that N2-arylsulfonyl-L-argininamides have an antithrombotic effect and, compared with the N2-dansyl-L-arginine esters or amides, have an even lower toxicity with the same effect.

The N2-arylsulfonyl-L-argininamides according to the invention correspond to the general formula

^%

C N ch2ch2ch2chcor

H2N I I (i h hns02

I.

Ar in which R and Ar have the meanings given in claim 1.

The invention further relates to the pharmaceutically acceptable salts of these N2-aryIsulfonyl-L-argininamides.

The invention also relates to medicaments which contain one of the 2 N-arylsulfonyl-L-argininamides mentioned or a pharmaceutically acceptable salt thereof in combination with customary binders, carrier materials and / or auxiliaries.

The invention thus relates to a group of N2-arylsulfonyl-L-arginine amides of the general formula I

c - N - ch? ch-> ch2chc0r HoN I I

H HNS02

I.

Ar in the R

1) a group of the general formula

633773

^ (ch2) ncoor2

in the

Rt for a C2-C10 alkyl group such as an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, a hexyl group, an octyl group, a decyl group or the like, an alkenyl group having 3 to 10 carbon atoms (preferably having 3 to 6 carbon atoms) such as an allyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group or the like, an alkynyl group having 3 to 10 (preferably 3 to 6) carbon atoms such as a 2-propynyl group, a 2- Butynyl group, a 3-butynyl group or the like, an alkoxyalkyl group having 2 to 10 (preferably 2 to 6) carbon atoms. such as a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group, a 2-propoxyethyl group, a 2-methoxypropyl group, a 3-methoxypropyl group, a 3-ethoxypropyl group, a 3 -Propoxypropyl group, a 4-methoxybutyl group, a 4-ethoxybutyl group, a 4-butoxybutyl group, a 5-butoxypentyl group or the like, an alkylthioalkyl group having 2 to 10 (preferably 2 to 6) carbon atoms, such as a methylthiomethyl group Ethylthiomethyl group, a propylthiomethyl group, a 2-methylthioethyl group, a

2-ethylthioethyl group, a 2-propylthioethyl group, a

3-methylthiopropyl group, a 2-methylthiopropyl group, a 3-ethylthiopropyl group, a 3-propylthiopropyl group, a 4-methylthiobutyl group, a 4-ethylthiobutyl group, a 4-butylthiobutyl group, a 5-butylthiopentyl group or the like, with an alkylsulfinyl group (preferably 2-alkylsulfinyl) to 6) carbon atoms, such as a methylsulfinylmethyl group, an ethylsulfinylmethyl group, a propylsulfinylmethyl group, a 2-methylsulfinylethyl group, a 2-ethylsulfinylethyl group, a 2-propylsulfinylethyl group, a 3-methylsulfinylpropyl group, or a 3-ethyl group a hydroxylalkyl group having 1 to 10 (preferably 1 to 6) carbon atoms, such as a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxypropyl group, a 4-hydroxybutyl group, a 3-hydroxybutyl group , a 5-hydroxypentyl group or the like, an alkoxycarbonylalkyl group having 3 to 10 (preferably 3 to

8) carbon atoms, such as a methoxycarbonylmethyl group, a 2-ethoxycarbonylethyl group, a 2-ethoxycarbononylpropyl group, a 3-methoxycarbonylpropyl group, a 1-methoxycarbonylbutyl group, a 2-ethoxycarbonylbutyl group, a 4-methoxycarbonylbutyl group, a 3-methoxycarbonylbutyl group to 10 carbon atoms such as a methylcarbonylethyl group or the like, a haloalkyl group having 1 to 10 (preferably 1 to 5) carbon atoms such as a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-chloropropyl group, a 3- Chloropropyl group, a 2-chlorobutyl group, a 4-chlorobutyl group or the like, an aralkyl group having 7 to 15 (preferably 7 to 10) carbon atoms, such as a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, one 6-phenylhexyl group, a 1-1-phenylethyl group, a 2-phenylpropyl group or the like, an a-carboxyaralkyl group with 8 to 15 (vo preferably 8 to 12) carbon atoms such as an a-carboxybenzyl group, an a-carboxyphenethyl group or the like, a C3-C10 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, one

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

633773

Cyclooctyl group, a cyclononyl group or a cyclo-dodeeylgruppe, a C4-C10 cycloalkylalkyl group such as a Cydopropylmethvlgruppe, a cyclopentylmethyl group, a cyclohexylmethyl group, a 2-Cyclohexyläthylgruppe, a Cyclooctylmethylgruppe or the like, a furfuryl group, a tetrahydrofurfuryl group optionally substituted with one or more C ] -C5-alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like and / or CrCa-alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, a 3-furylmethyl group, a tetrahydro-3-furylmethyl group, which is optionally substituted with one or more Q-Cg-alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like and / or C1-C5-alkoxy groups, such as methoxy group, ethoxy groups, propoxy groups, butoxy groups or the like, a tetrahydro-2 (-3 or -4) - pyranylmethyl group, if necessary s is substituted with one or more C, -Crralkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like and / or CrC5-A! koxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, a 1,4-dioxa-2 cyclohexylmethyl group, which is optionally substituted with one or more Cj-Cs-alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like and / or Ci-C5-alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, a 2- The-nyl group, a 3-thenyl group, a tetrahydro-2-thenyl group, optionally with one or more C] -C5-alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like and / or CrCs-alkoxy- groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, is substituted,

or a tetrahydro-3-thenyl group,

R2 represents a hydrogen atom, a C; -C10 alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a tert-butyl group, a hexyl group, an octyl group, a decyl group or the like, a C6-C10 aryl group, such as a phenyl group, a tolyl group, a naphthyl group or the like or an Ar alkyl group having 7 to 12 (preferably 7 to 10) carbon atoms. such as a benzyl group, a phenethyl group or the like and n represents an integer having a value of 1, 2 or 3;

2) a group of the general formula

- n / r3

xcii - (ch2) mc00r5 Ri,

in the

R3 represents a hydrogen atom, a CrC1 (1-alkyl group, such as a methyl group, an ethyl group, a propyl group,

a butyl group, an isobutyl group, a pentyl group, a hexyl group, an octyl group, a decyl group or the like, an alkenyl group having 3 to 10 (preferably 3 to 6) carbon atoms, such as an allyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group or the like, an alkynyl group having 3 to 10 (preferably 3 to 6) carbon atoms, such as a 2-propynyl group, a 2-butynyl group, a 3-butynyl group or the like, an alkoxyalkyl group having 2 to 10 (preferably 2 to 6) ) Carbon atoms, such as a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a 2-methoxy group

10th

äthvlgruppe, a 2-ethoxyethyl group, a 2-propoxy-ethyl group, a 2-methoxypropyl group, a 3-methoxy-propyl group, a 3-ethoxypropyl group, a 3-propoxy-propyl group, a 4-methoxybutyl group, a 4-ethoxy-5-butyl group , a 4-butoxybutyl group, a 5-butoxyptenyl group or the like, an alkylthioalkyl group having 2 to 10 (preferably 2 to 6) carbon atoms, such as a methylthiomethyl group, an ethylthiomethyl group, a propylthiomethyl group, a 2-methylthioethyl group, an io 2-ethythioethyl group a 2-propylthioethyI group, a 3-methylthiopropyl group, a 2-methylthiopropyl group, a 3-ethylthiopropyl group, a 3-propylthiopropyl group, a 4-methylthiobutyl group, a 4-ethylthiobutyl group, a 4-butylthiobutyl group, a 5-likethiobutyl group, a like or a same group, a 5-thiobutyl group, or the like having 2 to 10 (preferably 2 to 6) carbon atoms, such as a methylsulfinylmethyl group, an ethylsulfinylmethyl group, a propylsul finylmethyl group, a 2-methylisulfinylethyl group, a 2-ethylsulfinylethyl group, a 2-propylisulfi-20nylethyl group, a 3-methylsulfinylpropyl group, a 3-ethylisulfinylpropyl group or the like, a hydroxyalkyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms such as a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxy-25 propyl group, a 4-hydroxybutyl group, a 3-hydroxybutyl group, a 5-hydroxypentyl group or the like, an alkoxycarbonylalkyl group having 3 to 10 ( preferably 3 to 8) carbon atoms such as a methoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, a 2-eth-30 oxycarbonylpropyl group, a 3-methoxycarbonylpropyl group, a 1-methoxycarbonylbutyl group, a 2-ethoxycarbonylbutyl group, a 4-methoxycarbonylbutyl group the like, an alkylcarbonylalkyl group having 3 to 10 carbon atoms, such as a methylcarbonylethyl group or the like, a haloalk yl group having 1 to 10 (preferably 1 to 5) carbon atoms such as a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-chloropropyl group, a 3-chloropropyl group, a 2-chlorobutyl group, a 4-chlorobutyl group or the like , a 40 aralkyl group with 7 to 15 (preferably 7 to 10) carbon atoms, such as a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 6-phenylhexyl group, a 1-phenylethyl group, a 2-phenylpropyl group or the like, an a-carboxyaraikyl-45 group having 8 to 15 (preferably 8 to 12) carbon atoms, such as an a-carboxybenzyl group, an a-carboxyphen-ethyl group or the like, a Cj-Cjo-cycloalkyl group such as a cyclopropyl group Cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl-50 group, a cyclooctyl group, a cyclononyl group or a cyclodecyl group, a C4-C10 cycloalkylalkyl group such as a cyclopropylmethyl group ppe, a cyclopentylmethyl group, a cyclohexylmethyl group, a 2-cyclohexyl ethyl group, a cyclooctylmethyl group or the like, 55 a furfuryl group, a tetrahydrofurfuryl group, optionally with one or more Cj-Ca alkyl groups such as methyl groups, ethyl groups, propyl and the like and butyl groups / or CrC5-alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, 60 butoxy groups or the like, a 3-furyl-methyl group, a tetrahydro-3-furylmethyl group which may be substituted with one or more CrC-alkyl groups, such as methyl groups, ethyl groups, Propyl groups, butyl groups or the like and / or Cj-C5-alkoxy groups, 65 such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like is substituted, a tetra-hydro-2 - (- 3 or -4) -pyranyImethyl group, optionally with a or several Cj-C -, - alkyl groups such as Me-

11

633773

thyl groups, ethyl groups, propyl groups, butyl groups or the like, and / or QQ-alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, is substituted, a 1,4-dioxa-2-cyclohexyl-methyl group, optionally with one or more 5 Cj-Cj-alkyl groups such as methylene groups, ethyl groups, propyl groups, butyl groups or the like, and / or Cj-Q-alkoxy groups such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, a 2-thenyl group, a 3-thenyl group , a 10 Tl trahydro-2-thenyl group, optionally with one or more Ct-C5-alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, and / or CrC5-alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the 15 of the same, is substituted, or a tetrahydro-3-thenyl group,

R4 represents an alkyl group having 1 to 10 (preferably 1 to 5) carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a pentyl group or the like Phenyl group which is optionally substituted with one or more CrC5-alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, and / or Ct-C5-alkoxy groups, 2s such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, an aral- alkyl group with 7 to 12 (preferably 7 to 10) carbon atoms, such as a benzyl group, a phenethyl group or the like or a benzyl group substituted on the ring, 30 which as substituents is an alkyl group with 1 to 5 (preferably I to 3) carbon atoms, such as a methyl group,

has an ethyl group, a propyl group or an isopropyl group, or an alkoxy group with 1 to 5 (preferably 1 to 3) carbon atoms, such as a methoxy group, a 35 ethoxy group, a propoxy group or an isopropoxy group,

R5 represents a hydrogen atom, a Ci-C [0-alkyl group, such as a methyl group, an ethyl group, a propyl group,

a butyl group, a tert-butyl group, a hexyl group, an octyl group, a decyl group or the like, a CirC1Q aryl group such as a phenyl group, an m-tolyl group. a naphthyl group or the like or an Ar-alkyl group having 7 to 12 (preferably 7 to 10) carbon atoms such as a benzyl group, a phenethyl group or 45 the like, and m represents an integer of 0, 1 or 2;

3) a group of the general formula

R6

- N

\

R7 independently of one another for hydrogen atoms, alkyl groups with 1 to 10 (preferably 1 to 6) carbon atoms, such as methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, hexyl groups, octyl groups, decyl groups or the like, phenyl groups, Q-Cj-alk-oxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, C2-Ce-alkoxy-carbonyl groups such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, or carboxy groups and p represent an integer with a value from 1 to 4, the group R6 in the 2- or 3-position and the groups R7 can be in the 2-, 3-, 4-, 5- or 6-positions;

4) a group of the general formula COOR9

N

V <c

H

l) v which can optionally be substituted with one or more CrC5 alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, or CrC5 alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, in which

R9 represents a hydrogen atom, a Cj-C10 alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a tert-butyl group, a hexyl group, an octyl group, a decyl group or the like, a C5-C10 aryl group such as a phenyl group, an m-tolyl group, a naphthyl group or the like, or an ar-alkyl group having 7 to 12 (preferably 7 to 10) carbon atoms, such as a benzyl group, a phenethyl group or the like and r for an integer with a value of 1 , 2, 3 or 4 are;

5) a group of the general formula coor10

- N

\ /

- (CH2) q

50

55

(r7> P

in the

Rü for a group of the general formula -COORa,

in which Ra represents a hydrogen atom, a C 1 -C 10 -alkyl group, eo such as a methyl group, an ethyl group, a propyl group,

a butyl group, a tert-butyl group, a hexyl group,

an octyl group, a decyl group or the like, a CirC10 aryl group such as a phenyl group, an m-tolyl group, a naphthyl group or the like or an ar-65 alkyl group having 7 to 12 (preferably 7 to 10) carbon atoms, a benzyl group, a Phenethyl group or the like means.

in the

R10 represents a hydrogen atom, a Cj-S ^ -alkyl group, such as a methyl group, an ethyl group, a propyl group,

a butyl group, a tert-butyl group, a hexyl group, an octyl group, a decyl group or the like, a C6-C10 aryl group such as a phenyl group, an m-tolyl group, a naphthyl group or the like, or an aralkyl group having 7 to 12 (preferably 7 to 10) carbon atoms, such as a benzyl group, a phenethyl group or the like,

Z represents an oxygen atom (-0-), a sulfur atom (-S-) or a sulfinyl group (-SO-) and q represents an integer with a value of 0 or 1; or

6) a group of the general formula coor \

11

-N

/ ^ CH2) i \,

\ (ch2) z '

633773

in the

Rn for a hydrogen atom, a crc10 alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a tert-butyl group, a hexyl group, an octyl group, a decyl group or the like, a C6-C10 aryl group such as a phenyl group , an m-to-lyl group, a naphthyl group or the like, an aralkyl group having 7 to 12 (preferably 7 to 10) carbon atoms, such as a benzyl group, a phenethyl group or the like,

i represents an integer with a value of 0.1 or 2 and j represents an integer with a value of 0.1 or 2, the sum i + j representing an integer with a value of 1 or 2; and

Ar is a phenyl group or a naphthyl group, each with at least one substituent from the sulfoamino groups, carbamoyi groups, N, N-dialkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N - Diethyl-carbamoyl groups or the like, N-alkylcarbamoyl groups with 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl groups, N-ethylcarbamoyl groups or the like, amino groups, alkylamino groups

1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino groups, ethylamino groups, propylamino groups, butylamino groups or the like, mercapto groups, alkylthio groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio groups, ethylthio groups, propylthio groups, butylthio groups the like, aralkyl groups having 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl groups, phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups

2 to 10 (preferably 2 to 6) carbon atoms, such as meth-oxycarbonyl groups, ethoxycarbonyl groups or the like, carboxyalkyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl groups, 2-carb-oxyethyl groups, 2-carboxypropyl groups or the like, acyl amino groups such as alkylcarbonylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms such as acetylamino groups, propionylamino groups or the like, alkylcarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms such as acetyl groups, propionyl groups or the like, hydroxylalkyl groups with 1 to 10 ( preferably 1 to 5) carbon atoms, such as hydroxymethyl groups, 2-hydroxyethyl groups, 2-hydroxypropyl groups or the like, haloalkyl groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, Hydroxyalkoxy groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy groups, 2-hydroxyethoxy groups or the like and phenyl groups, which are optionally substituted with at least one hydroxyl group and / or C 1 -C 6 -alkoxy groups, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like, are substituted is;

a phenyl group or a naphthyl group, each with at least one substituent from the sulfoamino groups, carbamoyi groups, N, N-dialkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N-diethylcarbamoyI groups or the like, N-alkylcarbamoyl groups with 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl groups, N-ethylcarbamoyl groups or the like, amino groups, alkylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino groups, Ethylamino groups, propylamino groups, butylamino groups or the like, mercapto groups, alkylthio groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio groups, ethylthio groups, propylthio groups, butylthio groups or the like, aralkyl groups having 7 to 12 carbon atoms (preferably 7 to 10) carbon atoms, such as 7 to 10 carbon atoms, preferably 7 to 10 carbon atoms , Phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, carboxyalkyl groups with 2 to 10 (preferably 2 to 6) carbon atoms such as carboxymethyl groups, 2-carboxyethyl groups, 2-carboxypropyl groups or the like, acylamino groups such as Alkylcarbonylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, alkylcarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl groups, propionyl groups or the like, hydroxyalkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms such as hydroxymethyl groups, 2-hydroxyethyl groups, 2-hydroxypropyl groups or the like, haloalkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, hydroxyalkoxy groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as Hydroxymethoxy groups, 2-hydroxyethoxy groups or the like and phenyl groups which are optionally substituted with at least one hydroxyl group and / or QQ-alkoxy group, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, comprising a group and at least one substituent from the halogen atoms, nitro groups , Cyano groups, hydroxyl groups, alkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, alkoxy groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, dialkylamino groups having 2 to 20 (preferably 2 to 10) carbon atoms, such as a group comprising dimethylamino groups, diethylamino groups, dipropylamino groups or the like;

an oxanthrenyl group or dibenzofuranyl group which has at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, dialkylamino groups having 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino groups, diethylamino groups, dipropylamino groups or the like, sulfoamino groups, carbamoyl groups, carbamino groups Dialkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N-diethylcarbamoyl groups or the like, N-alkylcarbamoyl groups with 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl groups, N-ethylcarbamoyl groups or the like, amino groups, alkylamino groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino groups, ethylamino groups, propylamino groups, butylamino groups or the like, mercapto groups, alkylthio groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as Methylthio groups, ethylthio groups, propylthio group s, butylthio groups or the like, aralkyl groups with 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl groups, phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, Carboxyalkyl groups having 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl groups, 2-carboxyethyl groups, 2-carboxypropyl groups or the like, preferably acylamino groups, such as alkylcarbonylamino groups having 1 to 10) 12

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

example 1 to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, alkylcarbonyl groups having 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl groups, propionyl groups or the like, hydroxyalkyl groups having 1 to 10 (preferably 1 to 5) carbon atoms such as hydroxymethyl groups, 2-hydroxyethyl groups, 2-hydroxypropyl groups or the like, haloalkyl groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, hydroxyalkoxy groups having 1 to 10 (preferably 1 to 5) carbon atoms such as hydroxymethoxy groups, 2-hydroxyethoxy groups or the like, and phenyl groups optionally having at least one hydroxy group and / or C1-Cg-alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like is substituted, comprehensive group is substituted;

an oxanthrenyl group or dibenzofuranyl group which has at least one substituent from the alkyl group having 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, alkoxy groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as Group comprising methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like and at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, dialkylamino groups having 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino groups, diethylamino groups, dipropylamino groups or the like, sulfoamino groups Carbamoyl groups, N, N-dialkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N-diethylcarbamoyl groups or the like, N-alkyl-carbamoyl groups with 2 to 6 (preferably 2 to 4 ) Carbon atoms, such as N-methylcarbamoyl groups, N-ethylcarbam oyl groups or the like, amino groups, alkylamino groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino groups, ethylamino groups, propylamino groups, butylamino groups or the like, mercapto groups, alkylthio groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio groups, ethylthio groups Propylthio groups, butylthio groups or the like, aralkyl groups having 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl groups, phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups having 2 to 10 (preferably 2 to 6) carbon atoms such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, carboxyalkyl groups 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl groups, 2-carboxyethyl groups, 2-carboxypropyl groups or the like, acylamino groups, such as alkylcarbonylamino groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, alkylcarbonyl groups having 2 to 10 (preferably 2 to 6) carbon atoms such as acetyl groups, propionyl groups or the like, hydroxyalkyl groups having 1 to 10 (preferably 1 to 5) carbon atoms such as hydroxymethyl groups, 2-hydroxyethyl groups, 2-hydroxypropyl groups or the like , Haloalkyl groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, hydroxyalkoxy groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy groups, 2-hydroxyethoxy groups or the like and phenyl groups, optionally with at least one hydroxyl group and / or Cj-C5-alkoxy group, such as a methoxy group, an ethoxy group, a

13 633773

Propoxy group, a butoxy group or the like are substituted group;

a tetrahydronaphthyl group, a 2-ethylenedioxyphenyl group, a chromanyl group, a 2,3-ethylenedioxy-5 naphthyl group or a xanthenyl group, which groups have at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, dialkylamino groups with 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino groups, diethylamino-io groups, dipropylamino groups or the like, sulfoamino groups, carbamoyi groups, N, N-dialkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N -Diethyl-carbamoyl groups or the like, N-alkylcarbamoyl groups-15 pen with 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl groups, N-ethylcarbamoyl groups or the like, amino groups, alkylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms such as methylamino groups, ethylamino groups, propylamino groups, butyl-20 amino groups or the like, mercapto groups, Al kylthio groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio groups, ethylthio groups, propylthio groups, butylthio groups or the like, aralkyl groups with 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl groups, phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, carboxyalkyl groups with 2 to 10 (preferably 2 to 6) 30 carbon atoms, such as carboxymethyl groups, 2-carboxy-ethyl groups, 2-carboxypropyl groups or the like, acylamino groups, such as alkylcarbonylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, 35 alkylcarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms such as acetyl groups, propionyl groups or the like, hydroxyalkyl groups with 1 to 10 (preferably 1 up to 5) carbon atoms, such as hydroxymethyl groups, 2-hydroxyethyl groups, 2-hydroxypropyl groups 40 or the like, haloalkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, hydroxyalkoxy groups with 1 to 10 (preferably 1 to 5 ) Carbon atoms, such as Hy-45-hydroxymethoxy groups, 2-hydroxyethoxy groups or the like, oxo groups and phenyl groups, which are optionally substituted with at least one hydroxyl group and / or QQ-alkoxy group, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like 50 , comprehensive group are substituted;

a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylene-dioxynaphthyl group or a xanthenyl group, which groups have at least one substituent from the Al-55 alkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, alkoxy groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as a group comprising methoxy groups, ethoxy groups, propoxy groups, butoxy groups or 60 the like and at least one substituent from the halogen atoms, nitro groups, cyano groups. Hydroxy groups, dialkylamino groups with 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino groups, diethylamino groups, dipropylamino 65 groups or the like, sulfoamino groups, carbamoyi groups, N, N-di! Alkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethyl-carbamoyl groups, N, N-diethylcarbamoyl groups or the

633773

same, N-alkylcarbamoyl groups with 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl groups, N-ethylcarbamoyl groups or the like, amino groups, alkylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino groups, ethylamino groups, propylamino groups, Butylamino groups or the like, mercapto groups, alkylthio groups with

1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio groups, ethylthio groups, propylthio groups, butylthio groups or the like, aralkyl groups with 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl groups, phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups with 2 to 10 (preferably

2 to 6) carbon atoms such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, carboxyalkyl groups having 2 to 10 (preferably 2 to 6) carbon atoms such as carboxymethyl groups, 2-carboxyethyl groups, 2-carboxypropyl groups or the like, acylamino groups such as alkylcarbonylamino groups having 1 to 10 (preferably I to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, alkylcarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl groups, propionyl groups or the like, hydroxyalkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl groups, 2- Hydroxyethyl groups, 2-hydroxypropyl groups or the like, haloalkyl groups with ibis 10 (preferably 1 to 5) carbon atoms, such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, hydroxyalkoxy groups with 1 to 10 (preferably

I to 5) carbon atoms such as hydroxymethoxy groups, 2-hydroxyethoxy groups or the like, oxo groups and phenyl groups which are optionally substituted with at least one hydroxyl group and / or Cj-Cj-alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like , comprehensive group are substituted;

a naphthoquinonyl group, an anthryl group, a phenanthryl group, a pentalenyl group, a heptalenyl group, an azulenyl group, a biphenylenyl group, an as indacenyl group, an s-indacenyl group, an acenaphthylenyl group, a phenylcarbonylphenyl group, a benzoxyphenyl group, a phenoxyphenyl group, a phenoxyphenyl group, a benzoxyphenyl group, a benzoxyphenyl group, a benzoxyphenyl group , a benzo [b] thienyl group, an iso-benzothienyl group, a thianthrenyl group, a dibenzo-thienyl group, a phenoxathiinyl group, an indolyl group, an IH-indazolyl group, a quinolyl group, an iso-quinolyl group, a phthalazinyl group, a 1,8- Naphthridynyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, an acridinyl group, a phenazinyl group, a phenothiazinyl group, a phenoxazinyl group or a benzimidazolyl group, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, nitro groups, Hydroxyl groups, Al alkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, alkoxy groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, dialkylamino groups 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino groups, diethylamino groups, dipropylamino groups or the like, sulfoamino groups, carbamoyi groups, N, N-dialkylcarbamoyl groups

3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N-diethylcarbamoyl groups or the like, N-alkylcarbamoyl groups having 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarb-

14

amoyl groups, N-ethylcarbamoyl groups or the like, amino groups, alkylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino groups, ethylamino groups, propylamino groups, butylamino-5 groups or the like, mercapto groups, alkylthio groups with 1 to 10 (preferably 1 to 5) Carbon atoms such as methylthio groups, ethylthio groups, propylthio groups, butylthio groups or the like, aralkyl groups with 7 to 12 (preferably? To 10) carbon atoms such as io benzyl groups, phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as Methoxycarbonyl groups, ethoxycarbonyl groups or the like, carboxyalkyl groups having 2 to 10 (preferably 2 to 6) carbon

15 atoms, such as carboxymethyl groups, 2-carboxyethyl groups, 2-carboxypropyl groups or the like, acylamino groups, such as alkylcarbonylamino groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, alkylcar-

20 bonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl groups, propionyl groups or the like, hydroxyalkyl groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl groups, 2-hydroxyethyl groups, 2-hydroxypropyl groups or the like, Haloalkyl groups having 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, hydroxyalkoxy groups having 1 to 10 (preferably 1 to 5) carbon atoms such as hydroxy-30 methoxy groups, 2-hydroxyethoxy groups or the like , and phenyl groups optionally substituted with at least one hydroxy group and / or a C 1 -C 6 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like;

a CrC12-aralkyl group, a C9-C16-cycloalkylphenyl group, a C10-Cls-cycloalkylalkylphenyl group, a C9-C16-cycloalkoxyphenyl group, a C9-C18-cycloalkyI-thiophenyl group, a Cfl-C10-dihydroanthryl group, a 40 5.6, 7,8-tetrahydroanthryl group, a 9,10-dihydrophen-anthryl group, a 1,2,3,4,5,6,7,8-octahydrophenanthryl group, an indenyl group, an indanyl group, a fluoro-nyl group, an acenapthenyl group, a phenylthiophene group, an isochromanyl group, a 2,3-dihydrobenzo-45 furanyl group, a 1,3-dihydroisobenzofuranyl group, a thioxanthenyl group, a 2H-chromenyl group, a 3,4-dehydro-l-isochromanyl group, a 4H-chromenyl group, an indolinyl group, an isoindolinyl group, a 1,2,3,4-tetrahydroquinoyl group or a 1,2,3,4-tetrahydroiso-50 quinolyl group, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups, hydroxyl groups , Alkyl groups with 1 to 10 (preferably I to 5 ) Carbon atoms, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, alkoxy groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, dialkylamino groups with 2 to 20 (preferably 2 to 10 ) Carbon atoms, such as dimethylamino groups, diethylamino groups, dipropylamino groups or the like, sulfoamino groups, carbamoyl groups, N, N-dialkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoy] groups, N, N-diethylcarbamoyl groups or the like, N-alkylcarbamoyl groups with 2 65 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl groups, N-ethylcarbamoyl groups or the like, amino groups, alkylamino groups with 1 to 10 (preferably 1 to 5) Carbon atoms, such as methylamino

groups, ethylamino groups, propylamino groups, butylamino groups or the like, mercapto groups, alkylthio groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio groups, ethylthio groups, propylthio groups, butylthio groups or the like, aralkyl groups having 7 to 7 (preferably 12 to 12) ) Carbon atoms, such as benzyl groups, phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, carboxyalkyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl groups, 2-carboxyethyl groups, 2-carboxypropyl groups or the like, acylamino groups, such as alkylcarbonylamino groups with 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, alkylcarbonyl groups with 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl groups , Propionyl group s or the like, hydroxyalkyl groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl groups,

2-hydroxyethyl groups, 2-hydroxypropyl groups or the like, haloalkyl groups with 1 to 10 (preferably

1 to 5) carbon atoms such as chloromethyl groups, trifluoromethyl groups, bromomethyl groups, 2-chloroethyl groups or the like, hydroxyalkoxy groups having 1 to 10 (preferably 1 to 5) carbon atoms such as hydroxymethoxy groups, 2-hydroxyethoxy groups or the like, oxo groups or phenyl groups optionally substituted with at least one hydroxy group and / or a CrC5 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like;

or a phenyl group which is substituted by at least one substituent from the group comprising alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and alkoxycarbonylalkoxy groups, the substituent having 3 to 7 carbon atoms, the substituted phenyl group optionally further having at least one substituent from the group comprising methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms, such as a 3-propyl-4-methoxyphenyl group, a 3-tert-butyl-4-methoxyphenyl group, a 3-sec-butyl group -4-hydroxyphenyl group, a

3-propoxyphenyl group, a 3-methoxy-4-propoxyphenyl group, a 3-propoxy-4-methoxy-phenyl group, a 2,4-dimethoxy-3-propoxyphenyl group, a 3-butoxyphenyl group, a 2-butoxyphenyl group, one 2,5-dibutoxyphenyl group, 3,4-dibutoxyphenyl group, 2,4-dibutoxyphenyl group, 3-methyl-4-butoxyphenyl group, 3,5-dimethyl-4-butoxyphenyl group, 2,4-dimethoxy-3 -butoxy-phenyl group, a 2,4-dichloro-3-butoxyphenyl group, a 3-pentyoxyphenyl group, a 3-isopentyloxyphenyl group, a 3,5-dimethyl-4-pentyloxyphenyl group, a 2,4-dimethoxy-3-pentyoxyphenyl group, a 2,4-dimethoxy-3-hexyloxyphenyl group, a 2,4-dimethoxy-3- (3-bromo-propoxy) phenyl group, a 2,4-dimethoxy-3- (2-methoxy-ethoxy) phenyl group, a 2,4-dimethoxy-3- (2-ethoxy-ethoxy) pheny! group, a 3-methyl-4- (2-methoxyethoxy) phenyl group, a 3-methyl-4- (3-methoxypropoxy) - phenyl group, a 3-valeryl-4-methoxyphenyl group, a 2,4-dimethoxy-4- (3-methoxycarbonylpropoxy) phenyl group e and the like mean.

633773

Preferred groups R are

1) Groups of the general formula

- N

(CH2) nC00R2

in the

Rj is a C2-C10 alkyl group, an alkenyl group, a C2-C10 alkoxyalkyl group, a C2-C10-alkylthioalkyl group, a C2-C10-alkylsulfinylalkyl group, a C7-C15-Ar-alkyl group, a C3-C10-cycloalkyl group , a C4-C10-cycloalkylalkyl group, a furfuryl group, a tetrahydrofurfuryl group, a tetrahydro-2 - (- 3 or -4) -pyranylmethyl group or a 1,4-dioxa-2-cyclohexylmethyl group,

R2 represents a hydrogen atom, a c ^ cjj alkyl group, a c6-c10 aryl group or a c7-c12 aralkyl group and n is an integer with a value of 1, 2 or 3;

2) Groups of the general formula

CH- (CH-,) COORr-, 2'm 5

in the

R3 is a hydrogen atom, a Cj-Cjo alkyl group, a C3-C10 alkenyl group, a C2-C10 alkoxyalkyl group, a C2-C10-alkylthioalkyl group, a C2-C10-alkylsulfinyl-alkyl group, a C7-C15-aralkyl group, a C3- C10-cycloalkyl group, a c4-c10 cycloalkylalkyl group, a furfuryl group, a tetrahydrofurfuryl group, a tetrahydro - 2-3- or -4) -pyranylmethyl group or a 1,4-dioxa-2-cyclohexylmethyl group,

R4 is a CrC »-alkyl group, a phenyl group which is optionally substituted by at least one Cj-C5-alkyl group, a CrC5-alkoxy group or mixtures thereof, a C7-C12-araikyl group or a benzyl group substituted on the ring which has a CrCrralkyl group as substituents or has a Ci-C5-alkoxy group,

R5 represents a hydrogen atom, a CrC10 alkyl group, a C6-C10 aryl group or a C7-C12 aralkyl group and m represents an integer with a value of 0.1 or 2;

3) Groups of the general formula

«6

in the

R6 represents a group of the formula -COOR8 for a hydrogen atom, a CrCi0-alkyl group, a C6-C] 0-aryl group or a C7-Ci2-aralkyl group,

R, independently of one another, hydrogen atoms, Cj-C ^ AI-alkyl groups or phenyl groups,

p is an integer with a value from 1 to 4, the group R6 in the 2 or 3 position and the groups R7 in the 2, 3, 4, 5 or 6 position - can stand;

15

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

633773

16

4) Groups of the general formula coorq

C oqrj, -j / "

- n

V (ch2

\

z /

Yes in that

R10 is a hydrogen atom, a Q-Qq-alkyl group, a C6-Ci0-aryl group or a C7-C12-aralkyl group,

Z represents an oxygen atom, a sulfur atom or a sulfinyl group and q represents an integer with a value of 0 or 1; and

6) groups of the general formula co or] j in the

Rn is a hydrogen atom, a crc10 alkyl group, a C6-C10 aryl group or a C7-C12 aralkyl group,

i is an integer with a value of 0.1 or 2 and j is an integer with a value of 0.1 or 2 and the sum i + j is an integer with a value of 1 or 2.

The most preferred groups R are 1) groups of the general formula r

- n

1

(CH2) nCOOR2

2) Groups of the general formula

- n

: cHa) r which are optionally substituted with at least one C 1 -C 6 -alkyl group, CrC5-alkoxy group or mixtures thereof, in which

R9 represents a hydrogen atom, a CrC10-alkyl group, a C6-Ci0-aryl group or a C7-C12-aralkyl group and r represents an integer with a value of 1, 2, 3 or 4;

5) Groups of the general formula

CH- (CH2) mCOOR5 * 4

io in the

R3 is a hydrogen atom, a C1-C10-alkyl group, a C2-C6-alkoxyalkyl group, a C2-C6-alkylthioalkyl group, a C7-C10-aralkyl group, a C4-C10-cycloalkylalkyl group, a furfuryl group or a tetrahydrofurfuryl group, 15 R4 a CrCä- Alkyl group,

R5 represents a hydrogen atom or a CrC10 alkyl group and m represents an integer with a value of 0.1 or 2;

20 3) Groups of the general formula

R6

r

- n

V

(r7 ^ p

30 in

R6 is a group of the formula -COOR8, in which R8 represents a hydrogen atom or a Cj-C ^ -alkyl group,

R7 independently of one another are hydrogen atoms or Q-Cg-alkyl groups and 35 p is an integer with a value from 1 to 4

mean, where the group R6 in the 2- or in the 3-position and the groups R7 can be in the 2-, 3-, 4-, 5- or 6-positions;

4) Groups of the general formula

40

45

coor

- n

-tCH2) 'r which are optionally substituted with at least one Cj-C5-alkyl group, CrCfj-alkoxy group or mixtures thereof, so in the

R9 represents a hydrogen atom or a CrCi0 alkyl group and r represents an integer with a value of 1, 2, 3 or 4;

55 5) Groups of the general formula in the

Rj is a C2-C10-alkyl group, a C2-C6-alkoxyalkyl group, a C2-C6-alkylthioalkyl group, a C, -C10-aralkyl group, a C4-C10-cycloalkylalkyl group, a furfuryl group or a tetrahydrofurfuryl group,

R2 represents a hydrogen atom or a C, -C10-alkyl group and n represents an integer with a value of 1, 2 or 3;

coor V

10th

60

- n

\

lz

- (ph2ì

in the

65 R] 0 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms,

Z is an oxygen atom, a sulfur atom or a sulfinyl group and

q represents an integer with a value of 0 or 1; and

6) Groups of the general formula

COORjq x (ch2) j / ^

in the

Ru is a hydrogen atom or a CrC10 alkyl group, i is an integer with a value of 0, 1 or 2

and j represents an integer with a value of 0, 1 or 2, the sum i + j representing an integer with a value of 1 or 2.

Suitable groups Ar are phenyl groups or naphthyl groups, each with at least one substituent from the sulfoamino groups, carbamoyl groups, C3-C10-N, N-dialkylcarbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino groups, Ci-C10-alkylamino groups , Mercapto groups, CrC10-alkylthio groups, C7-C12-aralkyl groups, carboxy groups, C2-C10-alkoxycarbonyl groups, C2-C10-carboxyalkyl groups, CrC10-acylamino groups, C2-C10-alkylcarbonyl groups, CrC10-hydroxyalkyl groups, Cj-Cjq-haloalkyl groups -Cjo-hydroxyalkoxy groups or phenyl groups which are optionally substituted with at least one hydroxyl group, a CrC5 alkoxy group or mixtures thereof;

Phenyl groups or naphthyl groups, each with at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, CrC10-alkyl groups, Cj-Cm-alkoxy groups and C2-C20-dialkylamino groups and at least one substituent from the sulfoamino groups, carbamoyl groups , C3-C10-N, N-dialkylcarbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino groups, C1-Ci0-alkylamino groups, mercapto groups, CrC10-alkylthio groups, C7-C12-aralkyl groups, carboxy groups, C2-C10-alkoxycarbonyl groups , C2-C1 () - carboxyalkyl groups, C1-CJ0-acylamino groups, C2-C, "-alkylcarbonyl groups, crc10 -hydroxyalkyl groups, CrC10-haloalkyl groups, C1-C, 10-hydroxyalkoxy groups and phenyl groups, optionally with at least one hydroxy group, CrC5- Alkoxy group or mixtures thereof are substituted, comprehensive group are substituted;

Oxanthrenyl groups or dibenzofuranyl groups which contain at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-di-alkylamino groups, C2-C6-N-alkylcarbamoyl groups, C ^ C ^ -alkylamino groups, mercapto groups, CrC10-alkylthiogrup C2-C10-alkoxycarbonyl groups, Cj-Qo-hydroxyalkyl groups, Cj-Qo-haloalkyl groups and Q-Cm-hydroxyalkoxy groups are substituted;

Oxanthrenyl groups or dibenzofuranyl groups which have at least one substituent from the group comprising C 1-4 alkyl groups and CrC10 alkoxy groups and at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-di-alkylamino groups, C2- C6-N-alkylcarbamoyl groups, Cj-C10-alkylamino groups, mercapto groups, C1-C10-alkylthio groups, C2-C10-alkoxycarbonyl groups, C ^ C ^ -hydroxyalkyl groups, Ci-Ci0-haloalkyl groups and CrC10-hydroxyalkoxy groups are substituted ;

Tetrahydronaphthyl groups, 1,2-ethylenedioxyphenyl groups, chromanyl groups, 2,3-ethylenedioxynaphthyI groups or xanthenyl groups which are linked to at least one

633773

Substituents from halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-dialkylamino groups, C2-C6-N-alkylcarbamoyl groups, Q-CjQ-alkylamino groups, mercapto groups, Q-Cm-alkylthio groups, C2-C10-alkoxy-carbonyl groups, CrC10-hydroxy groups , CrC10 halo genalkyl groups, CrC10 hydroxyalkoxy groups and oxo groups are substituted;

T etrahydronaphthyl groups, 1,2-ethylenedioxyphenyl groups, chromanyl groups, 2,3-ethylenedioxynaphthyl groups or xanthenyl groups, which groups have at least one substituent from the group comprising CVCk, alkyl groups and Cj-CjQ alkoxy groups and at least one substituent from the halogen atoms , Nitro groups, cyano groups, hydroxy groups, C2-C20-dialkylamino groups, C2-C6-N-alkylcarbamoyl groups, C1-C10-alkylamino groups, mercapto groups, CrC10-alkylthio groups, C2-C10-alkoxycarbonyl groups, QC ^ -hydroxyalkyl groups, Cj- Cuj-haloalkyl groups, Q-Cm-hydroxyalkoxy groups and oxo groups are substituted;

Anthryl groups, phenanthryl groups, biphenylenyl groups, s-indacenyl groups, phenylcarbonylphenyl groups, phenoxyphenyl groups, benzofuranyl groups, benzo [b] thie-nyl groups, thianthrenyl groups, dibenzothienyl groups, phenoxathiinyl groups, quinolyl groups, isoquinoloxolinyl groups, quinoloxolinyl groups, quinolylolinyl groups, Phenazinyl groups, phenothiazinyl groups or phenoxazinyl groups, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups, hydroxy groups, Cj-C ^ alkyl groups, CrC10 alkoxy groups, C2-C20 dialkylamino groups and CrC10-hydroxy groups group comprising alkoxy groups are substituted;

C7-C12-aralkyl groups, C9-C16-cycloalkylphenyl groups, C10-Cie-cycloalkylalkylpheny] groups, C9-C16-cycloalkoxy-phenyl groups, 9,10-dihydroanthryl groups, 5,6,7,8-tetra-hydroanthryl groups, 9,10- Dihydrophenanthryl groups, 1,2,3,4,5,6,7,8-octahydrophenanthryl groups, indenyl groups, indanyl groups, fluorenyl groups, acenaphthenyl groups, phenylthiophenyl groups, 2,3-dihydrobenzofuranyl groups, thioxanthenyl groups, 2H-chromenyl groups or 1, 2,3,4-tetrahydrochinoIyl groups, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, CrC10-alkyl groups, CrC10-alkoxy groups, C2-C20-dialkylamino groups, C2-C6-N-alkylcarbamoyl groups , CrC10 hydroxyalkoxy groups and oxo groups are substituted;

or phenyl groups which are substituted with at least one substituent from the group comprising alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and alkoxycarbonylalkoxy groups, which substituent has 3 to 7 carbon atoms, the substituted phenyl groups optionally also with at least one substituent from the methyl groups , Ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms are substituted.

Preferred groups are Ar

Phenyl groups or naphthyl groups with at least one substituent from the amino groups, Q-Qj-alkyl-amino groups, Q-Qo-alkylthio groups, C7-C12-aralkyl groups, C2-C10-alkoxycarbonyl groups, Ci-C10-acylamino groups, C2-C10 -Alkylcarbonyl groups, C ^ Cnj-hydroxyalkyl groups, CrC10-hydroxyalkoxy groups and phenyl groups are substituted;

Phenyl groups or naphthyl groups, each with at least one substituent from the amino groups, CrC10-alkylamino groups, Cj-C ^ -alkylthio groups, C7-C12-

17th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

633773

Aralkyl groups, C2-Ci0-alkoxycarbonyl groups, Ci-C10-acyl-amino groups, C2-CI0-alkylcarbonyl groups, CrC10-hydroxyalkyl groups, CrC10-hydroxyalkoxy groups and phenyl groups and at least one substituent from the halogen atoms, hydroxyl groups, Cx-C10-alkoxy groups and a group comprising C2-C20 dialkylamino groups;

Dibenzofuranyl groups substituted with at least one halogen atom;

Dibenzofuranyl groups which are substituted with at least one substituent from the group comprising CrCi0-alkyl groups and Cj-C10-alkoxy groups and at least one halogen atom;

Tetrahydronaphthyl groups, 1,2-ethylenedioxyphenyl groups, chromanyl groups, 2,3-ethylenedioxynaphthyl groups or xanthenyl groups which are substituted by at least one halogen atom;

Tetrahydronaphthyl groups, 1,2-ethylenedioxyphenyl groups, chromanyl groups, 2,3-ethylenedioxynaphthyl groups or xanthenyl groups which are substituted with at least one substituent from the group comprising CrC10-alkyl groups and Ci-C10-alk-oxy groups and with at least one halogen atom;

Anthrenyl groups, phenanthryl groups, biphenylenyl groups, phenoxyphenyl groups, benzofuranyl groups, benzo [b] thienyl groups, dibenzothienyl groups, phenoxethyninyl groups, quinolyl groups, isoquinolyl groups, quinoxalinyl groups, acridinyl groups or phenazinyl groups, which are unsubstituted or with one or more halo groups, from or with one or more halo groups, with or Cj-C10 alkyl groups, CrC10 alkoxy groups and Cj-C] 0-hydroxyalkoxy groups are substituted;

C7-C12-aralkyl groups, C9-Cj6-cycloalkylphenyl groups, fluorenyl groups, thioxanthenyl groups, 2H-chromenyl groups or 1,2,3,4-tetrahydroquinolyl groups, which are unsubstituted or with one or more groups from the CrC, 0-alkyl groups, CrC] 0 -Alkoxy groups and oxo groups are substituted;

or phenyl groups which are substituted by at least one substituent from the group comprising alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and alkoxycarbonylalkoxy groups, which substituent contains 3 to 7 carbon atoms, the substituted phenyl groups optionally further having at least one substituent from the A group comprising methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms can be substituted.

The most preferred groups Ar are phenyl groups or naphthyl groups, each of which is substituted with at least one substituent from the amino groups, Cj-C ^ -alkylamino groups, C7-CJ2-aralkyl groups, CrC10 -acylamino groups, CrC10-hydroxyalkyl groups and CrC10-hydroxyalkoxy groups;

Phenyl groups or naphthyl groups, each with at least one substituent from the amino groups, Cj-C10-alkylamino groups, C7-C12-aralkyl groups, CrCJ0-acylamino groups, Cj-CjQ-hydroxyalkyl groups and ca-c10-hydroxyalkoxy groups and at least one substituent from the halogen atoms , Hydroxy groups, Cj-C10 alkyl groups and Ci-CjQ alkoxy groups are substituted;

Biphenylenyl groups, phenoxyphenyl groups, dibenzothienyl groups, phenoxathiinyl groups, quinolyl groups or quinoxalinyl groups, which are unsubstituted or substituted by one or more groups from the group comprising hydroxyl groups and CrCi0-alkyl groups;

C7-C12 aralkyl groups, C9-C16 cycloalkylphenyl groups, fluorenyl groups or 2H-chromethyl groups which are unsubstituted or substituted by one or more groups from the group comprising Cj-C10-alkyl groups, CrC10-alkoxy groups and oxo groups;

or phenyl groups which are substituted with at least one substituent from the group comprising alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and aikoxycarbonylalkoxy groups, which substituent has 3 to 7 carbon atoms, these substituted phenyl groups optionally also having at least one substituent from the A group comprising methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms can be substituted.

Preferred compounds according to the invention are:

1 - [N2- (quinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-pipe-ridin-carboxylic acid,

1- [N2- (3-methylquinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

1 - [Nz- (3-ethylquinoline-8-sulfonyl) -L-arginyl] -4-methyl - 2-piperidinecarboxylic acid,

l- [N2- (3-sec-butoxybenzene-l-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

1- [N2- (3,5-dimethyl-4-isopropoxybenzene-1-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

1 - [N2- (2,4-dimethoxy-3-butoxybenzene-1 -sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

1- [N2- (3-isopropoxybenzene-l-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

N2- (2-phenoxathiinylsulfonyl) -L-arginyl-N-tetrahydro-furfurylglycine,

N2- (2-fluorosulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine and l- [N2- (4-methoxy-3-cyclohexylbenzene-l-sulfonyl) -L-argi-nyl] -4 -methyl-2-piperidinecarboxylic acid.

The invention naturally also relates to the pharmaceutically acceptable salts of the above compounds.

To produce the compounds according to the invention, three different processes are used, which are defined in claims 5, 8 and 10 and explained in more detail below.

18th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

19th

633773

a) Condensation of an L-arginine amide with an arylsulfonyl halide according to the following reaction scheme:

H_\

H0N "

HN '

HN "

! IN "I

R '

:; x

H'iN '

"l"

H

- N -

I.

R "

CH-jCIHCHTCHCOOH

NH-,

CH0CH0CH1CHCOOH * "I HX

I.

U "1

- * ■ RH

- \ "- CI I '» Clio Cl ît CHCOR

! ~ I

r-f "il \

I.

(ii)

(m)

(IV)

(v)

- .V

I.

H

- CH.

CHoCH-.CHCOR "" l

XH2

+ ArSOgX

(VI)

(VII)

ethyl ether, diethyl ether / water and dioxane / water mixtures.

After the reaction has ended, the salt formed is extracted with water, the solvent is stripped off in the customary manner, for example by evaporation under reduced pressure, and the N2-arylsulfonyl-L-argininamide of the general formula I is obtained, which can be purified by trituration or by recrystallization in a suitable solvent, such as a diethyl ether / tetrahydrofuranio mixture, a diethyl ether / methanol mixture or a water / methanol mixture, or by chromatography on silica gel.

The L-argininamides of the general formula 15 VI required for the condensation reaction as starting materials are prepared in that the guanidino group and the a-amino group of L-arginine are preferably obtained by nitriding, acetylating, formylating, phthaloylerene, trifluoroacetylating, p-methoxybenzyloxycarbonylating, Protects benzoylating, benzyloxycarbonylating, tert-butoxycarbonyl-20 or tritylating and then condenses the ^ -substituted N2-substituted L-arginine of the general formula III obtained with a corresponding amino acid derivative of the general formula IV, for which a conventional method is used, for example the Acid chloride method, 25 the azide method, the mixed anhydride method, the activated ester method or the carbodiimide method, and then selectively cleaves the protective groups from the NG-substituted and ^ -substituted L-argininamide of the general formula V-30.

The amino acid derivatives of the general formula IV which are used as starting materials for the preparation of the ^ -substituted and N2-substituted L-argininamides of the general formula V correspond to the following 35 general formulas

HN "

%

H., X "

X - CIN CH-> CH n C HC OR

I ~ I

II IL \ SO2

(I)

H-.V

40

."1

( in the.

(ix;

c: i- (cn-j jn'-oon ^

Ar

In the above general formulas, R and Ar have the meanings given above, while X for a halogen atom, R "'for a protective group of the a-amino group, such as a benzyloxycarbonyl group or a tert-butoxycarbonyl group, and R' and R" for Hydrogen atoms and protective groups for the guanidino group, such as nitro groups, tolyl groups, trityl groups, oxycarbonyl groups and the like, are available, with at least one of the groups R 'and R "being a protective group for the guanidino group.

The N2-arylsulfonyl-L-argininamide of the general formula I is prepared by condensing an L-argininamide of the general formula VI with a substantially equimolar amount of an arylsulfonylhalide of the general formula VII, preferably using an arylsulfonyl chloride.

The condensation reaction is generally carried out in a suitable solvent which is inert to the reaction and in the presence of an excess of a base such as an organic base (triethylamine or pyridine) or a solution of an inorganic base (sodium hydroxide or potassium carbonate) at a temperature of from 0 ° C. to to the boiling point of the solvent for a period of 10 minutes to 15 hours. The preferred solvents for the condensation are benzene di

/

II-N 45 \

"OOP i

{■ <)

COOR;

50 / rev -. \

/

"-« ■ i y.,

XII)

H-.\

\

(AI)

H-V

COUP,

v (ch ;;

(xm)

55 in which formulas R1; R2, R3, R4, R5, R6, R7, R9, R10, Rn, Z, n, m, r, q, i and j have the meanings given above.

The amino acid derivatives of the general formulas VIII or IX can be prepared by condensing a haloacetate, 60 a 3-halopropionate or a 4-halobutyrate with a suitable amine of the general formulas RjNH2 or R3NH2 (see J. Org. Chem. 25 [1960] 728 bis 732).

The condensation reaction is generally carried out without a solvent or in a solvent such as benzene or an ether in the presence of an organic base such as triethylamine or pyridine at a temperature of 0 to 80 ° C for 10 minutes to 20 hours.

633773

20th

After the reaction has ended, the amino acid derivative formed is separated off in the customary manner, for example by extraction with a suitable solvent or by evaporation of the reaction solvent, and then purified by distillation under reduced pressure.

Of the amino acid derivatives, the tert-butyl esters of the amino acid are preferred because they can be readily obtained by acidolysis in the presence of an appropriate alcohol and using an inorganic acid (such as hydrochloric acid, sulfuric acid, etc.) or an organic acid (such as toluenesulfonic acid, trifluoroacetic acid, etc.). can be converted into other ester derivatives. The following reaction scheme is an example of a process for preparing the 2-piperidinecarboxylic acid derivatives of the general formula X:

XaOCl,

H

(XIV)

r>

i

C1 (XV)

KOH v

(XVI)

HCN

H ^ O

7

CN (Ht)

(XVU)

~ N AC02H

(xvni}

The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, benzene or the like.

b) Cleavage of the NG substituent of a ^ -substituted N2-arylsulfonyl-L-argininamide. The process can be illustrated by the following reaction scheme; the steps from compound II to compound V are the same as in scheme a)

10 h> Ï ^

C - N - CH2CH2CH2CHCOR

(V)

HM I

R '

15

20th

25th

HN

m '

I.

R '

%

- N I

R "

HN

HN I

R

C - X -

I.

R "

I.

HN i

R "

CH2CH0CH2CHCOR I

NH2

CHoCHCCH2CHC0R

(XIX)

ArS02X (VII)

I.

IINS02 I

Ar

(XX)

HN

In the first reaction of the above reaction scheme, an appropriately substituted piperidine of the general formula XIV is brought into contact with an aqueous sodium hypochlorite solution at a temperature of -5 to 0 ° C. The product of the general formula XV thus formed is isolated by extraction with a solvent, for example diethyl ether, and then treated with potassium hydroxide in a low molecular weight alkanol as solvent, the corresponding 1,2-dehydropiperidine of the general formula XVI being obtained. By reaction with suitable cyanating agents, for example hydrogen cyanide or sodium cyanide, the corresponding 2-cyano derivatives (of the general formula XVII) are obtained from the 1,2-dehy dropiperidines of the general formula XVI. Hydrolysis of the 2-cyanopiperidines of the general formula XVII in an inorganic acid, such as hydrochloric acid or sulfuric acid, gives the corresponding 2-piperidinecarboxylic acids of the general formula XVIII.

The arylsulfonyl halides of the general formula VII used as starting materials for the preparation of the N2-arylsulfonyl-L-argininamides of the general formula I are obtained, for example, by halogenating the required arylsulfonic acids or their salts, for example their sodium salts, using methods known per se.

In practice, halogenation is carried out without a solvent or in a suitable solvent, for example a halogenated hydrocarbon or dimethylformamide, in the presence of a halogenating agent, for example phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, at a temperature of - 10 ° C to 200 ° C for a reaction time of 5 minutes to 5 hours. After the reaction is completed, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.

30th

35

H-iN

. /

C - N - CH2CH2CH2CHCOR

I.

H

I.

HNS0-) I

Ar

(I)

where in the above general formulas R, Ar, X, R ', R "and R'" have the meanings given above.

The N2 arylsulfonyl-L-argininamides of the general formula I are prepared by cleaving off the NG substituent 40 of an NG-substituted N2-arylsulfonyl-L-argininamide of the general formula XX, which is achieved by acidolysis or by hydrogenolysis.

The acidolysis is generally carried out in such a way that the NG-substituted N2-aryisulfonyl-L-45-argininamide of the general formula XX with excess acid, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetra-hydrofuran or diorane), an alcohol (methanol or 50 ethanol) or acetic acid at a temperature of from -10 ° C to 100 ° C, and preferably at a temperature of 10 ° C to 60 ° C or more, and more preferably reacted at room temperature for 30 minutes to 24 hours. The products are isolated by evaporation of solvent 55 and the excess acid or by trituration with a suitable solvent, followed by filtration and drying.

Since the acid is used in excess, the product generally obtained is the acid addition salts of the 60 N2-arylsulfonyl-L-argininamides of the general formula I, which can be readily converted into the free amides by neutralization.

The nitro group and the oxycarbonyl group, for example the benzyloxycarbonyl group or the 65 p-nitrobenzyloxycarbonyl group, can be split off easily by hydrogenolysis. At the same time, the benzyl ester residue which may be contained in group R is converted into the carboxyl group by hydrogenolysis.

21st

633773

The hydrogenolysis is carried out in a solvent which is inert for the reaction, for example methanol, ethanol, tetrahydrofuran or dioxane, and in the presence of a hydrogen-activating catalyst, for example Raney nickel, palladium or platinum, in a hydrogen atmosphere at a temperature of from 0 ° C. to to the boiling point of the solvent and preferably at a temperature of 10 to 80 ° C for a period of 2 hours to 120 hours. The hydrogen pressure is not critical, so that atmospheric pressure is sufficient.

The N2-arylsulfonyl-L-argininamides of the general formula I are isolated by filtering off the catalyst and by evaporating the solvent. They can then be cleaned in the manner described above.

The NG-substituted N2-arylsulfonyl-L-argininamides of the general formula XX used as starting material are prepared by using an NG-substituted N2-substituted L-arginine of the general formula III (which in general as a NG substituent is a nitro group or a Acyl group and as N2 substituent has a protective group for the amino group, such as a benzyloxycarbonyl group, a tert-butoxycarbonyl group or the like) with a corresponding amino acid derivative of the general formula IV, selectively only the N2 substituent of an NG-substituted N2- substituted L-argininamide of the general formula V by catalytic hydrogenolysis or by acidolysis and then the NG-substituted L-argininamide of the general formula XIX obtained in this way with an arylsulfonyl halide of the general formula VII, preferably the corresponding chloride, in the presence of a Base condensed in a solvent. For this, reaction conditions are used as described above for the condensation of an L-arginine amide with an arylsulfonyl halide and for the elimination of the NG substituent of an NG-substituted N2-arylsulfonyl-L-arginine amide.

c) condensation of an N2-arylsulfonyl-L-arginyl halide with an amino acid derivative, which process can be illustrated by the following reaction scheme:

HN

hon-

HI

C - X - CIIoCHiCHoCHCOOH ~ I XHt

ArSOpX

10th

15

20th

25th

HN

H

'C - N - CHoCH2CII-> CHC00H HoN ~ ~ |

1I.VS Od I

Ar

(II) (VII) -4

(XXI) -3

IIN

h2n

30th

35

II

^ I

^ .C - N - CHoC1IOCII2CHC0X

I.

HNSOp

I.

Ar

+ RH

II

^ 1

C - N - CHoCHtCHoCHCOR HnN ~ I

US Oi

I.

Ar

(XXII)

HN

(IV)

U)

wherein in the above general formulas R, Ar and X have the meanings given above.

The N2-arylsulfonyl-L-argininamide of the general 40 formula I is obtained by condensation of an N2-arylsulfonyl-L-arginyl halide of the general formula XXII, preferably the corresponding chloride, with at least an equimolar amount of an amino acid derivative of the general formula IV Condensation reaction can be carried out without solvent in the presence of a base. However, satisfactory results are obtained when using a solvent such as a basic solvent (dimethylformamide, dimethylacetamide, etc.) or a halogenated solvent (chloroform, dichloromethane 50, etc.). The amount of solvent used is not critical and can correspond to about five times up to ten times the weight of the N2-arylsulfonyl-L-arginylhalogenide of the general formula XXII. The preferred temperatures of the condensation reaction are in the range from -10 ° C to 80 ° C and preferably in the range from 20 ° C to 50 ° C. The reaction time is not critical, but depends on the amino acid derivative of the general formula IV used. In general, reaction times of 5 minutes to 10 hours are suitable. 60 The N2-arylsulfonyl-L-argininamide obtained can be isolated and purified in the manner described above.

The N2-arylsulfonyl-L-arginyl halides of the general formula XXII required for the condensation reaction are prepared by expediently preparing an N2-aryl-65 sulfonyl-L-arginine of the general formula XXI with at least an equimolar amount of a halogenating agent, such as thionyl chloride , Phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus

22

633773

tribromide. The halogenation can be effected with or without the addition of a solvent. The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane and ethers such as tetrahydrofuran and dioxane. The amount of solvent to be used is not critical and can correspond approximately to 5 to 100 times the weight of the N2-arylsulfonyl-L-arginine of the general formula XXI.

The reaction temperature is preferably in the range from -10 ° C. to room temperature. The reaction time is not critical, but varies with the halogenating agent used and the reaction temperature. In general, reaction times of 15 minutes to 5 hours are suitable.

The N2-arylsulfonyl-L-arginines of the general formula XXI used as starting materials for the preparation of the N2-arylsulfonyl-L-arginyl halides of the general formula XXII are obtained by condensation of L-arginine of the formula II with a substantially equimolar amount of an arylsulfonyl halide of the general Formula VII was prepared using methods similar to those described for the condensation of an L-arginine amide with an arylsulfonyl halide.

It is readily apparent to the person skilled in the art that the ester derivatives of the N2-arylsulfonyl-L-argininamides of the general formula I in which R2, R5, R8, Rg, R10 or Ru represent alkyl groups, aralkyl groups or aryl groups are known per se, using Esterification methods from the corresponding carboxylic acid derivatives of N2-arylsulfonyl-L-argininamides of the general formula I, in which R2, Rg, R3, R9, Rî0 or Rn are hydrogen atoms, can produce. It can also be seen that the carboxylic acid derivative can be prepared from the corresponding ester derivative by customary hydrolysis or acidolysis. The conditions for the esterification, hydrolysis or acidolysis are readily apparent to the person skilled in the art.

The N2-arylsulfonyl-L-argininamides of the general formula I according to the invention form acid addition salts with a large number of inorganic and organic acids. Some of the N2-arylsulfonyl-L-argininamides, which have free carboxyl groups, that is to say those compounds in which the groups R2, Rg, Ra, Rg, R10 or Rn are hydrogen atoms, form salts with a number of inorganic or organic bases.

The products of the above reactions can be isolated in free form or in the form of their salts. Furthermore, the product can be prepared as a pharmaceutically acceptable acid addition salt by adding one of the free bases with an acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, succinic acid, lactic acid, tartaric acid, gluconic acid, benzoic acid , Methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid or the like. Similarly, the product can be obtained in the form of a pharmaceutically acceptable salt by combining one of the free carboxylic acids with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procain, dibenzylamine, 1-ephenamine, N, N'-dibenzyl-ethylenediamine , N-ethyl piperidine or the like.

Similarly, by treating the salts with a base or an acid, the corresponding free amides can be formed.

As already stated, the N2-arylsulfonyl-L-argininamides according to the invention and their salts are notable for an extremely specific inhibitory action against thrombin in mammals and for their extensive use

Lack of toxicity, making them diagnostic reagents for the determination of thrombin in blood and /

or can be used as a medicine to prevent thrombosis. The Verbin-5 fertilizers according to the invention are also useful inhibitors of platelet aggregation.

The antithrombotic effect of the N2-aryIsulfonyl-L-argininamides according to the invention was compared with that of a known antithrombotic agent, namely the N2- (p-ro-polyisulfonyl) -L-arginine methyl ester by determining the fibrinogen coagulation time. The fibrinogen coagulation time is determined as follows:

An 0.8 ml aliquot of a fibrinogen solution is mixed by dissolving 150 mg of 15 bovine fibrinogen (Cohn Fraction I), available from Armor Incorporated, in 40 ml of a borate / salt buffer (with a pH of 7.4), with 0.1 ml of a borate salt buffer with a pH of 7.4 (control) or a solution of the sample in the same 20 buffer and 0.1 ml of one Thrombin solution (containing 5 units per ml) obtained from Mo-chida Pharmaceutical Company, Limited, Japan, by making these additions in an ice bath.

Immediately after mixing, the 25 reaction mixtures are transferred from the ice bath to a bath kept at 25 ° C. The coagulation time is determined as the period between the transfer into the bath kept at 25 ° C. and the time at which fibrin threads first appear. If no drug samples are added, the coagulation time is 50 to 55 seconds.

The results obtained are summarized in Table II below. The expression “concentration to increase the coagulation time by a factor of 2” 35 stands for the concentration of an active ingredient that is required to extend the normal coagulation time from 50 to 55 seconds to 100 to 110 seconds.

The concentration for prolonging the coagulation time by a factor of 2, which is required for the known antitrombotic agent N2- (p-tolysulfonyl) -L-arginine methyl ester, is 1100 [xMol / I.

The thrombin inhibitors are given in the table on the 45 groups R and Ar of the general formula I and the acid residue.

If a solution containing an N2-arylsulfonyl-L-argininamide according to the invention is administered intravenously to animals, it is found that the strong anti-50 thrombotic effect in the circulating blood is maintained for one to three hours. It has been shown that the half-life of the antithrombotic compounds according to the invention in the circulating blood is about 60 minutes if the physiological conditions of the treated animals (rats, rabbits, dogs and chimpanzees) are well maintained. The experimental decrease in fibrinogen caused by infusion of thrombin can be combated satisfactorily by simultaneous infusion of the compounds according to the invention.

The acute toxicity of the compounds according to the invention (LD50), which was determined by intravenous administration of the compounds of the general formula I to mice (male mice weighing 20 g), ranges from about 150 to 600 mg / kg of body weight treated mice. Table I below shows representative LD50 values of some compounds according to the invention.

23

633773

TABLE 1

HN PHN "

Ar

Compound C-NH- (CH2) 3CHCOR

f

HNS02Ar R

^ OCH3

! j ^ ch3

\ ^ - och2CH ^

och3 ch3

0T "

x: ^ nO (CH2) 3CH3 OCHt och

, CHi

\

CH '.

-N VCH3

) P

cooh

-f ~ \ cn3 /

cooh

-! p ^ CH3

cooh

LDso (mg / kg)

173

170

250-300

Contain open masts and dyes and have been dewatered sufficiently to make the mixture suitable for pressing into a solid preparation. The compounds can also be administered orally in the form of solutions which may contain colorants and flavorings. The doctor can select the dosage of the active substances according to the invention, which depends on the route of administration and the compound used, in a suitable manner. Furthermore, the dosage varies depending on the patient to be treated.

If the medicaments according to the invention are administered by oral route, a greater amount of the active ingredient is required to achieve the same effect than when administered by the parenteral route.

ls The therapeutic dose per day is about 10 to 50 mg / kg for parenteral administration and about 10 to 500 mg / kg for oral administration.

The invention therefore also relates to medicaments which contain at least one of the above-described compounds according to the invention as active ingredient and which can be present in the administration forms indicated above, in particular in the form of individual doses.

The following examples serve to further explain the invention.

25th

example 1

-N CHr cooh cooh

270

■ cii-!

300

-ch2

-O

\

260

cii2cooh

In contrast, the LDS0 values of N2-Dan-syl-N-butyl-L-argininamide and N2-Dansyl-N-methyl-N-butyl-L-argininamide are below 10 mg / kg.

The active pharmaceutical ingredients according to the invention can be administered to mammals, including humans, alone or in combination with pharmaceutically acceptable carrier materials, the amount of which depends on the solubility and chemical behavior of the compound, the route of administration and customary pharmaceutical practice.

For example, the compounds can be administered parenterally, that is to say intramuscularly, intravenously or subcutaneously, by injection. For parenteral administration, the compounds can be used in the form of sterile solutions which can contain other dissolved components, for example salt or glucose, in sufficient amounts to render the solution isotonic. The compounds can be administered orally in the form of tablets, capsules or granules which contain suitable carrier materials such as starch, lactose, white sugar and the like. The compounds can also be administered sublingually in the form of tablets or lozenges which contain the active ingredient in mixtures with sugar or corn syrup, aroma

A) N2- (2-dibenzothienylsulfonyl) -L-arginine 30 A solution of 112.7 g of 2-dibenzothiophene sulfonyl chloride is added to a well-stirred solution of 83.6 g of L-arginine in 800 ml of a 10% potassium carbonate solution 800 ml of benzene. The reaction mixture is stirred for 5 hours at 60 ° C., during which time the product precipitates. After 1 hour at room temperature, the precipitate is filtered off, washed successively with benzene and with water and gives 127 g (yield = 76%) of N2- (2-di-benzothieny] sulfony]) - L-arginine.

40 B) N2- (2-dibenzothienylsulfonyl) -L-arginyl chloride A suspension of 4.21 g of N2- (2-dibenzothienylsulfonyl) -L-arginine in 20 ml of thionyl chloride is stirred for 2 hours at room temperature. The addition of cold, dry diethyl ether gives a precipitate which is filtered off and washed several times with dry diethyl ether, giving the desired N2- (2-dibenzothienylsulfonyl) -L-arginyl chloride.

C) N2- (2-Dibenzothienylsulfonyl) -L-arginyl-N-butyl-50 glycine tert-butyl ester

To a stirred solution of 2.67 g of N-butylglycine - tert-butyl ester in 20 ml of chloroform is carefully added the N2- (2-dibenzothienylsul-fonyl) -L-arginyl chloride obtained in the above manner. The reaction mixture 55 is left to stand at room temperature for 1 hour. After this period has elapsed, the reaction mixture is washed twice with 20 ml of saturated sodium chloride solution and then evaporated to dryness. The residue is triturated with a small amount of diethyl ether and a 60 amorphous solid is obtained. This solid is filtered off and precipitated from an ethanol / ethyl ether mixture, 3.1 g (yield = 49%) of N2- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine tert.- receives butyl ester.

65 IR spectrum (KBr): 3350, 1740, 1625 cm-1 Analysis: C28H3905N5S2. % H2S03

calc .: C 53.31 H 6.39 N 11.10% found: C 53.21 H 6.46 N 10.89%

633773

D) N2- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine To a solution of 2.00 g of N2- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine-tert.-butyl ester in 20 ml Chloroform is added 50 ml of a 15% solution of hydrogen chloride in ethyl acetate. The reaction mixture is stirred for 5 hours at room temperature. After this time, the reaction mixture is evaporated to dryness. The residue is washed several times with dry diethyl ether and then chromatographed over 80 ml of an ion exchange resin Daiaion ® SK 102 with a grain size of 0.045 to 0.074 mm (200 to 300 mesh) in the H + form, which is available from Mitsubishi Chemical Industries Limited is) which has been packed with water and washed with water, eluting with a 3% ammonium hydroxide solution.

The fraction eluted with the 3% ammonium hydroxide solution is evaporated to dryness and gives 0.9 g (yield = 53%) of N2- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine in the form of an amorphous solid.

IR spectrum (KBr) 3350, 1640, 1270 cm-1 Analysis: C24H31N505S2

calc .: C 54.01 H 5.86 N 13.12%

found: C 53.78 H 5.97 N 12.96%

Example 2

A) N2- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-meth-oxyethyl) glycine ethyl ester

To a stirred solution of 2.42 g of N- (2-methoxy-ethyl) -glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which is cooled with an ice / salt bath, 7.0 g of the N2- (2-dibenzothienylsulfonyl) -L-arginyl chloride obtained in the manner described above. The reaction mixture is stirred overnight at room temperature. Then 50 ml of chloroform are added, the chloroform solution is washed twice with 25 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue is washed with ethyl ether and 5.5 g of powdered N2- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-meth-oxyethyl) glycine ethyl ester are obtained.

Analysis: C25H23OgN5S2. ^ H2S03

calc .: C 50.49 H 4.07 N 11.78%

found: C 50.22 H 4.18 N 11.51%

B) N2- (2-dibenzothenylsulfonyl) -L-arginyl-N- (2-meth-oxyethyl) glycine

A solution of 5.5 g of N2- (2-dibenzo-thienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) -glvcinethyl ester in 15 ml of methanol and 15 ml of a 2N NaOH solution is heated to 40 ° C and maintains this temperature for 10 hours. At the end of this time, the reaction mixture is concentrated and chromatographed over 200 ml of an ion exchange resin (Daiaion®SK 102, with a grain size of 0.045 to 0.074 mm (200 to 300 mesh) in the H 'form, which is available from Mitsubishi Chemical Industries Limited, Japan), which resin is packed with water, washed with an ethanol / water mixture (1/4) and eluted with an ethanol / water / ammonium hydroxide solution (10/9/1).

The main fraction is evaporated to dryness, washed with ethyl ether and 3.05 g (yield = 62%) of N2- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine is obtained in the form of an amorphous Solid.

IR spectrum (KBr): 3400, 1630, 1280 cm-1

Analysis: C ^ HonCUSLS ;,

calc .: C 51.57 H 5.46 N 13.08%

found: C 51.35 H 5.63 N 12.86%

Example 3

A) NG-nitro-N2- (tert-butoxycarbonyl) -L-arginyl-N-butyl-glycine benzyl ester

12.4 ml of triethylamine are added in succession to a stirred solution of 28.4 g of NG-nitro-N2- (tert-butoxycarbonyl) -L-arginine in 450 ml of dry tetra-hydrofuran while maintaining a temperature of -5 ° C and 12.4 ml of isobutyl chloroformate. After 15 minutes, 35.0 g of N-butylglycine benzyl ester p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran are added and the mixture is stirred at -5 ° C. for 15 minutes. After this time, the reaction mixture is warmed to room temperature. The solvent is evaporated and the residue is taken up in 400 ml of ethyl acetate and then washed successively with 200 ml of water, 100 ml of a 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution is dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is dissolved in 20 ml of chloroform and the solution is applied to a column (80 cm × 6 cm) loaded with 500 g of silica gel, which column has been packed with chloroform. The product is first eluted with chloroform, namely with a 3% solution of methanol in chloroform. The fraction eluted with 3% methanol in chloroform is evaporated to dryness and gives 26.0 g (yield = 56%) NG-Ni-tro-N2- (tert-butoxycarbonyl) -L-arginyl-N-butyl-glycinbenzyl- ester in the form of a syrup.

IR spectrum (KBr): 3300, 1740, 1690 cm-1

B) NG-Nitro-L-arginyl-N-butyl-glycine benzyl ester hydrochloride

80 ml of a 10% solution of are added at 0 ° C. to a stirred solution of 26.0 g of NG-nitro-N2- (tert-butoxycarbonyl) -L-arginyl-N-butyl-glycine benzyl ester in 50 ml of ethyl acetate dry hydrogen chloride in ethyl acetate.

After 3 hours, 200 ml of dry ethyl ether are added to the solution obtained in order to precipitate a viscous oily product. The product is filtered off, washed with dry ethyl ether and 20.8 g of NG-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride are obtained in the form of an amorphous solid.

C) NG-Nitro-N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) - L-arginy I-N-buty I -gly cinb enzy 1 ester

To a stirred solution of 2.33 g of NG-nitro-L-arginyl-N-butyl-glycine benzyl ester hydrochloride in 10 ml of water and 40 ml of dioxane, 1.26 g of sodium bicarbonate and 2.2 are added in succession at 5 ° C. g of 3-cyclohexyl-4-methoxyphenylsulfonyl chloride and stirred for a further 3 hours at room temperature. After this time, the solvent is evaporated, the residue is dissolved in 100 ml of ethyl acetate and washed successively with 10 ml of a solution in hydrochloric acid, 20 ml of water, 20 ml of a 5% sodium bicarbonate solution and 10 ml of water.

The ethyl acetate solution is dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent is chromatographed on 50 g of silica gel, which has been packed in chloroform and washed with chloroform, eluting with a 3% solution of methanol in chloroform. The fraction eluted with the 3% methanol in chloroform is evaporated to give 2.6 g (yield = 77%) of NG-nitro-N2- (3-cyclo-

24th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

25th

633773

hexyl-4-methoxy-phenylsulfonyl) -L-arginyl-N-butyl-glycine-benzyl ester in the form of an amorphous solid.

IR spectrum (KBr): 3300, 2920, 1740, 1640, 1250 cm-1 Analysis: C32'H4608N6S

calc .: C 56.95 H 6.87 N 12.46%

found: C 56.49 H 6.63 N 12.38%

D) N2- (3-Cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl - N-butylglycine

To a solution of 3.00 g of NG-nitro-N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water, 5 g of palladium black and shake the mixture for 50 hours at room temperature in a hydrogen atmosphere. After this period of time, the ethanol solution is filtered to remove the catalyst and then evaporated to dryness. The residue is washed several times with dry ethyl ether and chromatographed over 80 ml of an ion exchange resin (Daiaion®SK 102, with a grain size of 0.045 to 0.074 mm (200 to 300 mesh), in the H + form, which is available from Mitsubishi Chemical Industries Limited , Japan, is available) which has been packed in water and washed with water, eluting with a 3% ammonium hydroxide solution.

The fraction eluted with the 3% ammonium hydroxide solution is evaporated to dryness and gives 1.5 g (yield = 72%) of N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butyl-glycine in the form of an amorphous solid.

IR spectrum (KBr): 3350, 2920, 1630, 1250 cm.-1 Analysis: C ^ sH ^ NjOjS]:

calc .: C 55.63 H 7.66 N 12.98%

found: C 55.32 H 7.39 N 12.84%

Example 4

A) 1- [NG-Nitro-N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, ethyl ester

To a well-stirred solution of 2.05 g of l- (NG-nitro-L-arginyl) -4-methyl-2-piperidinecarboxylic acid ethyl ester hydrochloride and 1.26 g of sodium bicarbonate in 10 ml of water and 40 ml of dioxane in portions while maintaining a temperature of 0 ° C 2.2 g of 3-cyclohexyl-4-methoxy-benzenesulfonyl chloride. The reaction mixture is stirred overnight at room temperature. After this period, the reaction mixture is evaporated to dryness. The residue is taken up in 50 ml of ethyl acetate and the ethyl acetate solution is washed successively with 10% citric acid solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The ethyl acetate solution is then evaporated and the residue is chromatographed on silica gel packed with chloroform, eluting with chloroform containing 3% methanol. The main fraction is evaporated to dryness and gives 2.6 g of l- [NG-nitro-N2 - (3-cyclohexyl-4-methoxybenzenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid ethyl ester.

IR spectrum (KBr): 3400, 1735, 1635, 1250 cm-1

B) 1- [N2- (3-Cyclohexyl-4-methoxyphenyl-isulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, ethyl acetate

To a solution of 2.6 g of l- [NG-nitro-N2- (3-cyclohexyl - 4-methoxyphenyIsulfonyI) -L-arginyl] -4-methyl-2-piperidine-carboxylic acid ethyl ester in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid are added 0.5 g of palladium carbon black and the mixture is then shaken for 15 hours at room temperature in a hydrogen atmosphere. The solution is filtered to remove the catalyst and evaporated to give an oily product. After precipitation with an ethanol / diethyl ether mixture, 2.4 g of 1- [N2 - (3-cyclohexyl-4-methoxyhenylsulfonyl) -arginyl] -4-methyl-2 - piperidinecarboxylic acid ethyl acetate are obtained.

C) 1- [N2- (3-Cyclohexyl-4-methoxyphenyl isulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid

A solution of 2.4 g of l- [N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidine-carboxylic acid ethyl ester acetate is stirred in 10 ml of ethanol and 10 ml of an ln -Sodium hydroxide solution at room temperature overnight. The reaction mixture is then concentrated and dissolved in 10 ml of water. The solution is neutralized with a 2N hydrochloric acid solution and a white, resinous precipitate is obtained, which is dissolved in 150 ml of chloroform. The chloroform solution is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo, 1.52 g of 1- [N2 - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-me- thyl-2-piperidinecarboxylic acid is obtained in the form of an amorphous solid.

IR spectrum (KBr): 3350, 2920, 1620, 1250 cm "1 analysis: C26H41OeN5S

calc .: C 56.60 H 7.49 N 12.70%

found: C 56.51 H 7.53 N 12.68%

Example 5

A) 1 - [N2- (3-Methyl-1,2,3,4-tetrahydro-8-quinoline sulfonyl) -NG-nitro-L-arginyl] -4-methyl-2-piperidinecarboxylic acid, ethyl ester

A solution of 4.08 g of 1-NG-nitro-L-arginyl) -4-methyl-2-piperidine-carboxylic acid ethyl ester hydrochloride and 3.03 g of triethylamine in 200 ml of chloroform are added with vigorous stirring and while maintaining the temperature 5 ° C. 3.69 g of 3-methyl-l, 2,3,4-tetrahydro-8-quinoline sulfonyl chloride were added in portions. The reaction mixture is stirred for 5 hours at room temperature. The reaction mixture is then washed with a saturated saline solution and dried over anhydrous sodium sulfate. The chloroform solution is evaporated and the residue is chromatographed on a silica gel column with chloroform; elution is carried out with chloroform containing 3% methanol. The main fraction is evaporated to dryness, leaving 3.61 g of l- [N2- (3-methyl-l, 2,3,4-tetrahydro-8-quinoline sulfonyl) -NG-nitro-L-arginyl] -4- -methyl-2-piperidine-carboxylic acid ethyl ester in the form of an amorphous solid; Yield 62% of theory.

IR spectrum (KBr): 3400, 1730 and 1635 cm-1 NMR spectrum (CD3OD) 5 (ppm):

6.5 (1H, t), 7.1 (1H, d), 7.4 (1H, d)

B) 1- [N2- (3-methyl-l, 2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidine-carboxylic acid ethyl ester acetate

A solution of 3.00 g of l- [N2- (3-methyl-l, 2,3,4-tetrahy-dro-8-quinoline sulfonyl) -NG-nitro-L-arginyl] -4-methyl-2-pipe -ridine-carboxylic acid ethyl ester in 100 ml of ethanol and 20 ml of acetic acid, 0.9 g of palladium black are added and the reaction mixture is then shaken in a hydrogen atmosphere for 15 hours at room temperature. The solution is filtered to remove the catalyst and evaporated; an oily product remains.

By reprecipitation with ethanol-diethyl ether, 2.38 g of l- [N2- (3-methyl-l, 2,3,4-tetrahydro-8-quino-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

633773

26

linsuIfonyl) -L-arginyl] -4-methyl-2-piperidine-carboxylic acid ethyl ester acetate obtained; Yield 78% of theory.

C) 1- [N2- (3-Methyl-l, 2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid

A solution of 2.00 g of l- [N2- (3-methyl-l, 2,3,4-tetrahy-dro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidine-carboxylic acid ethyl ester acetate in 20 ml of ethanol and 10 ml of 1 normal sodium hydroxide solution is stirred overnight at room temperature. The reaction mixture is then neutralized with 2-normal hydrochloric acid and concentrated in vacuo. A gummy precipitate is obtained, which is extracted three times with 150 ml of chloroform. The chloroform solution is washed with saturated saline, dried over anhydrous sodium sulfate and evaporated in vacuo.

1.45 g of l- [N2- (3-methyl-l, 2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid are obtained in the form of a amorphous solid; Yield 85% of theory.

5

IR spectrum (KBr): 3400, 1620, 1460 and 1380 cm-1 analysis for C2, H, rO = NbS:

found: C 54.31 H 7.13 N 16.52%

calc .: C 54.09 H 7.00 N 16.80%

10th

Various other N2-arylsulfonyl-L-argininamides and their acid addition salts were prepared using the procedures described in the examples above and are summarized along with their properties in Table II below.

HN. H

Connect ^ C-N-CH2CH2CH2CHCOR

dung HsN ^ "

No. H-N-SOa-Ar

Ar ct2 "o

OCH3

OCH 3

COCH3

-n;

-n:

ch „ch2och,

ch2cooh ch2ch2ch2ch3

ch2cooh tKit:

H

-n:

-n;

-n:

ch2ch2ch2ch3

ch2cooh ch2ch2och3

ch2cooh ch, choch, ch,

ch2cooh

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (lJ.Mol / 1)

Manufacturing Physi-

quay processes

according to th example

Elemental analysis (upper values: calculated, lower values: found)

JR-

Spectrum (KBr) cm-1

H

n

20th

38

19th

53.82

6.21

13.08

3,350, 1,630

53.59

6.11

12.78

1,270, 1,160

57.02

6.81

12.79

3,400, 1,630

56.69

6.65

12.84

1,260

55.63

7.66

12.98

3,350, 2,920

55.32

7.39

12.84

1.630, 1.250

49.57

6.66

17.34

3,400, 1,640

49.24

6.79

17.48

1.530, 1.160

46.95

5.71

19.17

3,400, 1,680

46.67

5.79

18.87

1.630, 1.380

50.89

5.96

14.13

3,400, 1,740

50.79

5.98

13.86

1,630

52.70

6.32

17.56

3,400, 1,620

52.66

6.19

17.82

1,380

54.32

5.70

15.84

3,400, 1,635

54.08

5.96

15.73

1.510

52.44

5.69

12.74

3,400, 1,630

52.43

5.86

12.58

1,290

!> w do c

r>

N> -J

C \

U »U» -J M

connection

HN. H

^ C-N-CH2CH2CH2CHCOR HsN ""

H-N-SOs-Ar

No.

Ar

Acid residue

10th

11

130Ö

-n:

-n;

ch2ch2och3 ~ ch2cooc2h5

ch2ch2och3

~ ch "cooh

HH2so3

12th

13

-n:

ch2ch2ch2ch3

ch2cooh

14

ch2ch2och3

-n:

chocooh

15

16

17th

-N

, -u

\

CH2C02H

Concentration to extend the coagulation time by d. Factor 2 (nmol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

H

N

ir-

Spectrum (KBr)

50.49

4.07

11.78

3,350, 1,735

50.22

4.18

11.51

1,620

51.57

5.46

13.08

3,400, 1,630

51.35

5.63

12.86

1,280

48.66

5.15

12.34

3,400, 1,625

48.85

5.03

12.05

1,270

54.01

5.86

13.12

3,350, 1,640

53.78

5.97

12.96

1,270

54.22

5.50

13.18

3,400, 1,700

54.08

5.36

12.95

1,635

55.00

7.28

12.34

3,400, 2,920

54.86

7.28

12.49

1.630, 1.250

53.74

6.93

11.19

3,400, 1,760

53.81

7.04

10.96

1.630, 1.220

54.23

7.10

12.65

3,350, 1,625

54.25

7.08

12.86

1,380, 1,150

Connection no.

Ar

HNn. H

^ C-N-CH2CH2CH2CHCOR

H2N ^

H-N-SOa-Ar R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (ixMol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

ir-

spectrum

(KBr)

cm-1

H

n

18th

19th

20th

21st

22

23

24th

25th

cn2-lo och-

\ o o,

olia

O

0

-n

'CH.

\

ch2c02h

-N

, 0

CH? - ^

\

cii2co2h

_n / CH2--0 \

ch2c02h

-O

-n

ch2c02c2h5

co2h

~ \ Z- ^ ~ ch '

MH2so3

1.5

1.5

0.1

OCH 3

56.33

6.48

12.17

3,350, 1,640

56.39

6.52

12.07

1,260

56.48

6.26

13.14

3,350, 1,630

56.47

6.08

13.28

1.385, 1.160

57.44

6.12

12.88

3,400, 1,630

57.63

5.99

12.76

1,150

51.78

5.41

12.12

3,350, 1,640

52.13

5.49

12.08

1,250

57.23

6.47

12.84

3,400, 1,630

56.95

6.45

12.76

1,160

55.40

6.62

12.43

3,400, 1,630

55.27

6.81

12.25

1,260

48.34

5.41

10.44

3,400, 1,740

48.56

5.46

10.33

1,630

56.60

7.49

12.70

3,350, 2,920

56.51

7.53

12.68

1.620, 1.250

dung

No.

26

27th

28

29

30th

31

32

33

Ar hns- h

3C-N-ch2ch2ch2chcor h2n

H-N-SOa-Ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (ixMol / l)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

IR

spectrum

(KBr)

cm-1

H

N

co2h ch-

2.5

OCH3

55.84 7.31 13.03 3.350, 1.620

56.07 7.46 13.08 1.380, 1.150

57.23 6.47 12.84 3.350, 1.620

57.15 6.70 12.75 1.260, 1.155

tox: ^

ono.

.oJLs.l °.

C02H

-v /

coph

-t>

COOH -N ^) - CH3

0.1

0.6

0.1

0.5

53.46 5.56 12.47 3,400, 1.625>

to W

53.55 5.63 12.51 1,460, £ 1.165

58.23 6.45 13.58 3.375, 1.620

TI o

58.08 6.51 13.62 1.385, 1.160%

59.18 6.30 13.27 3.350, 1.610

59.08 6.52 13.36 1,140

51.77 5.10 13.13 3,400, 1.630

52.05 5.08 12.98 1.160

53.65 5.22 12.51 3,400, 1.710

53.88 5.36 12.40 1.630

53.86 6.16 17.13 3.375, 1.620

54.08 6.07 17.39 1,460, 1.290

N 1 =

a orq

No.

34

35

36

37

38

39

40

41

42

Ar

HN ^ H

^ C-N-CH2CH2CH2CHCOR

HaN

H-N-SOz-Ar R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (p.Mol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

IR

spectrum

(KBr)

cm-1

H

N

57.32

7.66

12.38

3,400, 1,620

57.27

7.68

12.45

1,250

56.60

7.49

12.70

3,400, 1,620

56.82

7.36

12.86

1,140

56.85

6.84

11.05

3,400, 1,740

56.69

7.15

10.88

1,635

54.74

6.39

16.66

3,380, 1,620

54.81

6.53

16.45

1.460, 1.375

54.74

6.39

16.66

3,400, 1,620

54.50

6.25

16.85

1.460, 1.380

igr0

\ ^ S0CH3

OCH O

CIl3

CO, H

O

CH3 CH3

co2h ch3

co2c2H5

-Q-c.3

co2H

-t> ch3

CHoCOOH

0.5

0.1

0.25

powder

P "3ch2

54.74

6.39

16.66

3,380, 1,620

54.80

6.37

16.51

1,380, 1,160

54.74

6.39

16.66

3,380, 1,620

54.89

6.42

16.63

1,380, 1,285

55.58

6.61

16.21

3,350, 1,620

55.43

6.86

16.22

1,380, 1,150

55.58

6.61

16.21

3,375, 1,620

55.75

6.63

16.24

1.460, 1.380

>

dead

do

P>

S

ö

No.

43

44

45

46

47

48

49

50

51

Ar

HNv H

/ C-N-CH2CH2CH2CHCOR HsN ^

H-N-SOa-Ar r

Acid residue

Concentration to extend the coagulation time by d. Factor 2 ([xMol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

ir-

Spectrum (KBr) cm-1

H

n

powder

53.06 52.81

6.20 6.15

16.14 16.23

3,400, 1,630 1,385, 1,130

51.00

6.11

16.99

3,380, 1,620

50.86

6.08

17.25

1,380, 1,120

53.91

6.41

15.72

3,400, 1,620

53.76

6.53

15.81

1,380, 1,130

51.95

6.34

16.53

3,375, 1,625

52.21

6.35

16.45

1,380, 1,120

powder

54.20 54.00

7.32 7.18

16.49 16.28

3,360

1,600 (wide) 1,150

»

50.31 50.01

6.45 6.28

18.53 18.42

3,350

1,600 (wide) 1,155

»

54.20 54.11

7.32 7.11

16.49 16.28

3,350

1.610 (broad) 1.155

»

52.15 52.00

6.88 6.80

14.48 14.21

3,350

1,610 (broadj 1,160

»

50.49 50.65

6.66 6.51

14.02 14.32

3,350

1.620 (wide) 1.155

C1! JCH2

1

N-n-Cj ^ H9

nh2

H

N "—n —C

kn9

ch2ch20a

-n

\

CH.-0

ch2cooii

-n;

ch2ch2och,

~ ch2cooh -ch2-0

\

ch2cooh ch2ch2och3

-n:

ch2cooh

-0-3

cooh

>

to do r

r>

• fl o n>

g £

och2ch2oh

No.

52

53

54

55

56

57

58

59

60

Ar

HN \ H

^ .r-N-

HaN "

C-N-CH2CH2CH2CHCOR H-N-SOa-Ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 ([xMol / 1)

Manufacturing Physi-

quay processes

according to th example

Elemental analysis (upper values: calculated, lower values: found)

IR

spectrum

(KBr)

cm-1

H

N

Vi

0CH2CH20H

OCHoCHOH d I CHi

CiI2CU2CH2OH 1

ICH3 CH2CH0H

COOH

-n:

-n:

ch2ch2ch2ch3

ch2cooh ch2ch2och3

ch2cooh

-N;

ch2ch2sch3

ch2cooh

0.35

0.4

powder

50.49 50.28

6.66 6.35

14.02 13.89

3,300 (wide) 1,600 (wide) 1,155

53.61 53.42

6.56 6.38

13.03 13.01

3,300 (wide) 1,600 (wide) 1,155

55.26 55.36

6.76 6.87

13.43 13.21

3.360 (wide) 1.610 (wide) 1.155

55.26 55.11

6.76 6.67

13.43 13.39

3.350 (wide) 1.610 (wide) 1.155

56.39

7.82

12.69

3,400, 1,630

56.28

7.79

12.51

1,260

53.16

5.62

13.48

3,400, 1,625

53.01

5.78

13.46

1,280

55.68

6.04

13.53

3,400, 1,630

55.71

6.00

13.39

1,160

49.39 49.51

5.92 5.88

16.46 16.32

3,360 (wide) 1620 1,155

£ 03

W

r r

>

2nd

N C ö 0q

o t

-n:

ch2ch2sch2ch3

ch2cooh

48.22 5.23 11.72 3.360 (broad;

1620

47.99 5.21 11.56 1.155

HN- H

Concentra

Manufacturers

Physi

Elementary analysis ir-

^ C-N-ch2ch2ch2chcor

tion for calibration cal

(Upper values: be

spectrum

Connect

HaN- ^

extend procedure

Property calculates, lower

(KBr)

dung

H-N-S02-Ar

the coagula according to ten

Values: found)

cm-1

time around

example

d. Factor 2

No.

Ar r

Acid residue

([xMol / 1)

C H N

O\

C *>

w

-J

-a W

61

62

63

64

65

66

67

• 0 (CH2) 2CH3

-N

^ ch2CH2 - <^

'ch2cooii

CD

cc

; 00H

■ p cooh ch.

-N>

rO

-n;

-n;

CH-COOH CH3

ch2ch2och3

chcooh

I.

ch3

ch2ch2och3 "ch2ch2cooh h (> 3rd

COOH

59.24 5.86 12.34 3.360 (wide) 1.620

59.24 5.77 12.33 1.152

61.41 5.34 12.79 3,400, 1.630

61.29 5.38 12.68 1.180

54.74 6.39 16.66 3.380, 1.620

54.69 6.27 16.39 1.375

57.52 7.33 12.42 3.400, 1.740

57.48 7.42 12.39 1.630

i>

Cd M

r i-1>

O

N §

50.36 6.15 16.02 3.400, 1.630 92,

50.41 6.21 16.11 1.380, 1.120

50.36 6.15 16.02 3.400, 1.630

50.28 6.09 15.98 1.380, 1.120

53.10 7.09 14.08 3.300 (broad) 1.630

52.93 7.20 14.00 1.160

u>

68

0 (CH2) 3CH-J

53.98 7.29 13.69 3,300 (wide) 1,620

53.77 7.18 13.60 1.160

No.

69

70

71

72

73

74

75

76

Ar

HN ^ H

;; C-N-CH2CH2CH2CHCOR

han "

H-N-SOz-Ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 ([xMol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

H

N

0 (CH2) 3CH3

- * 3 ~ CH3

cooh

, ch.

, -U

-n

\

ch2cooh

0.8

53.98 7.29 13.69

53.71 7.21 13.28

52.35 7.07 13.27

52.27 7.19 13.00

° (ch2) ** ch3

CH2CH2CH3

OCH3

ch o chch2CH3

OCH 3

och 3rd

ch3

VCH3

CH3

-r>

cooh

CII3

-n

-N:

/ CH2

-O

\

ch2c00h

CH, CHj, OCH,

CH, COOH

r / CH2 • \

-O

ch2cooh

1.5

6.4

13

54.83 7.48 13.32

54.95 7.46 13.41

52.35 7.07 12.27

52.41 7.15 12.46

51.24 7.23 13.58

51.31 7.46 13.29

51.24 7.23 13.58

51.38 7.15 13.62

53.21 7.26 12.93

53.16 7.05 12.91

- £} ch:

cooh

0.75

54.83 7.48 13.32 54.97 7.48 13.36

No.

77

78

79

80

81

82

83

84

85

HN ^ _ H

HaN '

Ar

C-N-CH2CH2CH2CHCOR H-N-SC> 2-ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (p.Mol / 1)

Manufacturing Physi-

quay processes

according to th example

Elemental analysis (upper values: calculated, lower values: found)

IR

spectrum

(KBr)

cm-1

c

H

N

53.21

7.26

12.93

3,375, 1,630

52.95

7.31

13.15

1,255, 1,145

48.73

6.82

13.53

3,300, 1,620

48.93

6.90

13.48

1,110

52.35

7.09

13.27

3,350, 1,610

52.46

7.08

13.11

1,140

53.21

7.26

12.93

3,365, 1,620

53.11

7.56

12.78

1,245, 1,150

55.63

7.66

12.98

3,350, 1,610

55.49

7.54

13.01

1,400, 1,140

56.39

7.83

12.65

3,350, 1,620

56.43

7.85

12.49

1,380, 1,150

54.81

7.61

12.29

3,350, 1,630

54.76

7.60

12.35

1,145

53.99

7.29

13.69

3,400, 1,630

54.15

7.28

13.58

1,150

54.79

7.72

11.41

3,400, 1,740

54.86

7.54

11.46

1,630

TSC "'

0CH2CH20CH2 0CH2CH20CH3

r ^ V ° cH3

0 (ch2) 3OCH3

CH 3

(ch2) 3ch3

ch3

0- (ch2) 4ch3

ch-

ch -1 / ■> chch2ch3

oh ch-c - ch - CCII3 ^ gh3

l3

b

-n

-O

/ CH2 ^ ch2cooh ch, ch, och,

-N;

chocooh

-o cooh ch3

-n cHo-c y

2 X ox nch2cooh

-N ^ Yci y_ / 3h3

cooh

-ch '

y-s

COOC ^ Hj.

-N Vc ch3cooh

> tö

w r r>

o a

B

HN. H

Concentra

Manufacturers

Physi

Elemental analysis

IR

Connect

^ C-N-CH2CH2CH2CHCOR

tion for calibration cal

(Upper values: be

Spectrum manure

HaN ^

extend procedure

Property calculates, lower

(KBr)

No.

H-N-SOz-Ar

the coagula according to ten

Values: found)

cm-1

time around

example

d. Factor 2

Ar

R

Acid residue

([o.Mol / 1)

C H N

86

87

89

90

91

92

93

CO (CH2) 2ch3 OCII3

Cl

0 ~ (CH2) 3CH3 Cl

0- (CH2) 2CH3 OCH3

V ^> ^ 0- (CH2) 3CH3

\ ^ o- (ch2)

2! 3CH3

~ (cu2) 3cn3

0- (CH2) 3Cit3

/ ^ 0- {CH2) 3CH3

m 3 ^: 112) 30 ^^

(^ V0ch3

0- (CH2) 2CH3

OCH3

- ^ 0 »3

cooh

-N ^ CH2 \ 0

ch2cooh

-ry cooh

Mr

0.9

54.23 7.10 12.65 3,400, 1.680

54.48 7.04 12.63 1.630, 1.150

47.58 6.08 12.06 3.350, 1.630

47.36 6.15 12.08 1.150

52.35 7.07 13.27 3.420, 1.630

52.19 7.02 13.41 1.270, 1.165

55.55 7.77 12.00 3.410, 1.630

55.73 7.68 11.99 1.290, 1.170

55.55 7.77 12.00 3.420, 1.650

55.64 7.96 11.82 1.260, 1.165

54.07 7.56 11.68 3.350, 1.630

54.05 7.81 11.43 1.160

51.68 7.06 12.56 3.350, 1.630

51.44 7.12 12.67 1.380, 1.090

52.51 7.24 12.25 3.350, 1.630

51.99 7.15 12.30 1.460, 1.090

Connection no.

Ar

HN.s. H

7C-N-CH2CH2CH2CHCOR HaN- ^

H-N-SOa-Ar r

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (p, mol / l)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

ir-

spectrum

(KBr)

cm-1

H

N

O\

w

W

-4 (*>

94

95

96

97

98

99

100

101

r ^ jr- 0CH3

<yJ ^ 0- (CH2) 2CK3

och 3rd

och-;

0- (ch2) 3ch3

OCII3

-n:

-n;

-n;

-n ch2ch2och3

ch2cooh

_ (ch2) 4ch3

~ ch2cooh

(ch2) 3ch3

chcooh ch,

ch o

ch2c00h

-N

N.

ch2cooh

-n

/ 0>

\

ch2cooh

-n

\

ch2ch2cooh

-n ch2ch2

-0 \

ch2cooh

49.17 7.01 12.47 3,300, 1.630

49.31 7.13 12.52 1,400, 1.090

52.33 7.55 12.21 3.350, 1.630

52.47 7.23 12.31 1.460

52.33 7.55 12.21 3,400, 1.620

52.51 7.61 12.18 1.095

53.31 7.40 11.96 3.350, 1.620

53.28 7.28 11.77 1.450

53.87 6.43 12.08 3.400, 1.630

53.72 6.54 12.00 1.090

55.33 6.80 11.53 3.370, 1.635

55.49 6.71 11.51 1.580, 1.090

55.33 6.80 11.53 3.350, 1.620

55.21 6.75 11.34 1.455, 1.090

54.07 7.56 11.58 3.350, 1.620 a 54.12 7.34 11.52 1.090

N

e a tra u> 00

No.

102

103

104

105

106

107

108

109

HN ^ H

^ C-N-CH2CH2CH2CHCOR

HzN '

Ar

H-N-SOz-Ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 ftiMol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

H N

IR

Spectrum (KBr)

oh

o- (ch2) 2 (ch3

och-

och 3rd

O- (CH2) _CH3 OCÜ3

r ^ y 0c1 [3rd

0CH2CH20CH3

ocü3

OCH 3

0CH2CII2CH2Br OC H 3 focili

OCH2CH20CII2CH3 OCH 3

| ^ V ° C "3

0- (CH2) 3C02CH3 OCH3

/K.OCH3 ^^> - o- (cH2) 3CH3 ocii3

OCl ^ Cl ^ CH-y

^ CH3 CH3

cooh

-n:

ch2ch2och3

chpcooh

-n_> h3

cooch2ch3

-N

CH3

chjcooh

0.8

53.30 7.41 11.96 3.350, 1.620 53.41 7.42 12.03 1.455, 1.090

54.06 7.58 11.68 3.350, 1.625 54.16 7.69 11.70 1.460, 1.090

50.25 6.85 12.21 3,400, 1.630

>

50.39 6.79 12.30 1.455, 1.090 »

r r>

45.28 6.02 11.00 3,400, 1.620 h s

45.46 5.95 11.26 1,080

S

51.09 7.03 11.92 3,375, £ 1.620

51.20 7.14 11.87 1.455, 1.090

46.69 6.30 11.84 3,400, 1.720

46.48 6.41 11.88 1.630, 1.080

52.79 7.49 10.62 3,400, 1.735

52.83 7.65 10.43 1.625

54.83 7.48 13.32 3,300, 1.625

54.15 7.03 13.85 1,160

cooh

dung

No.

110

111

112

113

114

115

116

117

HN * HaN

Ar

H

C-N-ch2ch2ch2chcor H-N-SOa-Ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (p.Mol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

H

N

IR

Spectrum (KBr)

/ CH3

CH2CH3

CH 3

0CH2CKv

N CH3

OCH

/ cu3

\

CH-

o (CH2) 3CH3

CH-

OCH

CH3 CH3

Y ^ rCH3

OC o H c-

(CH2) 2CH3 0 (CH2) 2CHp

CH3

. 0 (CII2) 2CH3 CH 3

CH '

COOH

0.2

0.1

0.65

0.6

0.2

53.98 7.29 13.69 3.340, 1.620

53.77 7.09 13.38 1.380, 1.155

53.98 7.29 13.69 3.340, 1.610

53.79 7.11 13.81 1.380, 1.155

53.10 7.09 14.08 3.350, 1.620

53.00 7.00 14.00 1.380, 1.155

53.98 7.29 13.69 3.350, 1.620

53.71 7.08 13.72 1.380, 1.155

53.98 7.29 13.69 3,300, 1,600

53.92 7.33 13.60 1.380, 1.130

53.10 7.09 14.08 3.350, 1.620

53.08 7.09 14.11 1.380, 1.150

55.63 7.66 12.98 3.320, 1.620

55.59 7.74 12.99 1.380, 1.130

54.83 7.48 13.32 3,300, 1.630

54.80 7.53 13.30 1.380, 1.150

Connection no.

Ar

HN * s, H

^ C-N-ch2ch2ch2chcor HaN ^

H-N-SOz-Ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (yol. Mol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

IR

Spectrum (KBr)

H

N

118

119

120

121

122

123

124

125

Oil! '

ca-rc, 13

'CH 3

■ CH3 N GII3 OCH3

CII3

f / 7rCHNCH3

0 (cil2) 2CH3

ìfì (c "5

och

, ch3

\ ch o ch3

c "3

OC2h5

CH3

^ y ° ch3

0 (0112) 30113

l ^ yr och3

o (cH2) 4CH3

och-

0ch2 ch ^

och-

ch3 ch3

^ S-OCH 3 och 3

I. M ^ CHT

OCHoch2ch v j ^ * - ■ ^ CH-.

-q-ch,

cooh

0.1

0.5

0.75

0.55

56.39 7.83 12.65 3.350, 1.620

56.51 7.78 12.56 1.460, 1.155

57.80 8.14 12.04 3.350, 1.620 57.85 8.69 11.98 1.380, 1.140

54.83 7.48 13.32 3.350, 1.615

54.81 7.52 13.27 1.380, 1.150

53.98 7.29 13.69 3.350, 1.610

53.99 7.36 13.71 1.380, 1.150

53.21 7.26 12.93 3.350, 1.620

53.39 7.30 12.88 1,360, 1.155

53.02 7.60 12.88 3.350, 1.620

53.15 7.57 12.86 1.380, 1.160

52.51 7.24 12.25 3.330, 1.620

52.43 7.31 12.26 1.380, 1.160

53.30 7.41 11.96 3.330, 1.620

43.36 7.35 12.01 1.380, 1.160

No.

126

127

128

129

130

131

132

133

Ar

HN> ^ H

c-n-ch2ch2ch2chcor

HaN ^

H-N-SOa-Ar

R

^ .oc2H5

e>

CH '

oc2h5

w ^ 0CII3

<o-0c2h5

^ CCH3

ch ch3 cho

/ k-OCH3 k ^ A0 (CH2) 2CH3

0CH3

ocnr * 01'3

N CHo

A ^ och3 kJ ^ O (CH2) 3CH3 OCII3 .och 3

0 (CH2) 2CHt'CH :)

oh

ch3

/K.OCH3

ü (ch2) 3ch3

OCH3

0 »3 /

cooh ch3

CH '

~ N-

cooh

^ p-C2H5

cooh

»

ch,

, -D

-n

\

ch2cooh

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (nmol / 1)

Manufacturing process according to the example

Physical Properties

0.25

0.25

Elemental analysis (upper values: calculated, lower values: found)

IR

spectrum

(KBr)

cm-1

H

N

51.69

7.05

12.56

3,350, 1,630

51.75

7.00

12.56

1,380, 1,100

50.81

6.86

12.88

3,350, 1,610

50.79

6.91

12.84

1,380, 1,160

53.98

7.29

13.69

3,400, 1,620

54.15

7.26

13.76

1,150

52.51

7.24

12.25

3,350, 1,620

52.41

7.04

12.05

1,380, 1,160

53.98

7.29

13.69

3,300, 1,620

53.66

7.11

13.23

1,380, 1,155

53.30

7.41

11.96

3,350, 1,620

53.21

7.18

11.89

1,380, 1,155

54.06

7.58

11.68

3,350, 1,620

53.90

7.48

11.48

1,380, 1,155

52.51

6.44

14.13

3,370, 1,620

52.46

7.08

14.25

1.410, 1.090

!> 60 m r r>

H et-

c / a i

e &

Connection no.

Ar

HN.- H

^ C-N-CH2CHnCH2CHCOR HaN ^

H-N-SOz-Ar

R

Acid residue

Concentration to extend the coagulation time by d. Factor 2 (nmol / 1)

Manufacturing process according to the example

Physical Properties

Elemental analysis (upper values: calculated, lower values: found)

IR

spectrum

(KBr)

cm-1

H

N

134

och

\

, ch3 ch3

~ N

/ CII2

■ O

\

chocooh

53.06 6.20 16.14 3.350, 1.620 52.95 6.21 16.15 1.410, 1.150

135

136

137

138

ch3

0 (ch2) 2ch3

ch-

ch3

(ch2) 2ch3

(ch2) 2ch3

2 »5

/ \ / cho -N> -CH ^ J

) /> ch3

cooh

■ Ny_ / ~ C2 H5 cooh

-nOch3 /

cooh

54.83 7.48 13.32 3.355, 1.620

54.71 7.23 13.11 1.380, 1.150

55.63 6.66 12.98 3.360, 1.620

55.56 7.58 12.79 1.380, 1.150

ta m r c>

54.83 7.48 13.32 3.340, 1.620 g

1-1

54.90 7.41 13.29 1.380, 1.150 I.

S

D

e

54.83 7.48 13.32 3.350, 1.620 54.77 7.50 13.35 1.385, 1.140

4 ^

W

ON

iti W -4

633773

44

The compounds listed in Table III below were prepared in the same way. The literature references given in this table refer to the processes for the preparation of the compound indicated in the second column.

TABLE III

io

15

20th

25th

30th

35

40

45

50

55

60

65

P6

M 3 • O O

ti O u m o-

<

Cl

X o

V »/

X

e.g.

J ^ \

z z a £

o co -Z X

OD

a

3 <

O C

S <

co u

<a ~

K gii

-o «a

O ^ K>

^ N b «

Jh j_ o

C / 2 O -g

<Ow bû C 3

a> G i_

> 3Z

\ /

?

O

o = o ro \ D

\O

• -t • *>

W

m

X

o u o o o

CM

X

O

\ /

z; X

VO OS OS

<N

CQ

Ver ArSO ^ Cl or ArSOaH

bond or salt thereof

No. (reference)

Starting material amino acid ester

product

HN ^

^ C-NH- (CH2) 3CHCOR h2N ^ I

HNSOaAr

Ar

H ^ CO

ao2ci m. p. 55 ° C

cio2s

Cl '"°

Helv. Chim. Acta., 46, 727 (1963)

, ch0-L n J

HN

CH2CÜOCH2C (') H5

HN

\

Cl

CH2C00CH2CöHr

H ^ CO

-N

\

J

O

CH.jCOOH '

-CH,

O

-N

\

CHoCOOH

SO ^ Na Ber. 84, 1254 (1956)

Zhur. Obschei Khim 22, 866 (1952)

'3

H

N - T-CH-

HO3S

Zhur. Obschei Khim 22, 866 (1952)

HN SO

w

COOCoH r ^ D

HN

) /

G 0OGp H

HN S

W

COOCoH,

-N SO

COOH

-N O

W

COOH

-N S COOH

Ver bind

No.

8th

9

10th

11

12th

ArSC ^ CI or ArSOßH or salt thereof (reference)

Starting material amino acid ester

HN :; H2N

/

Product .C-NH- (CH2) 3CHCOR

I.

HNSOaAr

Ar

R

C102s> Y ^ Y'N <îrr0H

tSCt oh

Japanese Patent Published 26975/1964

och

HO3S Ber., 86, 951 (1953)

ÇOCH3 N- ^ SO3H

Ber., 86, 951 (1953)

hn

^ ch2cooc2h5

cooc2h5

HN \ v

TCCC

GOCH-I

N.

CO

CH

-CD

-N

2 O ^ ch ,, cooh

HO3S

goch-.

I.

N-

OK

Zhur Obschei Khim, 30, 1218 (1960)

14n cooc2h5

cocho I J ■ N

1

-N

P

cooh

Ver ArSOaCl or ArSCbH

binding or salt thereof No. (reference)

Starting material amino acid ester

HNv H2N ^

product

'C-NH- (CH2) 3CHCOR I

HNSOüAr

Ar

R

13

OC2H5

SOiNa oc2h5

CA, 25, 5420

Hl / CH 3

C02C2H

OC2H5

oc2h5

"y_ / ~ ch 3

COOH

14

S O 3N a

Ht / C? H5

C02C2Htj

-N y ~ C2H5 ':

COOH

15

CA, 22, 413

CA, 33.4227

S 0 3N a

H / ^ -CH3

C02C2H5

-n ^ Vch3

COOH

16

CJ ° 2S> V ^: SYX <: VY 'CONH2

Zhur Obshei Khim 18.1459 (1948)

HN y_CH.

co2c2h5

conh2

0 ^ 0

N) —CH3

/

COOH

Ver bind

No.

17th

18th

19th

20th

21st

ArSCteCl or ArSChH or salt thereof (reference)

Starting material amino acid ester

product

HN \

* ^ C-NH- (CH2) 3CHCOR H2N ^ I

HNSOaAr

Ar

R

soocl

Compt. rend 198, 2260 (1934)

ln vf hn ^ -ch3 /

cooc2n5

s

Compt. rend 198, 2260 (1934)

so2c.l

J. Chem. Eng. Data 12, 610 (1967) O

so2ci

J. Pharm. Soc. Japan 73, 1878 (1953)

NH '

HN \

%> H,

HN} -C2H5

cooc2H5

CH ^ hn ~ ^) - CH3 cooc2h ^

C ° 2c2H5

J. Pharm. Soc. Japan 76, 103 (1958)

0

cü2c2h5

"cv ch3

COOH

's ■ Or>

-N> -C2H5 cooh

60

-n \ -c2hr)

cooh ch

3rd

-NJ-CH,

COOH COONa

COONa

Ver ArSOaCl or ArSOsH

bond or salt thereof

No. (reference)

Starting material amino acid ester

22

23

24th

25th

26

27th

71

-N

S O-3 H U.S. 2,476,541

SO2CI J. Pr. (2) 118.15

• s- - Nll2

Photophysics Photochem, 58, 3 (1963)

SO3H

H3CO,

J. Gen. Chem., 16, 1873

HO3S

TOÛ

COCH-

Ber. 86, 951 (1953) H N-

i) D

HO3S

Zhur Obschei Khim, 30, 1218 (1960)

HN ^ -OCH /

COOCoHr

3rd

/ - \ HN / -CH3

COOC-.H r <= - ì

HN

CH-

COOCoH 5

HN

r \

CH '

CH

COOCoH,

\

CH-

■ v> ©

COOCoHr

HN ^ yCH3 "> -

C00C2

CH-

product

HN ^

^ C-NH- (CH2) 3CHCOR h2n i

HNS02Ar

Ar R

T0Û

\

COCH.

D

-N y-OCH- ^ COOH

-N ^) - CH3 COOH

H -CH, 3rd

COOll

-] -CH

CH 3 X CH.,

COOH

i> a

COOH

.CH

"S

COOH

3rd

CH3

Ver bind

No.

28

29

30th

31

32

33

product

ArSOaCl or ArSOaH

Source material

HNs.

or salt thereof

C-NH- (CH2) 3CHCOR

(Reference)

Amino acid esters

HaN- ^ 1

HNSOaAr

Ar

R

cl02svf ^ r ^

H

Bull. Soc. Chem. France, 1950, 466

so2ci

Bull. Soc. Chem. France, 1950, 466 0

s02c1

o2n 11

CA 62.14675b

/

co0c2h <5

HV>

COOC2H5

hn y-ch3

cooc2h 5

C \ <

HN ^ -CH3

coocphc

CA 26.4723

- ■ (> c2h5

cooh cooh

-Ç) -c "3

cooh i>

cooh ch -

02c1

J. Am., Chem. Soc., 57, 1533 (1935)

hn vc2h5

cooc2h

-CoH r cooh hn yc3h7 cooc 2h5

-N / -C3H7

COOI1

51

633773

TABLE III (continued)

X X

o o

\ /

3C o i l ~ \

X

cv •• * \

o o

0 \ with)

c 00

ff o

^ I

O

> o m o

m

Example 6

Tablets suitable for oral administration. Tablets which contain the constituents specified below can be prepared using procedures which are known per se.

component

10th

Amount per tablet

(mg)

15

N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine

Lactose

Cornstarch

talc

Magnesium stearate

250 140 35 20 5

20th

a total of

450 mg m

m

Example 7

25 capsules for oral administration.

The capsules consisting of the following ingredients are obtained by mixing the ingredients well and pouring the resulting mixture into hard gelatin capsules.

30th

component

Amount per capsule (mg)

35

N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butyI-glycine

Lactose

250 250

40

a total of

500 mg

45

Example 8 Sterile Infusion Solution.

The components listed below are dissolved in water suitable for intravenous perfusion and the solution obtained is sterilized.

50 components

Quantity (g)

N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine

55 buffer system

glucose

Distilled water

25th

in the desired amount

25th

500

60.

65

Production A)

Arylsulfonylchloride A) Sodium 3-butoxy-2,4-dimethoxybenzenesulfonate. 16.1 ml are added dropwise at a temperature of 0 to 4 ° C. to a well-stirred solution of 50.8 g of 2-butoxy-1,3-dimethoxybenzene in 160 ml of carbon tetrachloride

633773

52

Chlorosulfonic acid. The reaction mixture is stirred for 1 hour at room temperature, poured into crushed ice and then diluted to 300 ml with water.

After evaporation of the carbon tetrachloride, the aqueous layer is extracted with ether and neutralized with a 2N sodium hydroxide solution to precipitate white crystals, which are filtered off and dried, 64.3 g (yield = 85.1%) of sodium 3-butoxy-2 , 4 - dimethoxybenzenesulfonate is obtained.

B) 3-butoxy-2,4-dimethoxybenzenesulfonyl chloride.

69 ml of thionyl chloride are added dropwise over a period of 20 minutes at room temperature to a stirred suspension of 60.0 g of dry, powdered sodium 3-butoxy-2,4-dimethoxybenzene sulfonate in 150 ml of dry dimethylformamide. The reaction mixture is stirred for 15 minutes and then poured slowly into 1000 ml of ice water, whereupon the mixture is stirred vigorously. After 1 hour, the aqueous layer is decanted off, the remaining oil is extracted with benzene, washed with water, dried over anhydrous sodium sulfate, distilled to remove the solvent and then distilled again in vacuo, giving 47.5 g (yield = 80.1 %) 3-Butoxy-2,4-dimeth-oxybenzenesulfonyl chloride (boiling point 154 to 155 ° C / 1 mmHg).

TABLE IV (continued)

Connection 5 no.

Ar - SO2CI Ar

10 5

15

Analysis: C12H15C105S

calculated: found:

C 46.68 C 46.71

H 5.56% H 5.60%

The following Table IV shows arylsulfonyl chlorides which have not previously been described in the chemical literature and which have been prepared in the manner stated above.

TABLE IV

Compound no. Ar

Ar - SO2CI

Boiling point (melting point)

20th

25th

30th

35

10th

40

o (ch2) 3ch3

ch2ch2ch3 och3

och3 ch2ch3

chn i j c - cho i

och3 ch3

y ^ rch 3

^ Y ^ 0 (CH2) 3CH3

ch3 • ch3

0 (ch2) 4ch3

Boiling point (melting point)

143-145 ° C / 1 mmHg (48/51 ° C)

(41-2 ° C)

139-140 ° C / 1 mmHg

129.5-132 ° C / 1 mmHg

145-148 ° C / 1 mmHg

151.5-153.5 ° C / 1.5 mmHg

o (ch2) 2ch3

o (ch2) 3ch3

och2ch2ch ^

0 (CH2) ZtCH3

165-166 ° C / 45 11 10 mmHg (57.5-58.5 ° C)

, ch3 ch3

112-115 ° C / 1 mmHg (33-35C)

127-129 ° C / 0.5 mmHg

148-150 ° C / 1 mmHg

50

12

55

13

60

14

65

tT3

\ ^ 0 (CH2) 3CH3

ch3

0CH2CH20CH3

y ^ rr ch3

155-156 ° C / 2 mmHg

(44-45 ° C)

0CH2CH2CH20CH3

187 ° C / 1 mmHg

0ch3 198-200 ° C /

0CH2CH2CH2Br 2 mmHS

och3

am-

dun

No.

15

16

17th

18th

19th

20th

21st

22

23

24th

25th

53

633773

TABLE IV (continued)

TABLE IV (continued)

Ar - SO2CI Ar

Boiling point bin Ar - SO2CI (melting point) 5 dung

Ar

OCH3

0 (ch2) 3c02ch3 or 3

f ^ v0ch3 Y ^ o (ch2) 2ch3

OCH3

OCH3

210-220 ° c / 10 26 1 mmHg

160-162 ° c / 2 mmHg

154-155 ° c /

15

27th

0 (CH2) -jCH3 1 mmHg

28

och-

25th

OCH3

0 (ch2) i + ch3) ch3 ^ 0c "3

0 (ch2) 5ch3

OCH3

oc h 3

0ch2ch20ch3

3rd

cl

0 (ch2) 3ch3 o (ch2) 2ch3

ocho och

Cl

170-172 ° c / 2 mmHg

183-185 ° c / 1 mmHg

(46-47 ° c)

131 ° c / 1 mmHg

(65-66 ° c)

29

30th

35 30

40

31

45

32

o (ch2) 3ch3 0 (ch2) 3ch3 1 0 (ch2) 3ch3

33

(30-32 ° c)

34

o (ch2) 3ch3

0 (ch2) 3ch3

208-210 ° C / 1 mmHg 60

35

/

o (ch2) 3ch3

178-179 ° c / 2 mmHg

65

Boiling point (melting point)

oily substance

'c0 (ch2) 2ch3 OCH3

âr ™ 3

\ j ^ 0CH2CH20CPI2CH3 1 mmHg OCH3

165-168 ° c /

/ ch3

cliss ch2ch3

0c02c2h5

0c2h:

choc h

\

CH3

CH3 ochch2ch3

OCHoch

\

o (ch2) zich3

ch-

oc2h5

CH3

o (ch2) 2ch3

oily substance

109-110 ° c / 1.5 mmHg

111-116 ° c / 1 mmHg

oily substance

CH3 oily substance CH3

148-150 ° c / 1 mmHg

152-153 ° C / 2 mmHg

133-134 ° C / 1 mmHg

633773

54

TABLE IV (continued)

TABLE IV (continued)

Connection no.

36

37

38

39

40

Ar - SO2CI Ar

CH3

.ch-

och

\

ch-

v ^ VCH3

CH3

ch3

n ° (ch2) 2ch-3

ch-3

chr (/ \\ - 0ch ^ chi cih ch-

^ ch3

wchcch3

x CH3 .CH "]

w'ch ^ 3

41 6 / _y-o- (CH2) 2CH3

ch

\

-CH3 CH3

Boiling point bin Ar - SO2CI (melting point) 5 dung

Ar

142-143 ° C / 1 mmHg

121-122 ° C / 1 mmHg

133-135 ° C / 1 mmHg

136-139 ° C / 1 mmHg

(95-6 ° C)

(101-103 ° C)

10 42

15

43

20th

44

25th

45

30th

46

35

47

40

Boiling point (melting point)

vX \, (CH2) 2CH3

^^ o (ch2) 2ch3

och 3rd

142-144 ° C / 1 mmHg

(50-51 ° C)

ch '

\

ch-

158-160 ° C / 1 mmHg or 3 och-

/ ~ 3

& v- OCH. PH rw ^ CIÌ3 159 "160 ° c /

\ _v ~ och2 ch2ch n y mmh

\ CHq och 3

N ^ OC2H5

151-2 ° C / 1 mmHg

158-159 ° C / 1 mmHg

OCH3

v

Claims (11)

633773 ,/ 1 T.-H P T hn ( T? "I 60 with an arylsulfonyl halide of the formula ArSOaX (VI) (VII) in which Ar has the meaning given in claim 1 and 65 X represents a halogen atom, condenses and, if desired, the compound of formula I obtained is converted into the corresponding salt by reaction with a pharmaceutically acceptable acid. 1) a group of the general formula 15 - N 20th (CH2) nCOOR2 in the Rj is a C2-C10-alkyl group, a C2-C6-alkoxyalkyl group, a C2-C6-alkylthioalkyl group, a C7-C10-aralkyl-25 group, a C4-C10-cycloalkylalkyl group, a furfuryl group or a tetrahydrofurfuryl group, R2 represents a hydrogen atom or a C1-C10 ~ alkyl group and n represents an integer with a value of 1,2 or 3; 1) a group of the general formula C3-Cw-alkenyl group, a C2-C10-alkoxyalkyl group, a C2-Ci0-alkylthioalkyl group, a C2-Cw-alkylsulfinylalkyl group, a C7-C15-aralkyl group, a C2-C10-cycloalkyl group, a C4-C10- Cycloalkylalkyl group, a furfuryl-5 group, a tetrahydrofurfuryl group, a tetrahydro-2 - (-3 or -4) -pyranyimethyl group or a 1,4-dioxa-2-cy-clohexylmethyl group; R4 is a CrCI0-alkyl group, a phenyl group which is optionally substituted with at least one CrC5-alkyl group, CrC5-io alkoxy group or mixtures thereof, a C7-C12-aralkyl group or a benzyl group substituted on the ring, which as substituents Cj-Q- Has alkyl groups or CrC5 alkoxy groups; Rg represents a hydrogen atom, a Ci-Cio alkyl group, a 15 C6-C10 aryl group or a C7-C12 aralkyl group and m represents an integer with a value of 0, 1 or 2; 1 - N (ch2) ncoor2 in the Rj for a C2-C10-alkyl group, a C3-C10-alkenyl group, a C3-C10-alkynyl group, a C2-C10-alkoxyalkyl group, a C2-C10-alkylthioalkyl group, a C2-C10-alkylsulfinylalkyl group, a CrCi0-hydroxyalkyl group, a C3-C10-alkoxycarbonylalkyl group, a Cs-C10-alkylcarbonylalkyl group, a QC ^ -haloalkyl group, a C7-C15-ara'kyl group, a C8-C15-a-carboxyaralkyl group, a C3-C10-cycloalkyl group, a C4- C10 cycloalkylalkyl group, a furfuryl group, a tetrahydrofurfuryl group optionally substituted with at least one Cj-C3-alkyl group, Ci-C5-alkoxy group or mixtures thereof, a 3-furyl-methyl group, one optionally with at least one CrC;) -alkyl group, C, -C5-alkoxy group or Mixtures thereof substituted tetrahydro-3-furylmethyl group, one optionally substituted with at least one CrC5 alkyl group, CrC5 alkoxy group or mixtures thereof substituted tetrahydro-2- (3 or -4) pyranyimethyl group, one optionally with at least one CrC5 alkyl group, CrC5 Alkoxy group or mixtures thereof substituted 1,4-dioxa-2-cyclohexyl methyl group, a 2-thenyl group, a 3-thenyl group, a tetrahydro-2-thenyl group optionally substituted with at least one CrC5-alkyl group, Cj-Q-alkoxy group or mixtures thereof, or a tetrahydro-3-thenyl group, n \ r3 ch - (ch2) mcoor5 R4 group, a 3-furylmethyl group, a tetrahydro-3-furylmethyl group optionally substituted with at least one C1-C5-alkyl group, C1-C5-alkoxy group or mixtures thereof, one optionally with at least one CrC5-alkyl group, Cj-C5-alkoxy group or Mixtures thereof substituted tetrahydro-2- (3- or -4) pyranylmethyl group, a 1,4-dioxa-2-cyclohexylmethyl group optionally substituted with at least one QQ alkyl group, CrC5 alkoxy group or mixtures thereof, a 2-thenyl group, 10 a 3 -Thenyl group, a tetrahydro-2-thenyl group or a tetrahydro-3-thenyl group optionally substituted with at least one Cj-Cj-alkyl group, Cj-Q-alkoxy group or mixtures thereof, R4 for a CrC10-alkyl group, a phenyl group optionally substituted with at least one CrC5-alkyl group, CrC5-alkoxy group or mixtures thereof, a C, -C12-aralky] group or one on the ring with a Cj-Cj-alkyl group or C1 -C - alkoxy group substituted benzyl group, 20 R5 for a hydrogen atom, a CrCltl alkyl group, a C6-C10 aryl group or a C7-C12 araikyl group and m represents an integer with a value of 0.1 or 2; (1) a group of the general formula r 2 Ì e- Ar (XXII) x-ii-ch-ch ch-chcor 2 2 21 HI 2nd 65 with an arylsulfonyl halide of the formula ArS02X (vii) 633773 2) a group of the general formula 30th 35 40 - n / r3 ch- (ch0) coorj-, 2m 5 r. in the R3 is a hydrogen atom, a Cj-Cjo-alkyl group, a C2-C6-alkoxyalkyl group, a C2-C6-alkylthioalkyI group, a C7-CI0-aralkyl group, a C4-C10-cycloalkylalkyl group 45 pe, a furfuryl group or a tetrahydrofurfuryl group, R4 one CrC5 alkyl group, R5 represents a hydrogen atom or a Q-C ^ alkyl group and m represents an integer with a value of 0, 1 or 2; 50 3) a group of the general formula - N 55 60 in R- is a group of the formula -COOR8, in which R8 represents a hydrogen atom or a C1-C10-alkyl group, R7 independently of one another are hydrogen atoms or Cj-Q-alkyl groups and 65 p is an integer with a value from 1 to 4 mean, where the group R6 in the 2- or in the 3-position and the groups R7 can be in the 2-, 3-, 4-, 5- or 6-positions; 2) a group of the general formula -n ' r, ch- (cht) coorc, 2 m 5 r " in the 20th 25th r6 - n in the R6 is a group of the formula -COORs in which R8 is a hydrogen atom, a CrC10-alkyl group, a C6-C10-aryl group or a C7-C12-aralkyl group, R7 independently of one another are hydrogen atoms, Cj-C ^ -alkyl groups or phenyl groups and p is an integer with a value from 1 to 4, 35 where the group R6 in the 2- or 3-position and the groups R in the 2nd -, 3-, 4-, 5- or 6-position can be; 4) a group of the general formula CQOR9 40 - X (ch2) 45 50 which is optionally substituted with at least one CrC5 alkyl group, C] -C5 alkoxy group or mixtures thereof in the R9 represents a hydrogen atom, a CrCjo alkyl group, a C6-C10 aryl group or a ^ 7 "C12 aralkyl group and r represents an integer with a value of 1, 2, 3 or 4; 2. Compounds according to claim 1, characterized in that Ar is a phenyl group or a naphthyl group, each with at least one substituent from the sulfoamino groups, carbamoyl groups, C3-C10-N, N-dialkylcarbamoyl groups, C2-C6-NA! Kylcarbamoyl groups, Amino groups, C] -C] 0-alkylamino groups, mercapto groups, Cj-C10-alkylthio groups, C7-C] 2-aralkyl groups, carboxy groups, C2-Ci0-alkoxycarbonyl groups, C2-CI0-carboxyalkyl groups, C, -C10- Acylamino groups, C2-C10-alkylcarbonyl groups, Cj-Cj „-hydroxyalkyl groups, CrC10-haloalkyl groups, Cj-C10-hydroxyalkyl groups and phenyl groups, which are optionally substituted with at least one hydroxyl group, Q-Q-alkoxy group or mixtures thereof, are substituted; a phenyl group or a naphthyl group, each with at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, Cj-CjQ-alkyl groups, Cj-CiQ-alkoxy groups and C2-C20-di-io alkylamino groups and at least one substituent from the group Sulfoamino groups, carbamoyi groups, C3-C10-N, N-dialkylcarbamoyl groups, C2-Ce-N-alkyl-carbamoyl groups, amino groups, Cj-C ^ -alkylamino groups, mercapto groups, CrCjo -alkylthio groups, 15C, -C12-aralkyl groups, carboxy groups -C10-alkoxy-carbonyl groups, C2-C10-carboxyalkyl groups, Cj-Cj, -acyl-amino groups, C2-C10-alkylcarbonyl groups, CrC10-hydroxyalkyl groups, CrC10-haloalkyl groups, Cj-C ^ -hydroxyalkoxy groups and phenyl groups, the optionally substituted with at least one hydroxyl group, Q-Cs-alkoxy group or mixtures thereof; an oxanthrenyl or dibenzofuranyl group which contains at least one substituent from the halogen atoms, Ni-25 tro groups, cyano groups, hydroxyl groups, C2-C20-di-alkylamino groups, C2-C6-N-alkylcarbamoyl groups, Ci-C10-alkylamino groups, mercapto groups, Cj- C10-alkylthio groups, C2-C10-alkoxycarbonyl groups, QC ^ -hydroxy-alkyl groups, CrC10-haloalkyl groups and C ^ Cjo-Hy-30 hydroxyalkoxy groups is substituted; an oxanthrenyl or dibenzofuranyl group which has at least one substituent from the group comprising Q-Cj ,, - alkyl groups and Cj-Cj ,, - alkoxy groups and at least one substituent from the halogen atoms, nitro-35 groups, cyano groups, hydroxyl groups, C2-C20 -Dialkyl-amino groups, C2-C6-N-alkylcarbamoyl groups, C ^ C ^ -Al-kylamino groups, mercapto groups, Cj-Ci0-alkylthio groups, C2-Ci0-aikoxycarbonyl groups, C ^ C ^ -hydroxyalkyl groups, CrC10-haloalkyl groups and Cj -C ^ -Hydroxy-40 alkoxy group-substituted ;; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylene-dioxynaphthyl group or a xanthenyl group, each with at least one substituent from the halogen atom, 45 nitro groups, cyano groups, hydroxyl groups, C2-C20-di- aikylamino groups, C2-C6-N-alkylcarbamoyl groups, CrC1 (J-alkylamino groups, mercapto groups, Ci-Cj0-alkylthio groups, C2-CJ0-alkoxycarbonyl groups, Ci-C10-hydroxyalkyl groups, CrC10-haloalkyl groups, CrC10-hydroxy-50 alkoxy groups and a group comprising oxo groups; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylenedi-oxynaphthyl group or a xanthenyl group, each 55 with at least one substituent from the group comprising Cj-C10-alkyl groups and CrC10-alkoxy groups and at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-Cz0-di-alkylamino groups, C2-C6-N-alkylcarbamoyl groups, Ci-C10-60 alkylamino groups, mercapto groups, Q-Cjo-alkylthio groups, C2-C] 0-alkoxycarbonyl groups, CrCJ0-hydroxyalkyl groups, Ci-C ^ haloalkyl groups, Cj-Clü-hydroxyalkoxy groups and oxo groups are substituted; 65 an anthryl group, a phenanthryl group, a bi-phenylenyl group, an s-indacenyl group, a phenylcarbonylphenyl group, a phenoxyphenyl group, a benzofuranyl group, a benzoflthienyl group, a thianthrene group (2) a group of the general formula V (r-) ^ / yp in the R6 represents a group of the general formula -COOR8, in which Rs represents a hydrogen atom, a Cj-Cjo-alkyl group, a C6-C10-aryi group or a C, -C12-aralkyl group, R7 independently of one another hydrogen atoms, CrC10 alkyl groups. Phenyl groups, Cj-C5-alkoxy groups, C2-C6-40 alkoxycarbonyl groups or carboxy groups and p represent an integer with a value from 1 to 4, the Re group in the 2- or 3-position and the R7 groups in can be in the 2-, 3-, 4-, 5- or 6-position; (4) a group of the general formula 45 COOR9 VN - n y 50 \ '■ i'Hd in the Rs for a hydrogen atom, a CrC10-alkyl group, a C3-C] 0-alkenyl group, a C3-C10-alkynyl group, a C2-C10-alkoxyalkyl group, a C2-C10-alkylthioalkyl group, a C2-C10-alkylsulfinylalkyl group, a C1- CI0-hydroxyalkyl group, a Qj-Cjq alkoxycarbonylalkyl group, a Cs-Cj0-alkylcarbonylalkyl group, a CrC10-haloalkyl group, a C7-Ci5-aralkyl group, an -a-carboxy-aralkyl group, a C3-C10-cycioalkyl group, one C4-C10-cycloalkylalkyl group, a furfuryl group, a tetrahydrofurfuryl group optionally substituted with at least one CrC5 alkyl group, CrC5 alkoxy group or mixtures thereof which may optionally be substituted 55 with at least one Q-Cj-alkyl group, Q-Cj-alkoxy group or mixtures thereof, in which R9 represents a hydrogen atom, an Ore «, alkyl group, a C6-C10-aryl group or a C7-Ci2-aralkyl group and r represents an integer with a value of 1, 2, 3 or 4; 60 (5) a group of the general formula coor-i n \ / \ 65 N / " ^ CH2) ( 2nd PATENT CLAIMS 1. N2-arylsulfonyl-L-argininamides with therapeutic effect of the general formula I hn h2n ' % c - n - choch ~ chochc0r I AIA I - h hnso- i ' Ar (I) in the R 3) a group of the general formula - n / R1 (ch0) coor-2 n 2 in the R, a C2-C10-alkyl group, a C3-CJ0-alkylene group, a C2-C10-alkoxyalkyl group, a C2-C10-alkylthioalkyl group, a C, -C, 0-alkylsulfinylalkyl group, a C7-C15-ar-alkyl group , a C3-C10-cycloalkyl group, a C4-C10-cycloalkylalkyl group, a furfuryl group, a tetrahydrofurfuryl group, a tetrahydro-2 - (- 3 or -4) -pyranyimethyl group or a 1,4-dioxa-2-cyclohexylmethyl group ; R2 represents a hydrogen atom, a Cj-Qo-alkyl group, a Q-Cjo-aryl group or a C7-C12-aralkyl group and n represents an integer with a value of 1, 2 or 3; 3. Compounds according to claim 2, characterized in that the group R 3rd 633773 in the RI0 for a hydrogen atom, a CrC10 alkyl group, a C6-C10 aryl group or a C7-C12 aralkyl group, Z represents an oxygen atom, a sulfur atom or a sulfinyl group and q represents an integer with a value of 0 or 1; or (3) a group of the general formula 4) a group of the general formula CUORq (pH 2} which is optionally substituted with at least one Cj-Cj-alkyl group, a Cj-Cg-alkoxy group or mixtures thereof, in which R9 represents a hydrogen atom or a Cj-C10 alkyl group and r represents an integer with a value of 1, 2, 3 or 4; 4. Compounds according to claim 3, characterized in that R 5 in which R has the meaning given in claim 1, and the compound of formula I obtained, if desired, converted into the corresponding salt by reaction with a pharmaceutically acceptable acid. 5) a group of the general formula - N CO ° R10 / \ / - (Clio) in the R10 represents a hydrogen atom or a CrC10 alkyl group, Z represents an oxygen atom, a sulfur atom or a sulfonyl group and q represents an integer with a value of 1 or 0; or 5) a group of the general formula 55 C'OOF <10 - N 60 V, / i2) in the R, a hydrogen atom, a Cj-C10 alkyl group, a R10 represents a hydrogen atom, a CrC10 alkyl group, a C6-C10 aryl group or a C7-CI2 aralkyl group, 65 Z represents an oxygen atom, a sulfur atom or a sulfonyl group and q represents an integer with a value of 0 or 1; or 633773 5 633773 nyl group, a dibenzotienyl group, a phenoxathiinyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, an acridinyl group, phen-azinyl group, a phenothiazinyl group or a phenox-azinyl group, or each unsubstituted or in each case unsubstituted one or more groups from which halogen atoms, nitro groups, cyano groups, hydroxy groups, Cj-Cjo-alkyl groups, CrC10-alkoxy groups, C2-C20-dialkylamino groups and C] -C! 0-hydroxyalkoxy groups are substituted; a C7-C12 aralkyl group, a C9-CI6-cycloalkylphenyl group, a C10-C18-cycloalkylalkylphenyl group, a C9-Cj6-cycloalkoxyphenyl group, a 9,10-dihydroanthryl group, a 5,6,7,8-tetrahydroanthryl group, a 9 , 10-di-hydrophenanthryl group, a 1,2,3,4,5,6,7,8-octahydro-phenanthryl group, an indenyl group, an indanyl group, a fluorenyl group, an acenaphthenyl group, a phenylthiophenyl group, a 2,3- Dihydrobenzofuranyl group, a thioxanthenyl group, a 2H-chromenyl group or a 1,2,3,4-tetrahydroquinolyl group which is unsubstituted or by one or more groups from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, CrC10-alkyl groups, C] -C10- Alkoxy groups, C2-C20-dialkylamino groups, C2-C, jN-alkylcarbamoyl groups, Q-Cip-hydroxyalkoxy groups and oxo groups are substituted; or a phenyl group with at least one substituent from the alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups. Alkoxycarbonylalkyl groups and alkoxycarbonyl-alkoxy groups is substituted, the substituent contains 3 to 7 carbon atoms, wherein the substituted phenyl group may optionally be further substituted with at least one substituent from the group comprising methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxy groups and halogen atoms; means. 5 6. The method according to claim 5, characterized in that the acidolysis is effected in such a way that the N ° -substituted N2-arylsulfonyl-L-argininamide with an excess of an acid at a temperature of - 10 ° C to 100 ° C. brings in contact. 6) a group of the general formula pe which are unsubstituted or substituted by one or more groups from the group consisting of C 1 -C 6 -alkyl groups, C 1 -C 6 -alkoxy groups and oxo groups; or a phenyl group which is substituted with at least one substituent from the group comprising alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and alkoxycarbonylalkoxy groups, which substituent contains 3 to 7 carbon atoms, the substituted phenyl group optionally being substituted is further substituted with at least one substituent from the group comprising methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms, mean. 15 5. Process for the preparation of N2-ArylsuIfonyI-L - argininamides with therapeutic effect of the general formula I given in claim 1, in which R and Ar have the meanings given there, and their pharmaceutically acceptable salts, characterized in that 20 the guanidino group and the a-amino group of L-arginine: HN 25th hon -n-I H CH0CH2CH2CHCOOH NU ' (II) protects, the obtained NG-substituted N2-substituted L-Ar-30 gin in the formula: hn 35 HN ' I. r- n — ch2ch2ch2chcooh r " hn 1 r '" (iii) in the Rn is a hydrogen atom or a CrCI0 alkyl group, i is an integer with a value of 0.1 or 2 and j is an integer with a value of 0.1 or 2 and the sum of i + j is an integer with a value of 1 or 2; and Ar is a phenyl group or a naphthyl group, each of which is substituted by at least one substituent from the group consisting of amino groups, CrCi0-alkylamino groups, C7-CJ2-alkyl groups, CrC10-acylamino groups, CrC10-hydroxyalkyl groups and CrC10-hydroxyalkoxy groups; a phenyl group or a naphthyl group, each with at least one substituent from the amino groups, CrC10-alkylamino groups, C7-C2i-aralkyl groups, CrC10-acyiamino groups, CrC10-hydroxyalkyl groups and crc10-hydroxyalkoxy groups and at least one substituent from the halogen atoms, hydroxyl groups, C1 -C10 alkyl groups and a group comprising C, -C10 alkoxy groups are substituted; a biphenylenyl group, a phenoxyphenyl group, a dibenzothienyl group, a phenoxathiinyl group, a quinolyl group or a quinoxalinyl group, each of which is unsubstituted or substituted with one or more groups from the group comprising hydroxyl groups and CrC10-alkyl groups; a C7-CI2 aralkyl group, a C9-C16 cycloalkylene group, a fluorenyl group or a 2H-chromenyl group 40 with a corresponding amino acid derivative of the formula RH (IV) condensed, from the NG-substituted and N2-sub-45-substituted L-argininamide of the formula HN 50 Hpr ' r ■ N CH ^ CHoCH2CHC0R I I R "HN I. R "' (v) 55 by catalytic hydrogenolysis or by acidolysis selectively cleaves only the N2 substituent, the N ° -substituted L-argininamide of the formula hn obtained 60 HN I r ' 'c — n— ch ochochochc0r /! 2 2 2, R " nh (xix) 6) a group of the general formula (.cho) in the Rn is a hydrogen atom, a Q-Cuj-alkyl group, a Ce-C10-aryl group or a C, -C12-aralkyl group, i is an integer with a value of 0.1 or 2 and j is an integer with a value of 0.1 or 2 and the sum of i + j is an integer with a value of 1 or 2; and Ar is a phenyl group or a naphthyl group, each with at least one substituent from the amino groups, ci-c10-alkylamino groups, ci-cjo-alkylthio groups, c7-cj2 - aralkyl groups, c2-c10-alkoxycarbonyl groups, cj-cv acylamino groups, c2- c10-alkylcarbonyl groups, Q-Qo-hydroxyalkyl groups, crci0-hydroxyalkoxy groups and phenyl groups are substituted; a phenyl group or a naphthyl group, each with at least one substituent from the amino groups, CrC10-alkylamino groups, CrCi0-alkylthio groups, C7-C12-aralkyl groups, C2-C10-alkoxycarbonyl groups, Cj-Cjo-acyl-amino groups, C2-C10-alkylcarbonyl groups, Q-Cjo-hydroxyalkyl groups, CrC10-hydroxyalkoxy groups and phenyl groups and with at least one substituent from the halogen atoms, hydroxy groups, CrC, "- alkyl groups, CrC," - alkoxy groups and C2-C20-di-alkylamino groups are substituted; a dibenzofuranyl group substituted with at least one halogen atom; a dibenzofuranyl group which is substituted with at least one substituent from the group comprising Cj-C10-alkyl groups and C1-C10-alkoxy groups and with at least one halogen atom; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylenedioxynaphthyl group or a xanthenyl group, each of which is substituted by at least one halogen atom; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylenedioxy-naphthyl group or a xanthenyl group, which are each substituted with at least one substituent from the group comprising CrC10-alkyl groups and CrC10-alkoxy groups and at least one halogen atom ; an anthryl group, a phenanthryl group, a biphenylene group, a phenoxyphenyl group, a benzofuranyl group, a benzo [b] thienyl group, a dibenzothienyl group, a phenoxathiinyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, an acridinyl group or a phenazinyl group which are unsubstituted or substituted with one or more groups from the group consisting of halogen atoms, hydroxyl groups, CrC] 0-alkyl groups, CrCl0-alkoxy groups and CrC10-hydroxyalkoxy groups; a C7-C! 2-aralkyl group, a C9-C16-cycloalkylphenyl group, a fluorenyl group, a thioxanthenyl group, a 2H-chromenyl group or a 1,2,3,4-tetrahydrochinoyl group which are unsubstituted or with one or more groups from the group comprising CrCjo alkyl groups, CrC10 alkoxy groups and oxo groups; or a phenyl group which is substituted with at least one substituent from the alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and alkoxycarbonylalkoxy groups, which substituent contains 3 to 7 carbon atoms, the substituted phenyl group optionally further having at least one substituent from which methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms are substituted, io mean. 6 (6) a group of the general formula COOR11 ) (CH2) i in the Rn for a hydrogen atom, a CrC10 alkyl group, a Ce-C10 aryl group or a C7-C12 aralkyl group, i represents an integer with a value of 0.1 or 2 and j represents an integer with a value of 0.1 or 2 and the sum i + j represents an integer with a value of 1 or 2; and Ar is a phenyl group or a naphthyl group, each with at least one substituent from the sulfoamino groups, carbamoyl groups, C3-CJ0-N, N-dialkyl-carbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino groups, CrCI0-alkylamino groups, mercapto groups, CrC10 -A! Alkylthio groups, C7-Ci2-aralkyl groups, carboxy groups, C2-C, 0-alkoxycarbonyl groups, C2-C10-carboxy-alkyl groups, Ci-C10-acylamino groups, C2-C10-alkylcarbonyl groups, CrCj0-hydroxyalkyl groups, CrC10 -Halogen-alkyl groups, CrCj0-HydroxyIkoxygruppen and optionally substituted with at least one hydroxyl group, CrC5-alkoxy group or mixtures thereof substituted phenyl groups; a phenyl group or a naphthyl group, each with at least one substituent from the halogen atoms, Ni.rogruppen, cyano groups, hydroxyl groups, Ci-Ci0-AIkyI groups, CI-C] 0-alkoxy groups and C2-C20-dialkylamino groups and at least one substituent from the sulfoamino groups, carbamoyi groups, C "-C) 0-N, N-dialkylcarbamoyl groups, C2-CG-N-alkylcarbamoyi groups, amino groups, Cj-Cjo-alkylamino groups, mercapto groups, C, -C, 0-alkylthio groups , C7-C12-aralkyl groups, carboxy groups, C2-C10-alkoxycarbonyl groups, C2-CI0-carboxyalkyl groups, Ci-C] 0-acylamino groups, C, -C10-alkylcarbonyl groups, C, -CI0-hydroxyalkyl groups, C, -C10- Haloalkyl groups, CrC10-hydroxyalkoxy groups and optionally substituted with at least one hydroxyl group, C, -C -, - alkoxy group or mixtures thereof substituted phenyl groups; an oxanthrenyl group or dibenzofuranyl group which mi: at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-di-alkyamino groups, sulfoamino groups, carbamoyi groups, C, -C, 0-N, N-dialkylcarbamoyl groups, C2-C6- N-alkylcarbamoyl groups, amino groups, C, -CiG-alkylamino groups, mercapto groups, C] -Cj0-alkylthio groups, C7-CJ2-aralkyl groups, carboxyl groups, C2-C10-alkoxycarboxyl groups, C, -C10-carboxyalkyl groups, CrC10 -Acylamino groups, C, -Cu, -Alkylcarbonyl groups, C, -CiP H-hydroxyalkyl groups, CrC10-haloalkyl groups, CrC; 0-hydroxy'koxy groups and optionally with at least one hydroxy group, Cj-Cg-alkoxy group or mixtures thereof substituted group comprising phenyl groups; an oxanthrenyl group or dibenzofuranyl group which contains at least one substituent from the CrCi0-alkyl groups and CrC10-alkoxy groups and with at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-di-alkylamir-ogrupepn, sulfoamino groups, Carbamoyi groups, C, -C10-N, N-dialkylcarbamyl groups, C2-C6-N-alkyl-carbamoyl groups, amino groups, CrC10-alkylamino groups, mercapto groups, CrCi0-alkylthio groups, C7-Ci2-aralkyl groups, carboxyl groups, C2-Cyl-alkoxycarb -groups, C2-Ci0-carboxyalkyl groups, CrC10-acylamino groups, C2-Ci0-alkylcarbonyl groups, CrC10-hydroxyalkyl groups, Cj-C ^ -haloalkyl groups, CrC10-hydroxyalkoxy groups and optionally with at least one hydroxy group, Cj-Cj- Alkoxy group or mixtures thereof substituted phenyl group; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group. a chromanyl group, a 2,3-ethylene-dioxynaphthyl group or a xanthenyl group, which groups have at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-dialkylamino groups, sulfoamino groups, carbamoyro groups, C3-C10-N, N-dialkylcarbamoyl groups , C2-C6 - N-alkylcarbamoyl groups, amino groups, C1-C10-alkylamine groups, mercapto groups, CrC10-alkyl! Thio groups, C7-CJ2-aralkyl groups, carboxyl groups, C2-C10-alkoxy-carbonyl groups, C, C10-carboxyalkyl groups, CrC10-AcyI-amine groups, C2-C10-alkylcarbonyl groups, CrC10-hydroxyalkyl groups, Cj-Cjo-haloalkyl groups, C ^ Cjo-hydroxyalkoxy groups, oxo groups and optionally substituted with at least one hydroxyl group, CrC5 aikoxy group or mixtures thereof substituted phenyl groups are; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylenedioxynaphthyl group or a xanthenyl group, which groups with at least? a ^ m substituent from the group comprising C] -C10 alkyl groups and Cj-Cl0 alkoxy groups and at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxy groups, C2-C20 dialkylamino groups, sulfoamine groups, carbamoyi groups, C3-C10-N, N-Dialkylcarbanv ylgruppen, C2-Cc-N-AlkyIcarbamoylgruppen, amino groups, C1-Ci0-Al-kylamino groups, mercapto groups, CrC10-AlkyIthiogrup-pen. C7-CJ2 aralkyl groups, carboxyl groups, C2-C, 0-alk-oxycarbonyl groups, C2-C10-carboxyalkyl groups. CrC10-acylamino groups, C2-C10-alkylcarbonyl groups, CrC10-hydroxyalkyl groups, CrC10-haloalkyl groups, Cj "Cio" hydroxyalkoxy groups, oxo groups and optionally substituted with at least one hydroxyl group, a Cj-C-a'koxy group or mixtures thereof substituted phenyl groups; a naphthoquinonyl group, an anthryl group, a phenanthryl group, a pentalenyl group, a heptalenyl group. an azulenyl group, a biphenylenyl group, an as-indacenyl group, an s-indacenyl group, an acenaphthylenyl group, a phenylcarbonylphenyl group, a phenoxyphenyl group, a benzofuranyl group, an iso-benzofuranyl group, a benzo [b] thienyl group, an iso-benzothienyl group, an iso-benzothienyl group a dibenzo-thienyl group, a phenoxanthhiinyl group, an indolyl group, a 1 H-indazolyl group, a quinolyl group, an fsoquinolyl group, a phthalazinyl group, a 1 8-naphthidinyl group, a quinoxalinyl group., a quinazolinyl group, a cinnolinyl group, a carbazolyl group , a * 6 / 30th 35 ~ N R2 represents a hydrogen atom, a Cj-C30-alkyl group, a C5-C10-aryl group or a C7-CJ2-aralkyl group and n represents an integer with a value of 1, 2 or 3; 7. The method according to claim 5, characterized in that one carries out the hydrogenolysis in an inert solvent for the reaction in the presence of a hydrogen activating catalyst in a hydrogen atmosphere at a temperature of 0 ° C to the boiling point of the solvent. 7 633773 8. A process for the preparation of N2-arylsulfonyl-L-arginine amides having a therapeutic effect of the general formula I given in claim 1, in which R and Ar have the meanings given there, and their pharmaceutically acceptable salts, characterized in that L- Arginine of the formula HN \ h2N / -n-ch-ch-ch-chcooh I 2 2 2 h 2 h h, the latter with an amino acid derivative of the formula RH 8th in which Ar has the meaning given in claim 1 and x represents a halogen atom, condensed from the resulting NG-substituted N2-arylsulfonyl-L-argininamide of the formula HN \> HN I R ' -N-CH CH CH CHCOR I 2 2 2 1 R "HNS02 Ar (XX) in which R 'and R "represent hydrogen atoms or protective groups for the guanidino group, at least one of R' and R" being a protective group, cleaves the NG substituent by acidolysis or hydrogenolysis and, if desired, the compound of the formula I obtained by reaction with a pharmaceutically acceptable acid converted into the corresponding salt. 9. The method according to claim 8, characterized in that the N2-arylsulfonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature of from -10 ° C to + 80 ° C. 10. A process for the preparation of N2-arylsulfonyl-L - arginine amides with a therapeutic effect 15 1 given general formula I, in which R and Ar have the meanings given there, or their pharmaceutically acceptable salts, characterized in that the guanidino group and the a-amino group of L-arginine: 20th (ii) CN HoN 25th ■ x chochpchochcor I I h nh2 (ii) 30th protects, the N ° -substituted N2-substituted L-arginine obtained of the formula St. \ —N — ch „ch„ ch „chcooh / 1 2 2 2> (iii) h n h nh 35 40 with a corresponding amino acid derivative of the formula RH (IV) condensed from the N ° -substituted and N2-substituted L-argininamide of the formula formed with an arylsulfonyl halide of the formula ArS02X 45 (VII) X in which Ar has the meaning given in claim 1 and X represents a halogen atom, the N2-arylsulfonyl-L-arginine of the formula 50 obtained condenses hn 1 R ' / -n- i R1 ' -CH "ch" ch "chcooh e 1d d 1 hn I r '" (v) hn h2n V / HI ; c — Ï -ch „ch ch chcooh 2 2 2 1 hns0 1 2 Ar selectively cleaves the protective groups, the resulting L-argininamide of the formula HN, (XXI) 55 with a halogenating agent to an N2-arylsulfonyl-L-arginyl halide of the formula \, c — n — ch „ch„ ch „chc0x / 2 2 d, h ~ n kiis0 10th 15 20th 25th 30th 35 40 45 50 55 60 65 633773 Acridiniyl group, a phenazinyl group, a phenothi-azinyl group, a phenoxazinyl group or a benzimidazolyl group, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups, hydroxy groups, Cj-Cjo-alkyl groups, CrC10-alkoxy groups, C2 -C20-dialkylamino groups, sulfoamino groups, carbamoyl groups, C3-C10-N, N - dialkylcarbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino groups, CrCi0-alkylamino groups, mercapto groups, CrC10-AlkyIthio-C12 groups, C7 Carboxyl groups, C2-C10-alkoxycarbonyl groups, C2-C10-carboxyalkyl groups, C1-Cj0-acylamino groups, C2-CJ0-AI-alkylcarbonyl groups, CrC10-hydroxyalkyl groups, CrC10-haloalkyl groups, CrC10-hydroxyalkoxy groups and optionally with at least one hydroxyl group, C1-C5- Alkoxy group or mixtures thereof substituted phenyl group; a C7-C] 2-aralkyl group, a C9-C16-cycloalkylphenyl group, a C10-Ci8-cycloalkylalkylphenyl group, a C9-C16-cycloalkoxyphenyl group, a C9-C16-cycloalkyl-thiophenyl group, a 9,10-dihydroanthryl group, a 5 , 6,7,8-tetrahydroanthryl group, a 9,10-dihydrophen-anthryl group, a 1,2,3,4,5,6,7,8-octahydrophenanthryl group, an indenyl group, an indanyl group, a fluoro-enyl group. an acenaphthenyl group, a phenylthiophenyl group, an isochromanyl group, a 2,3-dihydro-benzofuranyl group, a 1,3-dihydroisobenzofuranyl group, a thioxanthenyl group, a 2H-chromenyl group, a 3,4-dehydro-l-isochromanyI group, a 4H-chromenyl - Group, an indolinyl group, an isoindolinyl group, a 1,2,3,4-tetrahydroquinolyl group or a 1,2,3,4-tetra-hydroisoquinolyl group, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups, Hydroxy groups, C ^ C ^ alkyl groups, CrC10 alkoxy groups, C2-C20 dialkylamino groups, sulfoamino groups, carbamoyi groups, C3-C10 - N, N-dialkylcarbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino groups, CrC10-alkylamino groups, mercapto groups, Ci "C.0-alkylthio groups, C7-Ci2-aralkyl groups, carboxyl groups, C? -C] 0-alkoxycarbonyl groups, C2-C10-carboxyalkyl groups, Cj-C10-acylamino groups, C2-C10-alkylcarbonyl groups , Q-Qo-hydroxyalkyl groups, Ci-C10-haloalky] group n, Ci-C, "- hydroxyalkoxy groups, oxo groups and optionally substituted with at least one hydroxy group, a Cj-Q-alkoxy group or mixtures thereof substituted phenyl groups; or a phenyl group which is substituted with at least one substituent from the group comprising alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and alkoxycarbonylalkoxy groups, the substituent having 3 to 7 carbon atoms, the substituted phenyl group optionally having at least one substituent the group comprising methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms is substituted, mean, and their pharmaceutically acceptable salts. 11. Pharmaceutical preparation, characterized in that it contains an antithrombotically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.