CH648293A5 - Process for the preparation of N2-arylsulphonyl-L-argininamides - Google Patents

Abstract

Novel compounds of the formula : <IMAGE> are prepared from corresponding compounds of the formula : <IMAGE> in which at least one of R' and R'' represents a protective group for the guanidino group and the other may denote a hydrogen atom, by acidolysis or hydrogenolysis. If desired, the reaction product is hydrolysed. Ar denotes various aromatic groups and R denotes one of the following groups : <IMAGE> The more detailed definition of the Ar groups and the symbols in the R groups are found in Claim 1. The compounds have a specific inhibitory action against thrombin; they can be used for the prophylaxis and treatment of thromboses, e.g. in the form of their pharmaceutically tolerable salts.

Description

The invention therefore relates to processes for the preparation of N2-arylsulfonyl-L-arginine amides, which processes are defined in claims 1, 4 and 6.

15 The preparation of the pharmaceutically acceptable salts of these N2-arylsulfonyI-L-argininamides is also an object of the invention.

The compounds provided by the invention can in vivo inhibit the action of thrombin 20 and suppress thrombin activation by giving a mammal a pharmaceutically (antithrombotic) effective amount of an N2-arylsulfonyl-L-arginine amide or a pharmaceutically acceptable salt of it administered. Administration is preferably carried out in the form of medicaments which contain an N2-arylsulfonyl-L-argininamide or a pharmaceutically acceptable salt thereof in combination with conventional binders, carrier materials and / or auxiliaries.

In formula I, R means

(1) a group of the general formula:

30th

- N

in which Ar has the meaning given above, R stands for one of the groups given above, in which R2, R5, R8, R9, Rio and Rn have the meanings given in claim 1, apart from that of a hydrogen atom, and the other symbols of these groups which in Have meanings given and R 'and R "represent hydrogen atoms or protective groups for the guanidino group, at least one of R' and R" being a protective group of the guanidino group, and at the same time cleaves off the benzyl groups of any benzyloxycarbonyl groups present by hydrogenolysis, the obtained Hydrolysed carboxylic acid esters and, if appropriate, converted the carboxylic acid formed into the corresponding salt by reaction with a pharmaceutically acceptable base.

Process according to Claim 6, characterized in that the hydrogenolysis is carried out in a solvent which is inert for the reaction in the presence of a hydrogen-activating catalyst in a hydrogen atmosphere at a temperature from 0 ° C to the boiling point of the solvent.

\

• Rl

(CH2) nC00R2

The invention relates to processes for the preparation of new N2-arylsulfonyl-L-arginine amides and their pharmaceutically acceptable salts which are of particular value owing to their excellent antithrombotic effects and their low toxicity.

Many attempts have been made in the past to provide new and better means of treating thrombosis. The N2- (p-tolysulfonyl) -L-arginine compounds have been shown to be suitable agents for this purpose which are effective for the dissolution of blood clots (see US Pat. No. 3,622,615, issued November 23, 1971). A family of connections that have proven to be highly

in the

35 R [for a Cî-Cio alkyl group, such as an ethyl group, a

Propyl group, cine-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, ac2-pcntenyl 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 2 to 10 (preferably 2 to 6) carbon atoms, such as a methoxy-ethyl 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-methoxy -50 propyl group, a 3-ethoxypropyl group, a 3-prop

oxy propyl group, ac4-methoxybutyl group, ac4-ethoxybutyl group, 4-butoxybutyl group, 5-butoxypentyl group or the like, an alkylthioalkyl group having 2 to 10 (preferably 2 to 6) carbon atoms, such as 55 a methylthiomcthyl group, an ethylthiomethyl

gruppc, a propylthiomethyl group, a 2-methylthio-ethyl group, a 2-ethylthioethyl group, cinc2-propyl-thioethyl group, a 3-methylthiopropyl group, a 2-mctliyltliiopropyl group, a 3-ethylthiopropyl group, 00 a 3-propyl group, 00 a 3-propyl group, 00 a 3-propyl group, 00 a 3-propyl group a 4-ethylthiobutyl group, a 4-butylthio-bulyl group, a 5-butylthiophene tylgi uppc or the like, an alkylsulfinylalkyl group having 2 to 10 (preferably 2 to 6) carbon atoms, such as a methylsulfinyl-65methyl group, an ethylsulfinylmethyl group

Propylsulfinylmethyl group, a 2-methylsulfinylethyl group, a 2-ethylsulfinylethyl group, a 2-propylsulfinylyl group, a 3-methylsulfinylpropyl group, a 3-

648 293

Ethylsulfinylpropyl group or the like, 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-hydroxydentyl group or the like, an alkoxycarbonylalkyl group having 3 to 10 (preferably 3 to 8) carbon atoms such as a methoxycarbonylmethyl group, a 2-ethoxycarbonyl-ethyl group, a 2-ethoxycarbonylpropyl group, a 3-methoxycarbonylproyl group, a 1-methoxy group, a 1-methoxy group a 2-ethoxycarbonylbutyl group, a 4-methoxycarbonylbutyl group or the like, an alkylcarbonylalkyl group having 3 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, a 6-phenylhexyl group, a 1-1-phenylethyl group, a 2-phenylpropyl group or the like, an a-carboxyaralkyl group having 8 to 15 (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 cyclo-butyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group or a cyclododecyl group, a C4-C10 cycloalkylalkyl group, such as a cyclopropylmethyl group, a cyclopentyl group Cyclohexylmethyl group, a 2-cyclohexylethyl group, a cyclooctylmethyl group or the like, a phenyl group, a furfuryl group, a tetrahydrofurfuryl group, optionally with one or more CrC5 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 like is substituted, a 3-furylmethyl group, a tetrahydro-3-furylmethyl group, which may optionally be substituted with one or more CrC5 alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, and / or QQ alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, or butoxy groups the like is substituted, a tetrahydro-2 (-3 or -4) -pyranyl-methyl group, optionally with one or more CrC5-alkyl groups, such as methyl 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-cyclohexylmethyl group, optionally with one or more CrC5-alkyl groups such as methyl groups, ethyl groups, propyl groups, butyl groups or the like and / or CpGrAlko-xy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, a 2-thenyl group , a 3-thenyl group, a tetra-hydro-2-thenyl group, optionally with one or more Q-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 like is substituted, or a tetrahydro-3-thenyl group,

R-2 represents a hydrogen atom, a C] -C1 () 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-Ci ( ) 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 and n is an integer with one Are 1, 2 or 3;

(2) a group of the general formula:

/ R3

—N \

ch - (ch2) mcoor5

in the

R3 represents a hydrogen atom, Ci-Ciq-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 AHyl 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, 4-ethoxybutyl group, 4-butoxybutyl group, 5-butoxypentyl group or the like, an alkylthioalkyl group having 2 to 10 (preferably 2 to 6) carbon atoms, such as a methylthio-methyl group, an 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-propylthio-propyl group, a 4-methylthiobutyl group, a 4-ethylthiobutyl group, a 4-butylthiobutyl group, a 5-butylthiopentyl group or the like, an alkyl group having 2 to 10 (preferably 2 to 6) carbon atoms, such as a methylsulfinylmethyl group, an ethylsulfinylmethyl group, a propylsulfinylmethyl group, a 2-methylsulfinylethyl group, a 2-ethylsulfonylethyl group, a 2-propylisulfinylethyl group, a 3-methylsulfinylpropyl group, a 3-methylsulfinylpropyl group, group or the like, a hydroxyalkyl 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, one

5-hydroxypentyl group or the like, an alkoxy-carbonyl alkyl group having 3 to 10 (preferably 3 to 8) carbon atoms, such as a methoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, a 2-ethoxycarbonylpropyl group, a 3-methoxycarbonylpropyl group, a 1-methoxycarbonylbutyl group , a 2-ethoxycarbonylbutyl group, a 4-methoxycarbonylbutyl group or the like, an alkylcarbonylalkyl group having 3 to 10 carbon atoms, such as a methylcarbonyl

6

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

648 293

ethyl 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- 5 chlorobutyl group or the like, an aralkyl group

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-phenylpropylio group or the like , with an a-carboxyaralkyl group

8 to 15 (preferably 8 to 12) carbon atoms such as an a-carboxybenzyl group, an a-carboxyphenethyl group or the like, a Q-Qo-cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclo-15-pentyl group, a cyclohexyl group, a cycloheptyl group group, a cyclooctyl group, a cyclononyl group or a cyclodecyl group, a C4-Q0-cycloalkylalkyl group such as a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a 2-20 cyclohexylethyl group, a cyclooctylmethyl group or the like, a furfuryl group, a turyl group, dieuryl group optionally substituted with one or more QQ alkyl groups such as methyl 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, a 3-furylmethyl group, a tetrahydro-3-furylmethyl group, the optionally with one or more QQ alkyls oil groups such as methyl 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, a tetrahydro-2 (-3 or -4) -pyranyl-methyl group, optionally with one or more 35 QQ-alkyl groups, such as methyl 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-cyclohexylmethyl group, 40 optionally with one or more CrC5 alkyl groups, such as methyl 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 45, a 2-thenyl group, a 3-thenyl group, a tetra-hydro-2-thenyl group, which are optionally also present one or more QQ alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like and / or QQ alkoxy groups such as methoxy groups, 50 ethoxy groups, propoxy groups, butoxy groups or the like, or a tetrahydro-3-thenyl group,

R4 for an alkyl group with 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, a phenyl group which is optionally substituted by one or more Q-Q-alkyl groups, such as methyl groups, ethyl groups, propyl groups, such as butyl groups or the like and / or Q-Q-alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups 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 or a benzyl group substituted on the ring, which has as substituents an alkyl group having 1 to 5 (preferably 1 to 3) carbon atoms, such as a

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

R5 represents a hydrogen atom, a Q-Q0 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 Q-Qo-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, and m is an integer with a value of 0, 1 or 2;

(3) a group of the general formula

- N

(r7)

25 in

7 'P

Rj for a group of the general formula -COORg, wherein R8 for a hydrogen atom, a Q-Q0-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 Q-Qo-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, a benzyl group, a phenyethyl group or the like, 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, QQ-alkoxy groups, such as methoxy groups, ethoxy groups, Propoxy groups, butoxy groups or the like, QQ-alkoxycarbonyl groups such as methoxycarbonyl groups, ethoxycarbonyl groups or the like, or he 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 in the 2-, 3-, 4-, 5- or 6 -Position can stand;

(4) a group of the general formula

COOR

- N

which may optionally be substituted with one or more QQ-alkyl groups, such as methyl groups, ethyl groups, propyl groups, butyl groups or the like, or Q-C5-alkoxy groups, such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups or the like, in which R9 represents a hydrogen atom, one Q-Q0 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 Q-Qo-aryl group such as a phenyl group, an m- Tolyl group, a naphthyl group or the like or one

648 293

Aralkyl group having 7 to 12 (preferably 7 to 10) carbon atoms such as a benzyl group, a phenethyl group or the like, and r represents an integer having a value of 1, 2, 3 or 4; (5) a group of the general formula coorj [o

\ 7

MCH2) q in the

R10 represents a hydrogen atom, a Q-Qo-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 Q-Qo-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 for an oxygen atom (-0-), a sulfur atom (-S-) or

• a sulfinyl group (-SO-) and q are an integer with a value of 0 or 1; or

(6) a group of the general formula COORn

V (CH2) iV <^

in the

Ru for a hydrogen atom, a Q-Qo-alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a tert-butyl group, a hexyl group, an acrylic group, a decyl group or the like, a Q-Qo-aryl group such as a phenyl group, an m-tolyl 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 phenylethyl group or the like,

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

Ar is a phenyl group or a naphthyl group, each with at least one substituent from the sulfoamino groups, carbamoyl groups, N, N-dialkylcarbamoyl groups with 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N-diethylcarba -moyl 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 with 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio groups, ethyl thio 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) 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 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 substituted with at least one hydroxyl group and / or Q-Q-alkoxy groups such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like;

a phenyl group or a naphthyl group, each with at least one substituent from the 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-diethyl-carbamoyl groups or the like, N-alkylcarbamoyl groups having 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 groups, butylthio groups or the like, aralkyl groups having 7 to 12 carbon atoms, preferably 7 to 10 groups, preferably 7 to 10 groups, preferably 7 to 10 groups, preferably 7 to 10 groups, Phenethyl groups or the like, carboxyl groups, alkoxycarbonyl groups with 2 to 10 (v or 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 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 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, like Hydro xymethoxy 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 , Cy-

8th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

ano 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 dimethylamino groups, diethylamino groups, dipropylamino groups or the like, is substituted;

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, carbamino groups, carbamino groups, N-dialkylcarbamoyl groups having 3 to 10 (preferably 3 to 7) carbon atoms, such as N, N-dimethylcarbamoyl groups, N, N-di-ethylcarbamoyl groups or the like, N-alkylcarbamoyl groups having 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 10 5) carbon atoms, such as methylthio groups, ethylthio groups, propylthio groups 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 alkyicarbonylamino 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 with 1 to 10 (before 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, which is optionally substituted with at least one hydroxy group and / or CrC5 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like;

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

648 293

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-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 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 10 to 7 to 7) from 10 to 7 to 7 to 7 to 10 to 12 carbon atoms such as benzyl groups, phenethyl groups or the like, carboxyl group n, 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 alkyicarbonylamino 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 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 up to 10 (preferably ise 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 CrC5 alkoxy group, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like Group is substituted;

a tetrahydronaphthyl group, a 2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylenedi-oxynaphtyl group or a xanthenyl group, which groups have at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, dialkylamino groups having 2 to 20 (preferably 2 to 20 10) carbon atoms such as dimethylamino groups, diethylamino groups, dipropylamino groups or the like, sulfoamino groups, carbamoyl groups, N, N-di-alkylcarbamoyl groups having 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-ethyl-carbamoyl 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

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

293 10

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 5 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) 10 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 15 (preferably 1 to 5) carbon atoms, such as chloromethyl groups, trifhiormethyl groups, bromomethyl groups, 2- Chloroethyl groups or the like, hydroxy-alkoxy groups with 1 up to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy groups, 2-hydroxy- '20 ethoxy groups or the like, oxo groups and phenyl groups, optionally with at least one hydroxyl group and / or CrC5 alkoxy group, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like, include the group substituted;

a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylenedi-oxynaphthyl group or a xanthenyl group, which groups have at least one substituent from the 30 alkyl groups 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 methoxy groups, ethoxy groups, propoxy groups, but 35 oxy groups or the like, comprising a group 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 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-di-ethylcarbamoyl groups or the like hen, 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 (preferably 7 to 12 s) 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, carb-60 oxyalkyl 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 having 1 to 10 (preferably 1 to 5) carbon atoms, such as acetyl 65 amino 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, oxo groups and phenyl groups, optionally with at least one hydroxyl group and / or Q-Cs-alkoxy group, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or de are the same substituted, comprehensive group is substituted;

a naphthoquinonyl group, an anthryl group, a phenanthryl group, a pentalenyl group, a hepta-lenyl group, an azulenyl group, a biphenylenyl group, an as-indacenyl group, an s-indacenyl group, an acenaphthylenyl group, a phenylcarbonylphenyl group, a phenoxyphenuryl group, a phenoxyphenuryl group, a phenoxyphenuryl group an isobenzofuranyl group, a benzo [b] thienyl group, an isobenzothienyl group, a thianthrenyl group, a dibenzothienyl group, a phenoxathiinyl group, an indolyl group, an 1H-indazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a phthalazinyl group, a phthalazinyl group, a phthalazinyl group, a phthalazinyl group 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, hydroxyl groups, cyano groups 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 with 2 up 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-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 with 1 to 10 (preferably 1 to 5) carbon atoms such as methylamino groups, ethylamino groups, propylamino groups, butylamino groups or the like, mercapt o 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 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 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)

11

648 293

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 5 (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-hydroxy-ioethoxy groups or the like, and phenyl groups, optionally with at least one hydroxyl group and / or a C1-C5 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like are substituted;

a C7-C12-aralkyl group, a C9-C16-cycloalkylphenyl group, a C10-Ci8-cycloalkylalkylphenyl group, a C9-Ci6-cycloalkoxyphenyl group, a C9-C16-cycloalkylthio-phenyl group, a C9-C10-dihydroanthryl group, a 20 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 fluorenyl group, an acenaphthenyl group, a phenyl-thiophenyl group, an isochromanyl group, a 2,3-! 5 dihydrobenzofuranyl group, a 1,3-dihydroisobenzo-furanyl group, a thioxanthenyl group, a 2H-chro-menyl group, a 3,4-dehydro-l-isochromanyl group,

a 4H-chromenyl group, an indolinyl group, an iso-indolinyl group, a 1,2,3,4-tetrahydroquinolyl group 0 or a 1,2,3,4-tetrahydroisoquinolyl group, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups , Cyano groups, hydroxy 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 dimethylamino groups, diethylamino groups, dipropylamino groups or the like, sulfoamino groups, carbamoyl groups, N, N-dialkylcarbamoyl groups having 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 with 1 to 10 50 (preferably 1 to 5) carbon atoms such as methylamino groups, ethylamino groups, propylamino groups, butylamino groups or the like, mercapto groups with alkylthio groups 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) carbon atoms, such as carboxymethyl groups, 2-carboxyethyl groups, 2-carboxypropyl groups or the like, acylamino groups, 65 such as alkylcarbonylamino groups having 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino groups, propionylamino groups or the like, alkylcarbonyl

45

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 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, which are optionally are 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 consisting of 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 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-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-propoxy-phenyl group, a 3-butoxyphenyl group, a 2-butoxy-phenyl group, a 2,5-dibutoxyphenyl group, a 3,4-dibutoxyphenyl group, a 2,4-dibutoxyphenyl group, a 3-methyl-4-butoxyphenyl group, a 3,5-dimethyl-4-butoxyphenyl group, a 2,4-dimethoxy-3-butoxyphenyl group, a 2,4-dichloro-3-butoxyphenyl group, a 3-pentyloxyphenyl group, a 3-isopentyloxyphenyl group, a 3,5-dimethyl -4-pentyloxyphenyl group, a 2,4-dimethoxy-3-pentyloxyphenyl group, a 2,4-dimethoxy-3-hexyloxyphenyl group, a 2,4-dimethoxy-3- (3-bromopropoxy) phenyl group, a 2,4-dimethoxy ->; z-methoxyethoxy) phenyl group, a 2,4-dimethoxy-3- (2-ethoxyethoxy) phenyl group, a 3-methyl-4- (2-methoxyoxyoxy) phenyl group, a 3-methyl-4- (3rd -methoxypro-poxy) phenyl group, a

3-valeryl-4-methoxyphenyl group, 2,4-dimethoxy-4- (3-methoxycarbonylpropoxy) phenyl group and the like.

Preferred groups R are

(1) Groups of the general formula

- N

(CH.,) COOR, z n 2

in the

Ri is a C2-Ci0-alkyl group, a C3-C10-alkenyl group, a C2-C10-alkoxyalkyl group, a C2-Ci0-alkylthioalkyl group, a C2-C10-alkylsulfinylalkyl group, a C7-C15-aralkyl group, a C3-Ci0- Cycloalkyl group, a C4-C10-cycloalkylalkyl group, a furfuryl group, a tetra-hydrofurfuryl group, a tetrahydro-2 - (-3 or-4) -pyranylmethyl group or a 1,4-dioxa-2-cyclohexyl-methyl group,

648 293

12

R2 is a hydrogen atom, a CrC10 alkyl group, a Q-Qo

Aryl group or a Q-Q2 aralkyl group and n is an integer having a value of 1, 2 or 3; (2) Groups of the general formula

- N

/ R3

CH- (CH2) mCOOR5 R4

in the

R3 is a hydrogen atom, a Q-Q0-alkyl group, a Q-Q0-alkenyl group, a Q-Q0-alkoxy alkyl group, a Q-Cio-alkylthioalkyl group, a Q-Q0-alkylsulfinylalkyl group, a Q-C15-aralkyl group, one Q-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 Q-C10-alkyl group, a phenyl group which is optionally substituted with at least one QQ-alkyl group, a QQ-alkoxy group or mixtures thereof, a Q-C12-aralkyl group or a benzyl group substituted on the ring which has a QQ-alkyl group as a substituent or has a QQ alkoxy group,

R5 is a hydrogen atom, a Q-Q0 alkyl group, a Q-Qo

Aryl group or a C7-C12 aralkyl group and m is an integer with a value of 0.1 or 2;

(3) Groups of the general formula

35

in the

R,

R

coor9

(5) Groups of the general formula coor10

—N

10th

\ ch2 |

/

in the Rio a hydrogen atom, a Q-Q0-alkyl group, a Q-Qo-aryl group or a Q-Ci2-aralkyl group,

15 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

25th

COORn

~ nch2) j in the row

30th

a hydrogen atom, a Q-C10-alkyl group, a Q-Qo-aryl group or a Q-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

—N

40

(ch2) nC00R2

; a group of the formula -COORg, in which R8 stands for a hydrogen atom, a Q-C10-alkyl group, a Q-Qo-aryl group or a C7-Q2-aralkyl group, 45 t independently of one another for hydrogen atoms, Q-C10-alkyl groups or phenyl groups,

is an integer with a value from 1 to 4, where the group R6 in the 2- or in the 3-position and the groups R7 in the 2-, 3-, 4-, 5- or 6-positions can be 50 ;

(4) Groups of the general formula in the

Rx is a C2-Qo-alkyl group, a Q-Q-alkoxy alkyl group, a C2-Q-alkylthioalkyl group, a C7-Q0-aralkyl group, a C4-C10-cycloalkylalkyl group, a furfuryl group or a tetrahydrofurfuryl group,

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

(2) Groups of the general formula

55

- n

CH- (CH.,) COORc I zm d

R4

60

which are optionally substituted with at least one Q-Q-alkyl group, Q-C5-alkoxy group or mixtures thereof, in the 65th

R (J is a hydrogen atom, a CrQ0 alkyl group, a Q-Qo

Aryl group or a C7-C12 aralkyl group and r represents an integer having a value of 1,2,3 or 4;

in the

R3 is a hydrogen atom, a Q-C10-alkyl group, a Q-Q-alkoxy alkyl group, a Q-Q-alkylthioalkyl group, a Q-Qo-aralkyl group, a C4-Q0-cycloalkylalkyl group, a furfuryl group or a tetrahydrofurfuryl group, R4 a Q-Q-alkyl group,

R5 represents a hydrogen atom or a Q-Q0 alkyl group and m represents an integer with a value of 0.1 or 2;

13

648 293

(3) Groups of the general formula

R6

- n in the

R6 is a group of the formula -COORg, in which R8 represents a hydrogen atom, a CrC10 alkyl group,

R7 independently of one another for hydrogen atoms or CrC6-

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

(4) Groups of the general formula C00Ro

—N

V,

(CH2) '

which are optionally substituted with at least one Q-Cj-alkyl group, CrC5-alkoxy group or mixtures thereof, in which

R9 represents a hydrogen atom or a Ci-CKralkyl group and r represents an integer with a value of 1, 2, 3 or 4; (5) groups of the general formula coor

10th

■ n v (ch2jl in the

R] 0 is a hydrogen atom or an alkyl group with 1 to

10 carbon atoms,

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 cooRn

—N

h1

n

CH2) j

in the

Ru is a hydrogen atom, or a C] -Cin 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, the sum i + j being an integer Represents a number 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-Ci (rN, N-dialkyl-carbamoyl groups, C2-C6-N-alky (carbamoyl groups, amino groups, Cj-Cm- Alkylamino groups, mercapto groups, Cr Cio alkylthio groups, C7-C12 aralkyl groups, carboxy group

pen, C2-C10-alkoxycarbonyl groups, C2-C] 0-carboxyalkyl groups, CrCio-acylamino groups, C2-C10-alkylcarbonyl groups, Ci-C10-hydroxyalkyl groups, CrCI0-haloalkyl groups, Cr Cio-hydroxyalkoxy groups or phenyl groups, which if necessary are substituted with at least one hydroxy group, a CrC5 alkoxy group or mixtures thereof;

Phenyl groups or naphthyl groups, each with at least one substituent from the Haigen atoms, nitro groups, io cyano groups, hydroxyl groups, CrCio-alkyl groups, CpCio-alkoxy groups and C2-C20-dialkylamino groups and at least one substituent from the sulfoamino groups, carbamoyl groups, C3-Ci0- N, N-dialkyl-carbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino-15 groups, Q-Cio-alkylamino groups, mercapto groups, Cr Cio-alkylthio groups, C7-Ci2-aralkyl groups, carboxy groups, C2-C10-alkoxycarbonyl groups, C2-C] 0-carboxyalkyl groups, Ci-C1 (r-acylamino groups, C2-Ci0-alkylcarbonyl groups, Ci-Cio-hydroxyalkyl groups, Ci-Qo-haloalkyl groups, Q-20 Qo-hydroxyalkoxy groups or phenyl groups, optionally with at least one hydroxy group, a QQ alkoxy group or mixtures thereof 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-dialkyl-amino groups, CrQ-N-alkylcarbamoyl groups, Q-Q0-alkylamino groups, mercapto groups, Q-Q0, alkylthiogr Qo-alkoxycarbonyl groups, Q-Q0-hydroxyalkyl groups, 30 Ci-Qo-haloalkyl groups and CrC10-hydroxyalkoxy groups are substituted;

Oxanthrenyl groups or dibenzofuranyl groups which contain at least one substituent from the group comprising Q-Q0-alkyl groups and Q-Qo-alkoxy groups and at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-Qo-dialkylamino groups, C2 -C6-N-alkylcarbamoyl groups, Ci-Ci0-alkylamino groups, mercapto groups, Ci-C10-alkylthio groups, C2-C10-alkoxycarbonyl groups, Ci-Cio-hydroxyalkyl groups, Q-Cio-Halo-40 genalkyl groups and CrCio-hydroxyalkoxy groups are substituted;

Tetrahydronaphthyl groups, 1,2-ethylenedioxyphenyl groups, chromanyl groups, 2,3-ethylenedioxy naphthyl groups or xanthenyl groups containing at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxy groups, C2-C20-dialkylamino groups, C2-C6 Alkyl carbamoyl groups, CrC10-alkylamino groups, mercapto groups, CrC10-alkylthio groups, C2-C10-alkoxycarbonyl groups, Ci-Cio-hydroxyalkyl groups, Q-Cio-haloalkyl groups, Cr 50 Cio-hydroxyalkoxy groups and oxo groups are substituted;

Tetrahydronaphthyl groups, 1,2-ethylenedioxyphenyl groups, chromanyl groups, 2,3-ethylenedioxynaphthyl groups or xanthenyl groups, which groups have at least one 55 substituents from the group comprising CrCi0-alkyl groups and CrCio-alkoxy groups and at least one substituent from the halogen atoms, nitro groups, cyano groups Hydroxy groups, C2-C20-dialkylamino groups, C2-C6-N-alkyl-carbamoyl groups, Ci-Ci0-alkylamino groups, Mercaptogrup-60 pen, CrC1 (ralkylthio groups, C2-Ci0-alkoxycarbonyl groups, Q-Qo-hydroxyalkyl groups, CrC10-haloalkyl groups, Q -Cio-hydroxyalkoxy groups and oxo groups are substituted;

Anthryl groups, phenanthryl groups, biphenylenyl groups, f'5 s-indacenyl groups, phenylcarbonylphenyl groups, phenoxy-phenyl groups, benzofuranyl groups, benzo [b] thienyl groups, thianthrenyl groups, dibenzothienyl groups, phenoxathiinyl groups, quinolyl groups, isoquinolol groups, isoquinolol groups

648 293

14

oxalinyl groups, quinazolinyl groups, cinnolinyl groups, carbazolyl groups, acridinyl 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, hydroxyl groups, CrCI (1-alkyl groups, CpQo-alkoxy groups A group comprising C20 dialkylamino groups and Q-Qo-hydroxyalkoxy groups;

C7-C12-aralkyl groups, Cg-C1 (, - cycloalkylphenyl groups,] 0 Qo-C18-cycloalkylalkylphenyl groups, Q-Qrrcycloalkoxy-phenyl groups, 9,10-dihydroanthryl groups, 5,6,7,8-tetra-hydroanthryl groups, 9,10- Dihydrophenanthryl groups, l, 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 , 2,3,4-tetrahydroquinolyl groups, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, CrC10-20 alkyl groups, Q-Q0-alkoxy groups, C2-C20-dialkylamino groups, QQN-alkylcarbamoyl groups , Q-C10-hydroxyalkoxy groups and oxo groups are substituted;

or phenyl groups which are substituted with at least one substituent 25 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, which substituted phenyl groups optionally also with at least one Substituents from the group consisting of methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms are substituted.

Preferred groups Ar are phenyl groups or naphthyl groups which have at least one substituent from the amino groups, Q-Q0-alkylamino groups, CrC10-alkylthio groups, C7-C12-aralkyl groups, C2-C10-alkoxycarbonyl groups, Q-Qo-acylamino groups, C2- CI (r alkylcarbonyl groups, CrCur hydroxyalkyl groups, CrQ0-hydroxyalkoxy groups and phenyl groups;

Phenyl groups or naphthyl groups, each with at least one substituent from the amino groups, Q-C10-alkylamino groups, CrCiq-alkylthio groups, C7-C12-aralkyl groups, 45-C2-Cio-alkoxycarbonyl groups, Q-Qo-acylamino groups, C2 -C10-alkylcarbonyl groups, Q-Q0-hydroxyalkyl groups, Q-Qo-hydroxyalkoxy groups and phenyl groups and at least one substituent from which halogen atoms, hydroxyl groups, Q-Q0-alkoxy groups and 50 Q-Qo-dialkylamino groups are substituted;

Dibenzofuranyl groups substituted with at least one halogen atom;

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

Tetrahydronaphthyl groups, 1,2-ethylenedioxyphenyl groups, chromanyl groups, 2,3-ethylenedioxynaphthyl groups 60 or xanthenyl groups which are substituted by at least one halogen atom;

Tetrahydronaphthylgruppen, 1,2 * Äthyl§ndißsyphenylgrupp-groups, Chromanylgruppen, 2,3-Äthyleiidioxynaphthylgrappen or Xanthenylgruppen, which with at least one Substitut- from the group comprising Q-Qo-alkyl groups and Q-Q0 alkoxy groups and with at least one halogen atom are substituted;

Anthryl groups, phenanthryl groups, biphenylenyl groups, phenoxyphenyl groups, benzofuranyl groups, benzo [b] thienyl groups, dibenzothienyl groups, phenoxathiinyl groups, quinolyl groups, isoquinolyl groups, quinoxalinyl groups, acridinyl groups, phenazinyl groups, which are unsubstituted or with or from one or more halogen groups, with the Q or unsubstituted group, from or with one of the unsubstituted or substituted groups, with or by Q, with or from the halogen group, which are unsubstituted or with or by Q, with or from the halogen group -Qo-alkyl groups, Q-Q0-alkoxy groups, Q-Qo-hydroxyalkoxy groups are substituted;

C7-Q2-aralkyl groups, C9-C16-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 Q-Qo-alkyl groups, Q- Qo-alkoxy 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 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 with at least one substituent from the amino groups, Q-Q0-alkylamino groups, C7-C12-aralkyl groups, Q-C10-acylamino groups, Q-C10-hydroxyalkyl groups and Q-Q0-hydroxyalkoxy groups comprehensive group are substituted;

Phenyl groups or naphthyl groups, each with at least one substituent from the amino groups, Q-Qo-alkylamino groups, C7-C12-aralkyl groups, Q-C10-acylamino groups, Q-Qo-hydroxyalkyl groups and Q-Qo-hydroxyalkoxy groups and at least one group Substituents from the group consisting of halogen atoms, hydroxyl groups, Q-Q0-alkyl groups and Q-Qo-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 Q-Q0-alkyl groups;

C7-C12 aralkyl groups, Cg-Qg-cycloalkylphenyl groups, fluorenyl groups or 2H-chromenyl groups which are unsubstituted or substituted by one or more groups from the group comprising Q-Q0-alkyl groups, Q-Q0-alkoxy groups and oxo groups;

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 has 3 to 7 carbon atoms, these 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.

Preferred compounds obtainable according to the invention are; 1- [N2- (quinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

i- [N2- (3-Methy! cliinolin-8-sulfc! ny!) - L-arginy!] - 4-msthyl-2-piperidlncafbowsäui'e,

1- [N2- (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,

15

648 293

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

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

l- [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-methoxyethyI) glycine and l- [N2- (4-methoxy-3-cyclohexylbenzoI-l-sulfonyl) -L-arginyl] -4-methyl- 2-piperidinecarboxylic acid.

Of course, the pharmaceutically acceptable salts of the above compounds are also preferred.

The process according to the invention and the preparation of the starting product of the formula XX can be illustrated by the following reaction scheme:

hn

V

h2n-

-n ch2ch2ch2chcooh

I 'I

H NH2

(II)

hn hn

I.

R

c n - ch2ch2ch2chcooh r "hn

I.

r, h + rh

(II)

(IV)

HNx hn!

r c n choCH2ch2chc0r r "hn

I.

r '"

(V)

hn hn

I.

r hn: hn

I.

r

>

-7-N-

r "

■ ch2ch2ch2chcor ArS02X - NH2 (XIX)

(VII)

c n ch2ch2ch2chcor

(XX)

r "

HN;

HpN

>

hnsop

I.

Ar

-ch2ch2ch2chc0r

(I)

hnso2

Ar

30th

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, tri-

tyl groups, oxycarbonyl groups and the like,

wherein at least one of the groups R 'and R "represents a protective group for the guanidino group.

The N2-AryIsulfonyl-L-argininamides of the general formula I are prepared by cleaving off the N ° substituent of an N ° -substituted N2-arylsulfonyl-L-argininamide of the general formula XX, which can be achieved by acidolysis or by hydrogenolysis.

The acidolysis is generally carried out in such a way that the NG-substituted N2-arylsulfonyl-L-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 a Ether (tetrahydrofuran or dioxane). An alcohol (methanol or 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 at room temperature during 30 minutes to 24 hours. The products are isolated by evaporation of the solvent and 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 N2-aryl-25 sulfonyl-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 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. The hydrogenolysis is generally carried out in a solvent which is inert to 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 0 ° C to the boiling point of the solvent and preferably at a temperature of 10 ° C 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 can be isolated by filtering off the catalyst and by evaporating the solvent. They can be purified by trituration or by recrystallization in a suitable solvent, such as a diethyl ether-tetrahydrofuran mixture, a diethyl ether-methanol mixture or a water-methanol mixture, or by chromatography on silica gel.

The N ° -substituted N2-arylsulfonyl-L-argininamides of the general formula XX used as the starting product can be prepared by the guanidino group and the ss a-amino group of L-arginine (formula II) by nitriding, acetylating, formylating, phthaloylating , Trifluoroacetylating, p-methoxybenzyloxycarbonylating, benzoylating, benzyloxycarbonylating, tert.-butoxycarbonylating or tritylating and then protecting the N ° -substituted N2-substituted 60 L-arginine of the general formula III (which in general as a N ° substituent is a nitro group or an acyl group and, as N2 substituents, a protective group for the amino group, such as a benzyloxycarbonyl group, a tert-butoxycarbonyl group or the like) is condensed with a corresponding f'5 amino acid derivative of the general formula IV, for which a customary method is used, for example the Acid chloride method, the azide method, the mixed anhydride method, the activated Es comprehensive

40

45

50

648 293

16

Method or the carbodiimide method, then selectively cleaves only the N2 substituent of an N ° -substituted N2-substituted L-arginine amide of the general formula V by catalytic hydrogenolysis or by acidolysis and then the N ° -substituted L obtained in this way -Argininamide of the general formula XIX with an arylsulfonyl halide of the general formula VII, preferably the corresponding chloride, condensed in the presence of a base in a solvent.

The condensation reaction between the compounds of formulas XIX and VII 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 0 ° C to the boiling point of the solvent for a period of 10 minutes to 15 hours. The preferred solvents for the condensation are benzene-diethyl ether, diethyl ether-water and dioxane-water mixtures.

After the reaction has ended, the salt formed is extracted with water, the solvent is removed in a customary manner, for example by evaporation under reduced pressure, and the N2-arylsulfonyl-L-argininamide of the general formula XX is obtained.

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

H-H

Ri

\ (CH2) nCÓOR2

(from left)

H-N

-r3

\ cH- (CH2) raCOOR5

Rj,

H-H

COORo

V «2) r

(X)

(IX)

(XI)

H-N

COOR ^ o r ~ \

iCH2) q

COOR

\

(XII)

H-N

i / uuni 7

\

(CH2) .j

(XIII)

in which formulas, R], R2, R3, R4, R5, Rô, R7, R9, Rio, R11, 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 halogen acetate, a 3-halogenopropionate or a 4-halogenobutyrate with a suitable amine of the general formulas RiNH2 or R3NH2 (see J. Org. Chem. 25 [1960] 728 to 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 ° C to 80 ° C for 10 minutes to 20 hours. 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 organic 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 the preparation of the 2-5 piperidinecarboxylic acid derivatives of the general formula X:

O"'

25th

30th

35

40

45

50

NaOCl,

" H

o "1

KOH,

Cl

(XIV)

(XV)

Q-

(XVI)

HCN x R7 -)

C02H

(XVII)

(XVIII)

:O

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 ° C to 0 ° C. The product of the general formula XV formed in this way 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, to give the corresponding 1,2-dehydropiperidine of the general formula XVI. By reaction with suitable cyanation agents, for example hydrogen cyanide or sodium cyanide, the corresponding 2-cyano derivatives (of the general formula XVII) are obtained from the 1,2-dehydropiperidines 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 XX are obtained by halogenating the required arylsulfonic acids or their salts, for example their sodium salts, using methods known per se.

In practice, halogenation is effected 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 55 acetate, chloroform or the like.

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

It is readily apparent to the person skilled in the art that the 60 esters of the N2-arylsulfonyl-L-argininamides of the general formula I in which R 2, R 5, R 1, R 9, Rm or R y represent alkyl groups, aralkyl groups or aryl groups are applied known esterification methods can be prepared from the corresponding carboxylic acid derivatives of N2-arylsulfonyl-L-argininamides 65 of the general formula I in which R2, Rs, Rg, R9, Rj0 or Rn represent hydrogen atoms. It can also be seen that the carboxylic acids can be prepared from the corresponding ester by conventional hydrolysis. The conditions

17 648 293

for the esterification and the hydrolysis are available to those skilled in the art without, in 40 ml of a borate salt buffer (with a pH further evident. value of 7.4), with 0.1 ml of a borate salt buffer The N2-arylsulfonyl-L-arginine obtainable according to the invention with a pH of 7.4 (control) or a solution of the amides of the general formula I form with a large number of samples in the same buffer and 0.1 ml of a thrombin solution from inorganic and organic acids acid addition salts. 5 (containing 5 units per ml) of which some of the N2-arylsulfonyl-L-argininamides, the free carboxyl company Mochida Pharmaceutical Company, Limited, Japan, have groups, that is, the compounds from which it is obtained , making these additions in an ice bath. Groups R2, R5, Rs, R9, Rio and Rn represent hydrogen atoms. Immediately after mixing, the reactions are transferred, formed with a series of inorganic or organic ion mixtures from the ice bath into a bath kept at 25 ° C. Bases salts. The coagulation time is determined as the period of time. The products of the above reactions can be seen in the free form, the transfer into the bath kept at 25 ° C and the or in the form of their salts. Furthermore, the time at which fibrin threads first appear can be passed. Product as a pharmaceutically acceptable acid addition salt. If no active ingredient samples are added, this is achieved by making one of the free bases with a coagulation time of 50 to 55 seconds. The results obtained, acid such as hydrochloric acid, hydrobromic acid, iodine-15, are summarized in Table II below. The hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, the expression “concentration to prolong the coagulation acetic acid, citric acid, maleic acid, succinic acid, lactation by a factor of 2” stands for the concentration of an active acid, tartaric acid, gluconic acid, benzoic acid, methanesulfonic ingredient required to convert the normal coaguic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonation time from 50 to 55 seconds to 100 to 110 seconds to acid or the like. Similarly, you can extend the 20.

Product in the form of a pharmaceutically acceptable salt The concentration to prolong the coagulation time is obtained by adding one of the free carboxylic acids with a factor of 2, which is known for the antithrombotic agent

Base, such as sodium hydroxide, potassium hydroxide, ammonium N2- (p-tolylsulfonyl) -L-arginine methyl ester is required,

hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, is 1100 µmol / 1.

N, N'-dibenzylethylenediamine, N-ethylpiperidine or the like. 25 The thrombin inhibitors are shown in the tables on the group

Chen implements. pen R and Ar of the general formula I and the acid residue

In a similar way, one can also specify by treating the salts.

a base or an acid, the corresponding free amides If you have a solution that form a obtainable according to the invention. Contains N2-arylsulfonyl-L-argininamide by intravenous route

As has already been stated, the animals administered according to the invention are noteworthy. It should be noted that the strong antithroma

available N2-arylsulfonyl-L-argininamides and their salts have a botical effect in the circulating blood for 1 to 3 hours

is maintained by an extremely specific inhibitory effect against the. It has been shown that the half

Thrombin in mammals and due to their largely lack of value of the antithrombotic available according to the invention

Toxicity, so that as diagnostic reagents for the compounds in the circulating blood it is about 60 minutes,

Determination of thrombin in blood and / or as a drug for 35 when the physiological conditions of the treated animals

Prevention of thrombosis can be used. The compounds (rats, rabbits, dogs and chimpanzees) which are retained in accordance with the invention and are well maintained are also useful. The experimental effects caused by the infusion of thrombin

inhibitors of platelet agglutination. Share fribrinogen removal can be satisfactory

The antithrombotic effect of the invention is obtained by simultaneous infusion of the compounds of the invention.

Lichen N2-arylsulfonyl-L-argininamides were combated with the 40 gene.

of a known antithrombotic agent, namely the N2- (p- The acute toxicity of the compound obtainable according to the invention

Tolylsulfonyl) -L-arginine methyl ester via the determination of fertilizers (LD50) by intravenous administration of the ver

Fibrinogen coagulation time compared. The determination of the bonds of general formula I to mice (male

Fibrinogen coagulation time is carried out as follows: mice with a weight of 20 g) was determined, extends

An aliquot of 0.8 ml of a fibri of approximately 150 to 600 mg / kg of body weight of the treated nogen solution is mixed, which is obtained by dissolving 150 mg of bovine fibrino mice. In Table I below are representative LD50

gene (Cohn fraction I), the values of some compounds given by the company Armor Incorporated.

648 293 18

Table I

Compound h n ^ g _ mi - (ch2) 3CHCOR LD50 (mg / kg)

2 HNS02Ar

Ar R

rrV0CH3

OCH3 * CH3 COOH

\\ A / CH3 -f H3

\ p ^ 0CH2CH ^

173

rxvjS-'0CH-3 r ~ \

u ^ o (ch2) 3ch3 1 \ _ych3

OCH3 COOH

170

OCH

-çy-CH3

^ ch3 COOH

250 to 300

COOH

^ rr ^. / CH2-tj

-N 0 260

CH2C00H

In contrast, the LD50 values of N2-dansyl-N-butyl-L-argininamide and N2-dansyl-N-methyl-N-butyl-L-argini-namide are below 10 mg / kg.

The active pharmaceutical ingredients 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 administered in the form of sterile solutions which contain other dissolved components, for example salt or glucose, in sufficient quantities

19th

648 293

Use amounts to make the solution isotonic. The compounds can be administered orally in the form of tablets, capsules or granules containing 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, flavorings and colorings and have been dehydrated to a sufficient extent to make the mixture suitable for compression into a solid preparation do. The compounds can also be administered orally in the form of solutions which can contain colorants and flavorings. The doctor can appropriately select the dosage of the active compounds according to the invention, which depends on the route of administration and the compound used. Furthermore, the dosage varies depending on the patient to be treated.

When the drugs are administered orally, a larger amount of the active ingredient is required to achieve the same effect than when administered by the parenteral route.

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.

example 1

A) NG-nitro-N2- (tert-butoxycarbonyl) -L-arginyl-N-butyl-glycine benzyl ester To a stirred solution of 28.4 g of NG-nitro-N2- (tert-butoxycarbonyl) -L-arginine in 450 ml of dry tetrahydrofuran are added in succession while maintaining a temperature of -5 ° C. 12.4 ml of triethylamine 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 for 15 minutes at -5 ° C. After this time, the reaction mixture is warmed up 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 x 6 cm) which has been charged with 500 g of silica gel and 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%) of NG-nitro-N2- (tert-butoxycarbonyl) -L-arginyI-N-butyl-glycine benzyl ester in the form of a Syrups.

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 dry hydrogen chloride 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 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-butyl-glycine benzyl ester hydrochloride are obtained in the form of an amorphous solid.

C) NG-Nitro-N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -

L-arginyl-N-butyl-glyeinbenzyl 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 are added in succession at 5 ° C1.26 g of sodium bicarbonate and 2.2 g of 3-cyclohexyl-4-methoxyphenylsulfonyl chloride and

25th

stir 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 over 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 and gives 2.6 g (yield = 77%) NG-nitro-N2- (3-cyclohexyl-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: QjH ^ OgNfiS

calculated: C 56.95 H 6.87 N 12.46%

found: C 56.49 H 6.63 N 12.38%

20th

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

0.5 g is added to a solution of 3.00 g of NG-nitro-N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butyl-glycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water 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. 30 The residue is washed several times with dry ethyl ether and chromatographed over 80 ml of an ion exchange resin (Daiaion® SK102, 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-methoxy-phenylsulfonyl) -40 L-arginyl-N-butyl-glycine in Form of an amorphous solid.

IR spectrum (KBr): 3350, 2920, 1630, 1250 cm "1.

Analysis: CjsH ^ NgOsSi calculated - C 55.63 H 7.66 N 12.98%

found: C 55.32 H 7.39 N 12.84%

45

Example 2

A) l- [NG-nitro-N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid ethyl ester 50 To a well-stirred solution of 2.05 g 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 are added in portions while maintaining a temperature of 0 ° C 2.2 g of 3-cyclohexyl -4-methoxybenzenesulfonyl-55 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 60 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 a "1.

648 293 20

B) l- [N2- (3-Cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -

Ethyl 4-methyl-2-piperidinecarboxylate To a solution of 2.6 g l- [N ° -Nitro-N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidine- carboxylic acid ethyl ester in 40 ml of ethanol, 10 ml of water and 20 ml of 5 acetic acid, 0.5 g of palladium carbon black is added 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-10 ether mixture, 2.4 g of l- [N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidine-carboxylic acid ethyl ester acetate are obtained .

C) 1- [N2- (3-Cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] - 15

4-methyl-2-piperidine-carboxylic 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 10 is stirred ml of ethanol and 10 ml of an in sodium hydroxide solution at room temperature overnight. 20 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 2J chloroform solution is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo, giving 1.52 g of l- [N2- (3-cyclohexyl-4-methoxy-phenylsulfonyl) -L-arginyl] -4- methyl-2-piperidinecarboxylic acid is obtained in the form of an amorphous solid.

IR spectrum (KBr): 3350, 2920, 1620, 1250 cm-1.

Analysis: C26H4i06N5S

calculated: C 56.60 H 7.49 N 12.70% found: C 56.51 H 7.53 N 12.68%

_. . , "35

Example 3

A) l- [N2- (3-methyl-l, 2,3,4-tetrahydor-8-quinoline sulfonyl) -N ° -nitro-L-arginyl] -4-methyl-2-piperidinecarboxylic acid ethyl ester

A solution of 4.08 g of l- (NG-nitro-L-arginyl) -4-methyl-2-piperidine-carboxylic acid ethyl ester hydrochloride and 3.03 g of tri-40 ethylamine in 200 ml of chloroform are stirred vigorously and while maintaining 3.69 g of 3-methyl-1,2,3,4-tetrahydro-8-quinoline sulfonyl chloride were added in portions to the temperature at 5 ° C. The reaction mixture is stirred for 5 hours at room temperature. Thereafter, the reaction mixture 45 is 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 3%

Chloroform containing methanol. The main fraction is evaporated to dryness, leaving 3.61 g of 1- [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 (CD3OC) ö (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 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 100 ml of ethanol and 20 ml of acetic acid, 0.9 g of palladium black are added and the reaction mixture is then in a hydrogen atmosphere for 15 hours at room temperature shaken. 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-quinoline sulfonyl) -L-arginyl] -4-methyl-2-piperidine obtained carboxylic acid ethyl acetate; Yield78% of theory.

C) 1- [N2- (3-methyl-l, 2,3,4-tetrahydro-8-quinoline sulfonyl) -

L-arginyl] -4-methyl-2-piperidinecarboxylic acid

A solution of 2.00 g of l- [N2- (3-methyl-l, 2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidine-carbonate, ethyl 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 choroform. The chloroform solution is washed with saturated saline, dried over anhydrous sodium sulfate and evaporated in vacuo. 1.45 g of 1- [N2- (3-methyl-l, 2,3,4-tetrahydro-8-quinoline sulfonyl) -L-arg-inyl] -4-methyl-2-piperidinecarboxylic acid are obtained in the form of a amorphous solid; Yield 85% of theory.

IR spectrum (KBr): 3400, 1620, 1460 and 1380 cm "1.

Analysis: C23H3605N6S

calculated: C 54.09 H 7.00 N 16.80%

found: C 54.31 H 7.13 N 16.52%

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.

Connection

No.

1

2nd

3rd

4th

5

6

7

8th

9

10th

21st

648 293

Table II

HN

h2n '

% H

, c-n-ch2ch2ch2chcor

H-N-S02-Ar

Ar

Acid Crc

Concentration- hearing aid- physics- elementary analysis (upper IR spectrum for analysis): calculated values, lower (KBr)

extension self-values: found)

dcrKoaguIa- driving shafts according to d. Factor 2 example

C H N cm "1

-N

IN

och "

\

ch2ch2och3 ch2cooh

20th

53.82 6.21 13.08 3.350, 1.630 53.59 6.11 12.78 1.270, 1.160

tr2 ~ o - <11:

0CH3

CH2CH2CH3 cooh

38 3

57.02 6.81 12.79 3.400, 1.630 56.69 6.65 12.84 1.260

-N

CH2CH2CH2CH3 chjjcooh

5 3

55.63 7.66 12.98 3.350, 2.920 55.32 7.39 12.84 1.630, 1.250

^ CH2CH2CH2CH3 - ^ - • «iCOCIIj -nNch, cooh

49.57 6.66 17.34 3.400, 1.640 49.24 6.79 17.48 1.530, 1.160

H

TO

H

-N

\

CH2CH2CH2CH3 ch-cooh

46.95 5.71 19.17 3.400, 1.680 46.67 5.79 18.87 1.630, 1.380

0 '* 0

-n

CH2CH2CH2CH3 ch ^ cooh

50.89 5.96 14.13 3.400, 1.740 50.79 5.98 13.86 1.630

-n

.X \

CHjCHjCHjCH ^ j ch2c00h

19 3

52.70 6.32 17.56 3.400, 1.620 52.66 6.19 17.82 1.380

~ N

\

.ch2ch2OCH3

ch2cooh

54.32 5.70 15.84 3,400, 1.635 54.08 5.96 15.73 1.510

-n ch2ch2ch2CH3

ch2cooh

52.44 5.69 12.74 3.400, 1.630 52.43 5.86 12.58 1.290

tic ©

-n

/ ch2ch2och3

\ ch2cooc2h5

/ 2H, SO,

50.49 4.07 11.78 3.350, 1.735 50.22 4.18 11.51 1.620

648 293

22

Table II (continued)

Ver- HNX Konzentra- Herstcl- Physika- Elcmcnlaranalysc (Upper IR Spacktrum bin- "lion for the relational values: calculated, lower (KBr)

extension C-N-CH-, CH_CH_CHCOR lengthening eigen-values: found)

No. w ^ 2 2 j dcrKoagula- driving shafts

2 'H-N-SO - Ar ÌÌTw'T fmiiss,

2 d. Factor 2 example

(nmol / 1)

Ar R acidity C H N cm

XHoCHaOCKn

,, I li I, -x -Nv - 9 5L57 5 "46 13-08 3,400,1,630

11 nch2c00h z 51.35 5.63 12.86 1,280

12

s o2

-n

/ ch2ch20ch: j \ ch2cooh

48.66 5.15 12.34 3.400, 1.625 48.85 5.03 12.05 1.270

13

-n

^, ch2ch2ch2ch3

\

ch2cooh

54.01 5.86 13.12 3.350, 1.640 53.78 5.97 12.96 1.270

14

-n

CH2CH20CH3 ch2cooh

54.22 5.50 13.18 3,400, 1.700 54.08 5.36 12.95 1.635

och 3rd

ch2c02h

0.7

55.00 7.28 12.34 3.400, 2.920 54.86 7.28 12.49 1.630, 1.250

■ 0

»

oco2c2H5

-N

^ CH2 \

-CJ

ch2co2h

2.5

53.74 6.93 11.19 3.400, 1.760 53.81 7.04 10.96 1.630, 1.220

ho

17th

he

&

2C ° 2 ^

54.23 7.10 12.65 3.350, 1.625 54.25 7.08 12.86 1.380, 1.150

18 O

ch,

-0

och-

/ uh2 "^ O 'NcH2C ° 2H

1.5

56.33 6.48 12.17 3.350, 1.640 56.39 6.52 12.07 1.260

[]

19 _ / nV_ ff)) -N '™ 2 ° - 1 5 3 56.48 6.26 13.14 3,350,1,630

ry - \ uy \ u / n \ ch2c02h 56a1 6-08 13-28 1.3s5 '1.160

20th

O.

, -U

-n

^ ch2-.0.

\

ch2c02h

57.44 57.63

6.12 5.99

12.88 12.76

3,400, 1,630, 1,150

Connection

No.

21st

22

23

24th

25th

26

27th

28

29

30th

23

648 293

HM

%. 11

h2n '

c-n-ch2ch2ch2chcor

H-N-S02-Ar

Ar

Table II (continued)

Concentration- Herstcl- Physics- Elemental Analysis (Upper IR Spectrum for the Relative Values: calculated, lower (KBr)

extension self-values: found)

The coagulation time according to d. Factor 2 example (jiMol / 1) -

Acid residue

H

N

-n ch,

.-O

ch2c02h

51.78 5.41 12.12 3.350, 1.640 52.13 5.49 12.08 1.250

-®— (ö> • "

^ CH2

O.

\

ch2c ° 2h

57.23 6.47 12.84 3.400, 1.630 56.95 6.45 12.76 1.160

igr®

.ch

-O

\

ch2co2h

55.40 6.62 12.43 3.400, 1.630 55.27 6.81 12.25 1.260

ts: ©

.-O

-n

/ CH2- ^ o- \

CH2C02C2H5

/ 2II2SO,

48.34 5.41 10.44 3.400, 1.740 48.56 5.46 10.33 1.630

0

och 3rd

co2h

-N ^ -ch3

0.1 4

56.60 7.49 12.70 3.350, 2.920 56.51 7.53 12.68 1.620, 1.250

&

-0

oh co2h

"0" ch3

2.5 4

55.84 7.31 13.03 3.350, 1.620 56.07 7.46 13.08 1.380, 1.150

och3

co2h

-0 "CIb

57.23 6.47 12.84 3.350, 1.620 57.15 6.70 12.75 1.260, 1.155

co2h

€ r0 30 - £>:

0.1

53.46 5.56 12.47 3.400, 1.625 53.55 5.63 12.51 1.460, 1.165

co2h

-Q- '

0.6

58.23 6.45 13.58 3.375, 1.620 58.08 6.51 13.62 1.385, 1.160

o co2h p) -O "5" 3

0.1

59.18 6.30 13.27 3.350, 1.610 59.08 6.52 13.36 1.140

648 293

24th

Connection no.

HN

S

Table II (continued)

Concentra

H2N

, C-N-CH0CH0CHoCHCQR l l L |

Ar

H-N-S 02-Ar

Acid residue

Hststel-Physika- Elementaryanalysc (Upper IR spectrum for the arithmetic values: calculated, lower (KBr)

extension self-values: found)

the coagulation times change according to d. Factor 2 example ((iMol / 1)

H

N

31

C02H) \ aj »

51.77 5.10 13.13 3,400, 1.630 52.05 5.08 12.98 1,160

32

Tsö® -5

53.65 53.88

5.22 5.36

12.51 12.40

3,400, 1,710, 1,630

33

, n,

.OlO.

cooh

»3

0.5 4

53.86 6.16 17.13 3.375, 1.620 54.08 6.07 17.39 1.460, 1.290

TeT®

v ^ still 3

co2h

34

-òc, 3 -

4th

57.32 7.66 12.38 3.400, 1.620 57.27 7.68 12.45 1.250

rf

35

"w ch j

A

56.60 7.49

12.70

3,400, 1,620

^^ och3

56.82 7.36

12.86

1,140

36

cv ° 2c2h5

"0 ^ H3

CH3COOH

4th

56.85 6.84 11.05 3,400, 1.740 56.69 7.15 10.88 1.635

\ ^ OCH3

37

CH3.

, N.

c02ii

-0H

0.5

powder

54.74 6.39 16.66 3.380, 1.620 54.81 6.53 16.45 1.460, 1.375

38 \\

CH3 '

»A C02»

0.1

powder

54.74 6.39 16.66 3.400, 1.620 54.50 6.25 16.85 1.460, 1.380

fîV55!

39

CH3

co2h

0.25

powder

54.74 6.39 16.66 3.380, 1.620 54.80 6.37 16.51 1.380, 1.160

N.

40

;H-

co2H

-ty

powder

54.74 6.39 54.89 6.42

16.66 3.380, 1.620 16.63 1.380, 1.285

25th

648 293

S. H

Ver HN bin

d "ng ^ .C-N-CH-CH-CH-CHCOR

No. "H N 2 2 2,

ll2w H-N-S02-Ar

Ar

R

Table II (continued)

Concentration- hearing aid- physics- elementary analysis (upper value for calculation values: calculated, lower elongation own values: found)

the coagulation time according to d. Factor 2 example (jiMol / 1)

IR spectrum (KBr)

Acid crust

H N cm-1

41

c02i {

-n ^ ~ ch3 - 2

d. 55.58 powder 55.43

6.61 6.86

16.21

16.22

3.350, 1.620, 1.380, 1.150

ch3

42

CH3CH2

. c021i

Vi

43

CH3

, -cj

-n

"Cii2-v0-

n ch2cooh

powder

55.58 6.61 16.21 55.75 6.63 16.24

3,375, 1,620 1,460, 1,380

powder

53.06 6.20 16.14 52.81 6.15 16.23

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

44

CH3

-n

CH2CH2och3 ch2cooh

51.00 6.11 16.99 3.380, 1.620 50.86 6.08 17.25 1.380, 1.120

45

ch-jch2

-n

-O

^ CH2- ^ O

^ ciigcooh

53.91 6.41 15.72 3.400, 1.620 53.76 6.53 15.81 1.380, 1.130

46

ch3 <: H2

-n

\

, CH2ch20chj ch2cooh

51.95 6.34 16.53 3.375, 1.625 52.21 6.35 16.45 1.380, 1.120

47

-N ^ -CH> cooh d. 54.20 7.32 16.49 tu -a r 54.00 7.18 16.28 ^ ^

48

ol "v> ch;

nh2 cooh d. 50.31 6.45 18.53 ,, ...

r 50.01 6.28 18.42 ^ ^

49

h 0>

3,350

d, 54.20 7.32 16.49 'f "„ .a powder 54.11 7.11 16.28 \ f5 ° 5 (brclt)

50

0

2nd

3,350

52.15 6.88 14.48, .a powder 52.00 6.80 14.21 ^ bre ^

1,160

ch2ch20h cooh

648 293

26

Connection no.

HN

Table II (continued)

% »

h2n '

Ar

, C-N-CH2CH2CH2CHCOR

H-N-S02-Ar

Acid residue

Concentration- Manufacture- Physics- Elementary analysis (upper IR spectrum for corrective values: calculated, lower (KBr)

extension self-values: found)

the coagulation time according to d. Factor 2 example

(y. mol / 1)

C H N cm "'

51

O

och2ch2oh

-n) -ch.

cooh

powder

50.49 50.65

6.66 6.51

14.02 14.32

3,350

1.620 (wide) 1.135

c0 -N Vch3 _ 9 P i 50-49 6-66 14-02 i finn ^ re-A

•) - '50.28 6.35 13.89 (wide)

0ch2gh20h cooh 1'155

53

54

55

OLoch2çhoh ch n cooh

0>

0

cii3 ch2choh

56

X)

oc2h5

"nvD ~ ° H:

ch2ch2ch20h cooh

"O:

cooh ch3

-n ch2ch2ch2ch3 ch-icooh

57

J5CÖ

-n

^ CH2CH20CHj

N

ch2c00h p, 53.61 6.56 13.03 fbre! | j r 53.42 6.38 13.01 ^ ^

p. 55.26 6.76 13.43 ^ reî ^ r 55.36 6.87 13.21 (wide)

p, 55.26 6.76 13.43 fbre "}

Powder 55.11 6.67 13.39 (broad)

56.39 7.82 12.69 3.400, 1.630 56.28 7.79 12.51 1.260

0.35 1

53.16 5.62 13.48 3.400, 1.625 53.01 5.78 13.46 1.280

XÏ „x *

.0 ch2ch20ch3 ^ 55.68 6.04 13.53 3,400,1,630

^ ^ ch2c00h 55-71 6-00 1339 1'160

cn T _ ^ .CH2CH2SCH3 3,360 (wide)

59 Tr C «2C00H - 2 S 5M £ 32; .e»

60

jSCÖ - "<

, CH2Cll2SCH2CH3 ch2cooh

48.22 47.99

5.23 5.21

11.72 11.56

3,360 (wide)

1,620

1,155

27th

648 293

Connection no.

HN

Table II (continued)

Konzentra- Hörstel- Physika- elementary analysis (upper IR spectrum for the relational values: calculated, lower (KBr)

C-N-CH2CH2CH2ÇHCOR extension own values: found)

S H

"~ I of the coagulating shafts

2 H-N-S02 working time according to

Ar

Acid residue d. Factor 2 example (fiMol / i)

H N cm

61

.ch2ch2

ch2cooh

59.24 5.86 12.34 (wide)

59.24 5.77 12.33

1,620 1,152

62

tic © -ÇO

COOH

61.41 5.34 12.79 3.400, 1.630 61.29 5.38 12.68 1.180

63

.ch;}

Q

cooh

54.74 6.39 16.66 3.380, 1.620 54.69 6.27 16.39 1.375

64

0 "nnch-cooh CH?

^ V ^ rC2 "5

57.52 7.33 12.42 3.400, 1.740 57.48 7.42 12.39 1.630

67

Lxy ... "O":

'0 (ch2) -2ch

3 cooh

53.10 7.09 14.08 3.300 (broad) 52.93 7.20 14.00 Y'YYY

68

^ ko (ch2) 3ch3 cooh

53.98 7.29 13.69 53.77 7.18 13.60

3,300 (wide)

1,620

1,160

»CCÌL" 0e "3

0 (ch2) 3ch3 cooh o, p

53.98 7.29 13.69 ^^ 9 (brat) 53.71 7.21 13.28 J'Jg

70

O.

,-O

-N

/ CH2 ^ O- \,

(ch2) 3ch3 cii2cooh

52.35 7.07 13.27 3.370, 1.630 52.27 7.19 13.00 1.255, 1.155

648 293

28

Ver HN. H

bin- ^

dung

No. H2N

Table II (continued)

C-N-CH-CH-CH-CHCOR

L i. L |

H-N-S02-Ar

Ar

Acid Crcsl

Konzentra- Herstcl- Physika- Elementaryanalysc (Upper IR spectrum tionforcorresponding values: calculated, lower (KBr)

elongation ver eigenvalues: found)

the coagulation period according to d. Factor 2 example

(nmol / 1)

C H N cm "1

71

(fjx -o-CH3

0 (ch2) /, ch3 cooh

54.83 7.48 13.32 350 (wide)

54.95 7.46 13.41

1,620 1,155

72

ch2ch2ch3 "n \

/ CH2

-o och3

ch2c00h

1.5

52.35 7.07 12.27 3.380, 1.630 52.41 7.15 12.46 1.255, 1.135

73

/ CH3 chch2ch3

och 3rd

-n ch2ch2och3 chocooh

6.4

51.24 7.23 13.58 3.350, 1.630 51.31 7.46 13.29 1.250, 1.150

74

och3

ch3

ch3 cii3

-N

ch2ch2och3 chocooh

13

51.24 7.23 13.58 3.350, 1.630 51.38 7.15 13.62 1.255, 1.155

75

f ^ ìl 'CH;

och 3rd

ch3 ch3

ch

—N

.-O

\

ch2cooh

53.21 7.26 12.93 3.400, 1.635 53.16 7.05 12.91 1.260, 1.160

76

not

/ j c -ch3

och3

cii3

cooh

0.75 4

54.83 7.48 13.32 3.400, 1.630 54.97 7.48 13.36 1.260, 1.160

, -0

77 Tû * 01? - "\ mz ^ ° '

0- (ch2) 3ch3 nch2cook

53.21 7.26 12.93 3.375, 1.630 52.95 7.31 13.15 1.255, 1.145

78

ch3

rK

CH2CH2OCH3

och2ch2och3 nch2cooh

48.73 6.82 13.53 3.300, 1.620 48.93 6.90 13.48 1.110

79 ft "3 -n \ -ch3

• ^^ OCHoClUOCHa) —f * j cooh

52.35 7.09 13.27 3.350, 1.610 52.46 7.08 13.11 1.140

80 T ^ ir00 "3 -o-

0 (ch2) 30ch3 cooh

53.21 7.26 12.93 3.365, 1.620 53.11 7.56 12.78 1.245, 1.150

29

648 293

Table II (continued)

Ver 11 Nv j, Konzentra- Manufacture- Physics- Elemental Analysis (Upper IR Spectrum Binding to Crystalline Values: Calculated, Lower (KBr)

dung c-n - chnch-ch-chcor extension-eigen- values: found)

No. m »i I of the Koagula driving shadow

2 H-N-SO - working time at according to

.2 * d. Factor 2 example

(^ Mol / i)

Ar R acid residue C H N

81

txCH *

"0" C "3

(c »2 ^ 3ck3 cooh ch3

55.63 7.66 12.98 3.350, 1.610 55.49 7.54 13.01 1.400, 1.140

v £ VCH3 82 ^ V ^ O- (ch2) /, CH3 -N _ ^ "ch3 CH3 C00H

56.39 7.83 12.65 3.350, 1.620 56.43 7.85 12.49 1.380, 1.150

ch3

83 k ^ »o- (CH2) l, CH3 ~ N \ °

c "- 0

cu2c00h

54.81 7.61 12.29 3.350, 1.630 54.76 7.60 12.35 1.145

84

oil / * 3

chch2ch3

Oh

"0 ^ h3

cooh

-

4th

53.99 54.15

7.29 7.28

13.69 13.58

3,400, 1,630, 1,150

85

/ ÇH3

v ^ C ^ -ch3 cch3 ch3

-Q-ch,

cooc2h5

CH3COOH

4th

54.79 54.86

7.72 7.54

11.41 11.46

3,400, 1,740, 1,630

86

^ C0 (CH2) 2ch3

0ch3

■ {D-0 "3

cooh

-

4th

54.23 54.48

7.10 7.04

12.65 12.63

3,400, 1,680, 1,630, 1,150

87

Cl

(ch2) 3ch3

cooh o- (ch2) 2ch3 yj ch3

och3

cooh

89

ì ^ ìr ° - (CH2) 3CH3 _, rVcH3

^> ^ 0- (CH2) OCHT

2 ^ 3 3

cooh

47.85 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

90

| <V "(CH2) 3CH3 / - \

U -K / ch3

0- (CH2) 3CH3

cooh

55.55 7.77 12.00 3.420, 1.650 55.64 7.96 11.82 1.260, 1.165

648 293

30th

Table II (continued)

Ver HN. "Concentration- Hörstel- Physika- elementary analysis (upper IR spectrum combination" to the values of the computation: calculated, lower (KBr)

extension C-N-CH9CH0CH «CHCOR extension self-values: found)

No. S * Z Z 2 | shadow of the coagulation

"7 H-N-SÒ working time according to

2 d. Factor 2 example

(nmol / 1) -

Ar

R

Acid residue

H N cm "1

^ s ^ o-cchs) 3ch3

91

ch3 fch2) 3o

<2-0

^ ch2-. n ch2c00h

54.07 7.56 11.68 3.350, 1.630 • 54.05 7.81 11.43 1.160

92

OCH3 COOH

51.68 7.06 12.56 3.350, 1.630 51.44 7.12 12.67 1.380, 1.090

3 / - \

y. OCH '

93 ^ ^ 0- (CH2) 2CH3

och3 COOH

0.9 4

52.51 7.24 12.25 3.350, 1.630 51.99 7.15 12.30 1.460, 1.090

- OCH '

94 ^^ 0_ (CH2) 2CH; j -N (OCH 3

^ CH2CH20CH-j ch2cooh

49.17 7.01 12.47 3.300, 1.630 49.31 7.13 12.52 1.400, 1.090

^ ^ och3

-X

. (CH2) i, CH3

95 J ^ O- (CH2) 2CH3 "NCH2C00H OCH 3

52.33 7.55 12.21 3.350, 1.630 52.47 7.23 12.31 1.460

96

och-

_N - "(CH2) 3CH3

0- (ch2) 2ch3 çhcooh och 3

ch-

52.33 7.55 12.21 3.400, 1.620 52.51 7.61 12.18 1.095

f ^ Y ° CH3 .s ^ z-O

97 O- (CH2) 3Cii3 w * N'v

N

CHoCOOH

och3

54.07 7.56 11.58 3.350, 1.620 54.12 7.34 11.52 1.090

| ^ Yoch3

98 o- (CH2) 3CH3 -N

OCH 3

-Yes

S

ch-, cooh

53.31 7.40 11.96 3.350 1.620 53.28 7.28 11.77 1.450

99

| ^ Y ° CH3

0- (CH2) 3CIl3

och 3rd

ch2cooh

53.87 6.43 12.08 3.400, 1.630 53.72 6.54 12.00 1.090

r ^ Y0CH 3

100 0- (Cll2) 3cii3

och3

\

• CH2-0

ch2ch2c00h

55.33 6.80 11.53 3.370, 1.635 55.49 6.71 11.51 1.580, 1.090

31

648 293

Table II (continued)

Ver- JJJJ Konzentra- Herstcl- Physika- Elemental analysis (upper IR spectrum bin- ^ H tion zurVrul- lische values: calculated, lower (KBr)

dung r —N — CH CH CH CHCOR elongation self-values: found)

No. 2 2 2 | dcrKoagula1- ferries shade

H H H-N-SO - Working time according to

* • Z d. Factor 2 example

(liMoI / 1): -

Ar

Acid residue

H N cm "'

101

r ^ V00 "^ n / ch2ch2 ~ c = y o- (cH2) 3CH3 NnsCH2COOH

0CH3

55.33 6.80 11.53 3.350, 1.620 55.21 6.75 11.34 1.455, 1.090

102

oh

och-

o- (ch2} / jch3

cooh

0.8 4

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

'OCH3

103

och 3rd

o- (ch2) 5ch3 -iT ^ -c »3

cooh

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

104 ^ och2CH2OCH3

och3 cooh

50.25 6.85 12.21 3.400, 1.630 50.39 6.79 12.30 1.455, 1.090

105 jx 0CH2CH2CH2Br ^ "3

och3 cooh

45.28 6.02 11.00 3.400, 1.620 45.46 5.95 11.26 1.080

106

Oil,

OCH2CH2OCH2Cll3 -n / "° h3

och 3rd

cooh

51.09 7.03 11.92 3.375, 1.620 51.20 7.14 11.87 1.455, 1.090

107

-n fiT00 "3

Y ^ - (ch2) 3co2ch3 nch2cooh och3

/ ch2ch2och3

Y

46.69 6.30 11.84 3.400, 1.720 46.48 6.41 11.88 1.630, 1.080

och3

108 l ^ l ^ o- (ch2) 3ch3 y ^ h-3 CH3COOH

och3 cooch2ch3

52.79 7.49 10.62 3.400 1.735 52.83 7.65 10.43 1.625

109

^ C »3 och, ch ~ chv

- 2 \ ch3 cooh

ch3

54.83 7.48 13.32 3.300, 1.625 54.15 7.03 13.85 1.160

110

och

CH3

"f> CH3

0.2

ch2ch3 cooh

53.98 7.29 13.69 3.340, 1.620 53.77 7.09 13.38 1.380, 1.155

648 293

32

Table II (continued)

HU. Concentration, physics, and elemental analysis (upper IR spectrum binding for compulsory values: calculated, lower (KBr)

extension ^ C-N-CHoCH „CH„ CH COR elongation-eigen- values: found)

No.

H, N

2 2 2

H-N-S02-Ar

Ar

Acid residue from the coagulation process creates time according to d. Factor 2 example (uMol / l)

H N cm "1

111

(à

_iP \ cH3

OCH2CHv) - '

CH3 COOH

0.1

53.98 7.29 13.69 3.340, 1.610 53.79 7.11 13.81 1.380, 1.155

112

cu3 COOH

0.65 2

53.10 7.09 14.08 3.350, 1.620 53.00 7.00 14.00 1.380, 1.155

113 - ^^ - 0 (ch2) 3ch3 -i> h3

COOH

53.98 7.29 13.69 3.350, 1.620 53.71 7.08 13.72 1.380, 1.155

114

CH3 COOH

0.6

53.98 7.29 13.69 3.300, 1.600 53.92 7.33 13.60 1.380, 1.130

115

0C2H5

-NJkh3

COOH

53.10 7.09 14.08 3.350, 1.620 53.08 7.09 14.11 1.380, 1.150

116

(ch2) 2ch3 -fy ch3

0 (CH2) oCHn) - *

COOH

55.63 7.66 12.98 3.320, 1.620 55.59 7.74 12.99 1.380, 1.130

117

3 / - \

-N) -CHt ° (CH2.) 2CH3) -

CH3 COOH

0.2

54.83 7.48 13.32 3.300, 1.630 54.80 7.53 13.30 1.380, 1.150

ch-ch3

ch ^ ch3

I.

118 OCH 3

-f "VcH3

ÒHrCH3 l3

NCHo c ° OH

56.39 7.83 12.65 3.350, 1.620 56.51 7.78 12.56 1.460, 1.155

1.9 - ^ C "3

CHCCH3 ^

kCH-

COOH

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

CH3 COOH

0.1

54.83 7.48 13.32 3.350, 1.615 54.81 7.52 13.27 1.380, 1.150

33

648 293

Table II (continued)

Ver Uli. Concentration- Herstcl- physics- elementary analysis (upper IR spectrum, combination with the values of the calculation: calculated, lower (KBr)

-CN-CH9CH, CH „CHCOR elongation-eigen- values: found)

No. UM 2 | of the coagular shafts

2 H - N - SO working time according to

1 2 d. Factor 2 example

(| iMol / l) -:

Ar R acid residue C H N cm-1

121

ch;

oc2 »5

cu-

O

/

cooh

0.5

53.98 7.29 13.69 3.350, 1.610

53.99 7.36 13.71 1.380, 1.150

122

^ V0C »3

0 (CH2) ^

-O":

ch »j cooh

53.21 7.26 12.93 3.350, 1.620 53.39 7.30 12.88 1.360, 1.155

123

• sb:

-N y ~ CH '

OCH3

otchaj / jchj cooh

53.02 7.60 12.88 3.350, 1.620 53.15 7.57 12.86 1.380, 1.160

124

0: ~ *

och-

och-ch ch3 "\ _ /" CH3

2 nch'j '

j cooh

0.75

52.51 7.24 12.25 3.330, 1.620 52.43 7.31 12.26 1.380, 1.160

125 érch :) -ch3 _, 0-ch3

k ^ -0CH2CH2CH ^ cH3 yJ och3 3 cooh

0.55

53.30 7.41 11.96 3.330, 1.620 53.36 7.35 12.01 1.380, 1.160

126

) - ^ 0C2Hj

0 "CH3

oc2H5

-o cooh

51.69 7.05 12.56 3.350, 1.630 51.75 7.00 12.56 1.380, 1.100

127

\ J3CH-,

£ 5-oc2h och-

-Ç> "CH3

cooh

50.81 6.86 50.79 6.91

12.88 3.350, 1.610 12.84 1.380, 1.160

128

xch3 CHv nCH3

cooh ch; CH ^

53.98 7.29 13.69 3.400, 1.620 54.15 7.26 13.76 1.150

och-

129, s ^> ^ 0 (CH2) 2CH3

-K ^) - C2H5 och3 cooh

0.25 1

52.51 7.24 12.25 3.350, 1.620 52.41 7.04 12.05 1.380, 1.160

130

oc „cck3 -Çy-w,

ch '

cooh

0.25

53.98 7.29 13.69 3.300, 1.620 53.66 7.11 13.23 1.380, 1.155

648 293

34

Connection no.

HN

h2N "

S. H

^ C-N-CH2CH2CH2CHCOR

H-N-S02-Ar

Ar

Table II (continued)

Concentration- Manufacture- Physics- Elemental analysis (upper IR spectrum for corrective values: calculated, lower (KBr)

extension self-values: found)

the coagulation time according to d. Factor 2 example ((iMol / 1)

Acid Crc

H

N

«1 ^ x" ck2) 3CK3

OCH3

COOH

53.30 7.41 11.96 3.350, 1.620 53.21 7.18 11.89 1.380, 1.155

132

^ xO (CH2) 2CH <; «3 -Q-C2H5

OCH-

COOH

54.06 7.58 11.68 3.350, 1.620 53.90 7.48 11.48 1.380, 1.155

133

ljy ^ O (CH2) 3CH3 2

OCH3

CH, CHgCOOH

52.51 6.44 14.13 3.370, 1.620 52.46 7.08 14.25 1.410, 1.090

134

^ ch3 CH3

-N

^ CHgCOOH

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

- N VcilC'0 "3", 54.83 7.48 13.32 3.355, 1.620

1 „, ~ f f ~ '1 Jt.OJ l.to JlJ.Ji x, uz.u

^ ch3) - 'CIt3 1 54.71 7.23 13.11 1,380,1,150

0ch \ CH3 COOH

136

.O (CH2) 2CH3 ~ Ny_ / ~ C2H:

CH3

COOH

^ CH3 -kO-

J <tAo (CH2) 2CH3 N— '

137

CH3

CH '

✓

COOH

138

^ (c "2.2oh3 OC2H5

/

COOH

55.63 6.66 12.98 3.360, 1.620 55.56 7.58 12.79 1.380, 1.150

54.83 7.48 13.32 3.340, 1.620 54.90 7.41 13.29 1.380, 1.150

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

648 293

35

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

ArS02Cl or ArS03H compound or salt thereof No. (reference)

Starting material amino acid ester

HN ^

j, C - NH - (CH2)

h2n

product

, CHOOR 3I

HNSO ^ r

Ar

R

1

Ber. 31.1663

/CH..-L.)

^ CH2CO'OC (CH3) 3

0-

\

n ch2cooh

2nd

o-3- © -80: »"

Ber. 26, 996

ch hnf *

ch2cooc (ch3): j

n / CH2-U \

nch2c00h

3rd

0 ~ 0rso2c1

/ H ^ CO m.p. 55 ° C

HN ^ A

xch2cooch2c6h5

u h ^ jco

: or nch2c00h

4th

0

c102s

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

hn ^ - 0

ch2cooch2c6h5

m / c »2-q \

nch2cooh

5

SO-jNa Ber. 84,1254 (1956)

hn / \; o

W

COOC-, Hr * 5

oq

-o 'so cooh

6

SO3H

Hf / \)

) —F cooc2h5

JO

-t / ^ 3

> —7

cooh

Zhur. Obschei Khim 22, 866 (1952)

648 293

36

Table III (continued)

ArS02Cl or ArS03H compound or salt thereof No. (reference)

Starting material

Amino acid esters

7

ho3s

Zhur. Obschei Khim 22, 866 (1952)

HN S

w

0OOCgH 5

product

HN ^

C - NH - (CH2) 3CH00R "2N HNSO ^ r

Ar

R

N_CH-

) /

COOH

cio2s tYT0H -ce ^

NCH2C00C2H5 ^^ N ^ OH XCH ,, COOH

Japanese Patent Published 26975/1964

HO3S

OCH., I J

N ^ ar.

OCH '

HN

COOCoH r * 5

Ber. 86, 951 (1953)

COCH'i 1 y

I <PVVN> 1- 'S0 ^ H

i »0_J

COOCoH r,

COCH 3

COOH

~ ^ b

Ber. 86, 951 (1953)

11

[■> '

HO3S

COCH3 1

N-

HN7 ^

) - C00C2H ^

COCH 'I

0 ^ "o

COOH

Zhur Obschei Khim, 30, 1218 (1960)

J0Q "(3" ch:

COOH

OCoH,

OC2H5

-Q - <= «5

COOH

12

so2c

Ber. 54,102 (1921)

* q- <

HN / -ch3

C ° 2C2H5

0C-.H

13

h /> c,

c02c2h5

CA, 25, 5420

37

648 293

Table III (continued)

Compound ArS02CI or ArSOjHung or salt thereof No. (Literalurstellc)

Starting material

Amino acid cster hn,

h2n

product

.c - nh - (œ2) 3choor

HNSO ^ jAr

Ar

14

SO yeah

CA, 22, 413

h »T) -c2h5

co2c2h5

cooh

15

Hv> CH3

co2c2H5

- <p-

cooh ch '

CA, 33.4227

16 C102sC0NH2 HÇy ~ CH3

^ 0 c02c2h5

Zhur Obschei Khim, 18.1459 (1948)

17th

SvrS02C'1 HN ^ ~ CH 3

'(>

COOC2H5

Compt. rend 198, 2260 (1934)

- cqo "3"

° 2

/ - \ HN / -C2H5

COOCoH.

Compt. rend 198, 2260 (1934)

s02c1

19th

hn

V ^ yh-CoH,

cooc2h5

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

20th

cooc2h5

tocc o

cooh

CH '

oqo - ^} "ch:

cooh

cooh

GO

cooh

CH '

-i -CH -

cooh

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

648 293

38

Table III (continued)

Compound ArS02Cl or ArSOjHung or salt thereof No. (reference)

Starting material

Amino acid esters

product

HN «

"C - NH - (OO-XHCOR

HN I

2 HNSOjAr

Ar

R

21 HO3S

NO

H

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

COpCoHr COoCp H r;

* - J

nh2

N ^ H 0

COONa i

COONa

22

SO3H

"O -0CH3 /

COOC2H5

o OCH3 CÓOH

U.S. 2,476,541

23

1 N

'N H

S02CJI J. Pr. (2) 118, 75

HN / -CH3

cooc2h5

COOH

H? ° 3H

24th

"(!> c

CH3 COOC2H5

-0-Chj

COOH

Photophysics Photochem., 58.3 (1963)

SO3H

- h3c ° to

/ - \ ch-hn vchf "") 'n ch-

cooc2h5

COOH

. ch3

\

ch.

J. Gen. Chem., 16.1873

»H ° 3sv0û, hi> © toà

COCH3 C00C2H5 COCH ^ COOH

Ber. 86, 951, (1953)

J COOC, Hr COOH

<= 5

Zhur, Obschei Khim, 30, 1218 (1960)

39 648 293

Table III (continued)

Compound ArS02CI or ArSOjIIung or salt thereof No. (reference)

Starting material amino acid ester

HN ^

^ .c - nh - (ch2)

h2n

Product, cb00r

1 "

HNSO-jAr

Ar

R

28

c102svtv ^^ s

.u;, /

H

Bull. Soc. Chem. France, 1950, 466

"O" 02 "5 /

c00c2h5

ISO

H

-i> a "5

COOH

29

SOpCl

"so

H

HV>

cooc2h5

êo h

-v>

x: ooh

Bull. Soc. Chem. France, 1950, 466

30th

0

° 2n s02c1 o2n h

CA, 62.14675b

/ - \

hn vch'j c00c2h5

O

Q2MTSÒDT

~ h û2n

- (> ch3 COOH

31

h? ° 3na

0O§

CA, 26, 4723

nÇycn,

cooc2h5

Cûê

cooh

32

(n

"^ 502CI

cl

J. Am., Chem. Soc.,

57.1533, (1935)

»0-CzH5

cooc2h5

~ çy * 2H5

COOH

33

S0'N "

CA, 45, 9063i hl /

cooc2h5

cooh

34

0

sm3k

/ V ^ CH "

HN / -CMC j yj nch3 cozc2tìrj

0 0

-N VCHN

^ r Un ^

cooh

Org. Synth. II, 539

648 293

40

Table III (continued)

product

HN,

h2n

"C - NH - (Oi,), CHOOR

'/ Yy

HNSO ^ l

Ar

~ © --0

r ~ \.-N_y ~ CHo cooh

Compound ArSOjG or ArS03H dung or salt thereof No. (literature reference)

Ausgngsmnterinl

Amino acid cslcr

35 CIq2S- <3- 0 ~ (^^) ~~ y ~ cH3

cooc2h ^

Beilstein 11, II 135

Example 4

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

20th

Components

Quantity (g)

component

Amount per

Tablet (mg)

Nz- (3-cyclohexyl-4-methoxyphenylsulfonyl) -

250

L-arginyl-N-butyl-glycine

Lactose

140

Cornstarch

35

talc

20th

Magnesium stearate

5

a total of

450

Example 5 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.

N2- (3-cyclohexyl-4-methoxyphenylsulfonyI) -L-arginyl-N-butyl-glycine 25 buffer system

glucose

Distilled water

35

40

45

component

Amount per

Capsule (111g)

N2- (3-cyclohexyl-4-methoxyphenylsulfonyI) -

250

L-arginyl-N-butyl-glycine

Lactose

250

a total of

500

50

EXAMPLE 6 Sterile Infusion Solution The components listed below are dissolved in water suitable for intravenous perfusion and the solution obtained is sterilized.

fiO

65

25th

in the desired amount 25 500

30th

Production A)

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

B) 3-butoxy-2,4-dimethoxybenzoisulfonylchloride. 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-dimethoxybenzoisulfonate in 150 ml of dry dimethylformamide. The reaction mixture is stirred for 15 minutes and then slowly poured into 1000 ml of ice water, followed by vigorous stirring. 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-dimethoxybcnzolsulfonylchiorid receives (boiling point 154 to 155 ° C / l mm Hg).

Analysis: CijH ^ QOjS calculated: C 46.68 H 5.56%

found: C 46.71 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.

41

648 293

Table IV

Ar - S02C1 Boiling Point (Melting Point) Compound No.

Ar

165-166 ° C / 10 mmHg (57.5-58.5 ° C)

0 (ch2) 2ch3

0 (CH2) 3CH3

112-115 ° C / 1 mmHg (33-35 ° C)

ch3

0CH2CH2CH \

CH3

127-129 ° C / 0.5 mmHg

0 {CH2) kC1lj

148-150 ° C / 1 mmHg

0 (ch2) 3ch | j

I I

143-145 ° C / 1 mmHg (48-51 ° C)

ch2cii2ch3 OCH3

(41-2 ° C)

/ ch3 139-140 ° C / 1 mmHg ch

X CH2CH3 OCH3 J

129.5-132 ° C / 1 mmHg ori 3

CCH3 ch3

648

Verb;

9

10th

11

12

13

14

15

16

42

Table IV (continued)

Ar - SOiCl

Ar

Boiling point (melting point)

> ^ Vch3

X ^ O (ch2) 3CH3 ch3

145-148 ° C / 1 mmHg ch3

0 (ch2) ^ ch3

ch3

151.5-153.5 ° C / 1.5 mmHg tXCH3

^^ O (ch2) 3CH3

155-156 ° C / 2 mmHg

©

ch3

och2ch2och3

(44-45 ° C)

CiL

Td och2ch2ch2och3

187 ° C / l mmHg r ^ V ° CH 3

0CH2CH2CH2Br och3

198-200 ° C / 2 mm Hg

^ ~ och3

° (ch2) 3co2ch3

och-

210-220 ° C / 1 mm Hg

^ V ° cH3

^ 0 (^ 2) 2 ^ 5

och3

160-162 ° C / 2 mm Hg

43

648 293

Table IV (continued)

Connection no.

Ar-SO, Cl

Ar

Boiling point (melting point)

17th

OCH3

0 (CH2) ^ CH3

OCH 3

154-155 ° C / 1 mm Hg

18th

f ^ ir och '

o (CH2) z4cH3 OCH3

170-172 ° C / 2 mm Hg

19th

rVCH3

o (ch2) 5ch3

och 3rd

183-185 ° C / 1 mmHg

20th

och 3rd

och2ch2och3

OCH3

(46-47 ° C)

21st

Cl

0 (ch2) ^ ch3

Cl

131-C / l mmHg

22

"HC!

° (ch2) 2ch3

och

(65-66 ° C)

23

T®

0 (ch2) 3ch3 0 (CH2) 3CH3

(30-32 ° C)

24th

0 (ch2) 3CH3

o (ch2) 3ch3

208-210 ° C / l mm Hg

648

verb

25th

26

27th

28

29

30th

31

32

44

Table IV (continued)

Ar - S02CI

Ar

Boiling point (melting point)

o (ch2) 3ch3

o (ch2) 3ch3

178-179 ° C / 2 mmHg co (ch2) 2ch3 och3

oily substance och3

0ch2ch20CH2CH3

och3

165-168 ° C / 1 mmHg

CH

\

, ch 'choch oco2 ^ C2H ^

2 3

oily substance

L \

oc2h5

109-110 ° C / 1.5 mmHg ch-

och

\

ch3

111-116 ° C / 1 mmHg ch3

>> X /

> ochch2ch3

oily substance ch-

0ch2ch

\

ch *

oily substance

45

Table IV (continued)

648 293

Connection no.

Ar - S02C1

Ar

Boiling point (melting point)

33

0 (ch2) 4ch3

148-150 ° C / 1 mmHg

* ^ OC2H5

ch3

38

ch3

0 (ch2) 2ch3

CH-3

133-135 ° C / l mmHg

39

ch-

/ ch3

ch3

136-139 ° C / 1 mmHg

10th

ch

/ nvoch-

ch3

Clin ch

\

ch3 ch3

(95-6 ° C)

648

verb

41

42

43

44

45

46

47

M

46

Table IV (continued)

Ar - SO; CI

Ar

Boiling point (melting point)

CH-CH3 <ch3

// _ y-0- (ch2) 2ch3

ch ^ ch3 xch3

(101-103 ° C)

tir

(ch2) 2ch3

0 (ch2) 2ch3

142-144 ° C / 1 mmHg och3 0c2h5

och

(50-51 ° C)

OCH 3

// \\ / ch3

'/ ^ V-OCHoCH ^

nch3

och3

158-160 ° C / 1 mmHg och.

ch-

2nd

och2ch2ch ^

ch3 och3

159-160 ° C / 1 mmHg woc2h5

^ "ch3

oc2h5

151-2 ° C / l mmHg och-

"Ch-

och och3

\

ch-

158-159 ° C / 1 mmHg

Claims (2)

648 293 PATENT CLAIMS 1 Ar (XX) HN ^ / C HN I. r ' -n ch2ch2ch2chcor r " HNSOo i Ar (XX) 65 in which Ar has the meaning given above, R stands for one of the groups given above, in which R2, R5, R8, R9, Rio and Ru have the meanings given in claim 1 apart from that of a hydrogen atom, and the other symbols of these groups have the claim 1 have the meanings given and R 'and R "represent hydrogen atoms or protective groups for the guanidino group, at least one of R' and R" being a protective group of the guanidino group, split off by acidolysis, hydrolyzed the carboxylic acid ester obtained and optionally the carboxylic acid formed by reaction converted into the corresponding salt with a pharmaceutically acceptable base. 5. The method according to claim 4, 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 in contact. 648 293 6. A process for the preparation of N2-arylsulfonyl-L-arginine amides having a therapeutic effect, of the general formula I, in vvclchcr Ar has the meanings given in claim 1 and R represents one of the following groups: COORr X (CH) COOR-2 n 2 -N CH- (CH-) COOR-I 2 m 5 R " COOR., °? ° ho ) - \ -N Z VPHV ^ r 'Mcilji COOR, \ (CH). 1. Process for the preparation of N2-arylsulfonyl-L-arginine amides with therapeutic action, of the general formula: hn V -n-h -ch2ch2ch2chcor. h2n ^ "hnso, in which R (1) is a group of the general formula: r (I) ■ Ar (ch2) ncoor2 in the Rj for a C2-CI0-alkyl group, a C3-Ci0-alkenyl group, a C3-C10-alkynyl group, a C2-C10-alkoxyalkyl group, a C2-Ci0-alkylthioalkyl group, a C2-C10-alkylsulfinylalkyl group, a Ci-Ci0 -Hydroxyalkyl group, a C3-C10-alkoxycarbonylalkyl group, a C3-Cio-alkylcarbonylalkyl group, a Q-Qo-haloalkyl group, a C7-C] 5-aralkyl group, a Cg-Ci5-a-carboxy-xyaralkyl group, a C3 -Ci0-cycloalkyl group, a C4-Qo-cycloalkylalkyl group, a phenyl group, a furfuryl group, a tetrahydrofurfuryl group optionally substituted with at least one CrC5 alkyl group, Ci-C5 alkoxy group or mixtures thereof, a 3-furylmethyl group, optionally with at least one Ci -C5-alkyl group, CrC5-alkoxy group or mixtures thereof, substituted tetrahydro-3-furylmethyl group, a tetra-hydro-2 - (- 3 or -4) -pyranylmethyl group optionally substituted with at least one CpCs-alkyl group, CrC5-alkoxy group or mixtures thereof, one with at least one at least one Ci-C5-alkyl group, Ci-C5-alkoxy group or mixtures thereof substituted 1,4-dioxa-2-cyclohexylmethyl group, a 2-thenyl group, a 3-thenyl group, one optionally with at least one Cr Cs-alkyl group, CrC5- Alkoxy group or mixtures thereof substituted tetrahydro-2-thenyl group or a tetrahydro-3-thenyl group, R2 for a hydrogen atom, a CrCltralkyl group, a C6- Qo-aryl group or a C7-Ci2-aralkyl group and n stands for an integer with a value of 1,2 or 3; (2) a group of the general formula tetrahydro-3-furylmethyl group optionally substituted with at least one Ci-C5 alkyl group, CrQ alkoxy group or mixtures thereof, a tetrahydro-2 optionally substituted with at least one CrC5 alkyl group, CrC5 alkoxy group or mixtures thereof (-3 or -4) -pyranylmethyl group, a 1,4-dioxa-2-cyclohexyl-methyl group, a 2-thenyl group, a 3-thenyl group, 10 one optionally substituted with at least one CrC5-alkyl group, CrC5-alkoxy group or mixtures thereof at least one QQ alkyl group, Ci-Cj-alkoxy group or mixtures thereof substituted tetrahydro-2-thenyl group or a tetrahydro-3-thenyl group, R4 is a CrCl0 alkyl group, a phenyl group optionally substituted with at least 15 C ^ Cs alkyl group, CrC5 alkoxy group or mixtures thereof; a C7-C12 aralkyl group or a benzyl group substituted on the ring with a CrC5 alkyl group or Ci-C5 alkoxy group, 20 R5 represents a hydrogen atom, a CrC10 alkyl group, a C6-Cio-aryl group or a C7-Ci2-aralkyl group and m represents an integer with a value of 0.1 or 2; (3) a group of the general formula 25th 30th - N in the r, 35 R7 40 represents a group of the general formula-COOR8, in which R8 represents a hydrogen atom, a CrC10-alkyl group, a C6-Qo-aryl group or a C7-Cn-aralkyl group, independently of one another hydrogen atoms, CrCi0-alkyl groups, phenyl groups, Q-Cs -Alkoxy groups, C2-C6-alkoxycarbonyl groups or carboxy groups and p represent an integer with a value from 1 to 4, the group R6 in the 2- or in the 3-position and the groups R7 in the 2-, 3- , 4-, 5- or 6-positions can stand; (4) a group of the general formula 45 COOR9 - N - N R3 CH - (CH2) mCOOR5 I. 50 55 in the R3 for a hydrogen atom, a CrCltralkyl group, a C3-C10-alkenyl group, a C3-C10-alkynyl group, a C2-Cm-alkoxyalkyl group, a C2-C10-alkylthioalkyl group, a C2-C10-alkylsulfinylalkyl group, a CrCi0-hydroxyalkyl group, a C3-C1 (ralkoxycarbonylalkyl group, a C3-Ci (ralkylcarbonylalkyl group, a CrCi0-halogenoalkyl group, a C7-C15-aralkyl group, a C8-Ci5-a-carboxyaralkyl group, a C3-Cio-cycloalkyl group, a C4-CI0-cycloalkylalkyl group , a furfuryl group, a tetrahydrofurfuryl group optionally substituted with at least one CrC5 alkyl group, Ci-C5 alkoxy group or mixtures thereof, a 3-furylmethyl group, one optionally substituted with at least one Ci-C5 alkyl group, Cr C5 alkoxy group or mixtures thereof can in the Rg for a hydrogen atom, a Q-cw alkyl group, a Q- C10 aryl group or a C7-C12 aralkyl group and r represents an integer having a value of 1, 2, 3 or 4; (5) a group of the general formula COORj ^ q 60 - N 65 / H2) ( in the R10 represents a hydrogen atom, a CrCi0-alkyl group, a C6-C10-aryl group or a C7-C12-aralkyl group, Z for an oxygen atom, a sulfur atom or a sul- finyl group and q represent an integer with a value of 0 or 1; or (6) a group of the general formula COOR-, 1 in the Ru for a hydrogen atom, a Ci-C10-alkyl group, a C6- Cjo-aryl group or a C7-Ci2-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; and Ar is a phenyl group or a naphthyl group, each with at least one substituent from the sulfoamino groups, carbamoyl groups, C3-Ci0-N, N-dialkylcarbamoyl groups, C2-QN-alkylcarbamoyl groups, amino groups, Cj-Cio-alkylamino groups, mercapto groups , Q-Cio-alkylthio groups, C7-C! 2-aralkyl groups, carboxy groups, C2-C10-alkoxycarbonyl groups, C2-Cio-carboxyalkyl groups, Q-Qo-acylamino groups, C2-C10-alkylcarbonyl groups, Ci-Ci0 -Hydroxyalkyl groups, CrC10-haloalkyl groups, CrClfrHydroxyalkoxygruppen and optionally substituted with at least one hydroxy group, Cr C5-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, nitro groups, cyano groups, hydroxyl groups, CrC10-alkyl groups, CrCio-alkoxy groups and C2-C20-dialkylamino groups and at least one substituent from the sulfoamino groups, carbamoyl groups, C3 -Cio-N, N-dialkylcarbamoyl groups, C2-C6-alkyl-carbamoyl groups, amino groups, Ci-Cio-alkylamino groups, mercapto groups, Ci-CI0-alkylthio groups, C7-Cn-aralkyl groups, carboxy groups, C2-Ci0-alkoxycar bonyl groups , C2-Qo-carboxyalkyl groups, Ci-C10-acyl-amino groups, C2-Ci0-alkylcarbonyl groups, CrCvr hydroxyalkyl groups, CrC10-haloalkyl groups, Cr C1 (r-hydroxyalkoxy groups and optionally substituted with at least one hydroxyl group, CrC5-alkoxy group or mixtures thereof substituted phenyl groups is; an oxanthrenyl group or dibenzofuranyl group which has at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-dialkylamino groups, sulfoamino groups, carbamoyl groups, C3-Cio-N, N-dialkylcarbamoyl groups, C2-C6-N-alkylcarbamoyl groups, Q-Qo-alkylamino groups, mercapto groups, Ci-C] 0-alkylthio groups, C7-Ci2-aralkyl groups, carboxyl groups, C2-Cio-alkoxycarbonyl groups, C2-C10-carboxyalkyl groups, Cr C10-acylamino groups, C2-C10-alkylcarbonyl groups , Cr C1 (l-hydroxyalkyl groups, Ci-Cio-haloalkyl groups, CpCm-hydroxyalkoxy groups and optionally substituted with at least one hydroxyl group, CrC5-alkoxy group or mixtures thereof substituted phenyl groups; an oxanthrenyl group or dibenzofuranyl group which 648 293 with at least one substituent from the Q-Qo-alkyl groups and CrC1 (ralkoxy groups and with at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C20-dialkylamino groups, sulfoamino groups, carbamoyl groups, C3-C10-N, N-dialkylcarbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino groups, Ci-C10-alkylamino groups, mercapto groups, Ci-C10-alkylthio groups, C7-C12-aralkyl groups, carboxyl groups, C2-C10-alkoxycarbonyl groups, C2-C10-carboxyalkyl groups, CrC10 acylamino groups, C2-Ci0-alkylcarbonyl groups, Ci-C10-hydroxyalkyl groups, Ci-Ci0-haloalkyl groups, CrC10-hydroxyalkoxy groups and optionally substituted by at least one hydroxyl group, CrC5-alkoxy group or mixtures thereof substituted phenyl groups; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylenedi-oxynaphthyl group or a xanthenyl group, which groups have at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, C2-C2 (] - dialkylamino groups , Sulfoamino groups, carbamoyl groups, C3-C10-N, N-dialkylcarbamoyl groups, Cz-QN-alkylcarbamoyl groups, amino groups, Q-C10-alkylamino groups, mercapto groups, C1-C10-alkylthio groups, C7-C12-aralkyl groups, carboxyl groups -Cio-alkoxycarbonyl groups, C2-C1o-carboxyalkyl groups, Ci-Cio-acylamino groups, C2-Ci0-alkylcarbonyl groups, Ci-C10-hydroxyalkyl groups, CrC10-halogenoalkyl groups, CrC10-hydroxyalkoxy groups, oxo groups and optionally with at least one hydroxyl group, Q -C5- Alkoxy group or mixtures thereof substituted phenyl groups are substituted; a tetrahydronaphthyl group, a 1,2-ethylenedioxy-phenyl group, a chromanyl group, a 2,3-ethylened i-oxynaphthyl group or a xanthenyl group, which groups with at least one substituent from the group comprising Cr C10-alkyl groups and Cj-Cio-alkoxy groups and at least one substituent from the halogen atoms, nitro groups, cyano groups, hydroxy groups, C2-C2o-dialkylamino groups, sulfoamino groups, carbamoyl groups , C3-C10-N, N-dialkylcarbamoyl groups, C2-Câ-N-alkylcarbamoyl groups, amino groups, Cr Cio-alkylamino groups, mercapto groups, Cj-Cio-alkylthio groups, C7-Ci2-aralkyl groups, carboxyl groups, C2-C10- Alkoxycarbonyl groups, C2-Cio-carboxyalkyl groups, Ci-Qo-acylamino groups, C ^ -Cm-alkylcarbonyl groups, Q-Cjo-hydroxyalkyl groups, Cj-Cio-halogenoalkyl groups, Ci-C10-hydroxyalkoxy groups, oxo groups and optionally with at least one hydroxy group a Ci-C5-alkoxy group or mixtures thereof substituted phenyl groups are substituted; a naphthoquinonyl group, an anthryl group, a phenanthryl group, a pentalenyl group, a hepta-lenyl group, an azulenyl group, a biphenylenyl group, an as-indacenyl group, an s-indacenyl group, an acenaphthylenyl group, a phenylcarbonylphenyl group, a phenoxyphenuryl group, a benzoxyphenyl group, a phenoxyphenuryl group an isobenzofuranyl group, a benzo [b] thienyl group, an isobenzothienyl group, a thianthrenyl group, a dibenzothienyl group, a phenoxathiinyl group, an indolyl group, an 1H-indazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a phenyl group, a phenyl group, Quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, an acridinyl group, a phen-azinyl group, a phenothiazinyl group, a phen 3rd 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 648 293 25th oxazinyl group or a benzimidazolyl group, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups, hydroxyl groups, CrCi0-alkyl groups, Ci-C10-alkoxy groups, C2-C2o-dialkylamino groups, sulfoamino-5 groups, carbamoyl groups, C3-C10-N, N-dialkylcarbamoyl groups, C2-C6-N-alkylcarbamoyl groups, amino groups, C1-C10-alkylamino groups, mercapto groups, Cj-Cjo-alkylthio groups, C7-C12-aralkyl groups, carboxyl groups, C2- C10-alkoxycarbonyl groups, C2-C10-car-10 boxyalkyl groups, CrC10-acylamino groups, C2-C10-alkylcarbonyl groups, CrCi0-hydroxyalkyl groups, Q-Cio-haloalkyl groups, Ci-C10-hydroxyalkoxy groups and optionally with at least one hydroxy group, Ci-C5- Alkoxy group or mixtures thereof substituted group comprising 15 phenyl groups; a C7-C12-aralkyl group, a C9-C16-cycloalkylphenyl group, a C10-C18-cycloalkylalkylphenyl group, a C9-Cifi-cycloalkoxyphenyl group, a C9-C16-cycloalkylthiophenyl group, a 9,10-dihydroanthryl group, a 20 5, 6,7,8-tetrahydroanthryl group, 9,10-dihydrophen-anthryl group, 1,2,3,4,5,6,7,8-octahydrophenanthryl group, indenyl group, indanyl group, fluoro-renyl group, one Acenaphthenyl group, a phenylthio-phenyl 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-isochromanyl group, one 4H-chromenyl group, an indolinyl group, an isoindolinyl group, a 1,2,3,4-tetrahydroquinolyl group or a 30 1,2,3,4-tetrahydroisoquinolyl group, which groups are unsubstituted or with one or more groups from the halogen atoms, nitro groups, cyano groups , Hydroxy groups, Ci-C10-alkyl groups, CrClr alkoxy groups, C2-C2o-D ialkylamino groups I sulfoamino groups, carbamoyl groups, C3-C10-N, N-dialkylcarbamoyl groups, C2-QN-alkylcarbamoyl groups, amino groups, Q-C10-alkylamino groups, mercapto groups, Ci-C10-alkylthio groups, C7-Cioxyl-aralkyl groups C2-C10-alkoxycarbonyl groups, Q-Cio-carboxyalkyl groups, CrC10-acylamino groups, C2-C10-alkylcarbonyl groups, CrC1 (r-hydroxyalkyl groups, CrC10-haloalkyl groups, CrCi0-hydroxyalkoxy groups, oxo groups and optionally with at least one hydroxy group, Ci-C5 alkoxy group or mixtures thereof substituted group comprising 45 phenyl groups; or a phenyl group which is substituted by at least one substituent from the group consisting of alkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkoxycarbonylalkyl groups and alkoxycarbonyl- 50 alkoxy groups, which substituent has 3 to 7 carbon atoms, the substituted phenyl group optionally is substituted with at least one substituent from the group comprising methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxyl groups and halogen atoms, mean, and their pharmaceutically acceptable salts, characterized in that the N ° substituents of a ^ -substituted N2-arylsulfonyl-L-argininamide of the general 60 formula: in which R and Ar have the meanings given above and R 'and R "represent hydrogen atoms or protective groups for the guanidino group, at least one of the groups R' and R" representing a protective group for the guanidino group, split off by acidolysis or hydrogenolysis and, if appropriate, the one obtained Compound of formula I converted into the corresponding salt by reaction with a pharmaceutically acceptable acid. 2. The method according to claim 1, 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 in contact. 3. The method according to claim 1, 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. 4. A process for the preparation of N2-arylsulfonyl-L-arginine amides having a therapeutic effect, of the general formula I, in which Ar has the meanings given in claim 1 and R represents one of the following groups: COORn -N \ (CH2) nCOOR2 -N % CH- (CH3) COORj-1 2 m 5 Marg COORn \ -X C ^ 0R10 -N Z V (cHpr dr V- (crf ^ C00R " \ CH2), j in which R2, R5, Rs, R9, R10 and Rn represent a hydrogen atom and the other symbols have the meanings given in claim 1, but the meanings alkoxycarbonyl group and alkoxycarbonylalkyl group are each replaced by carboxyl group and carboxyalkyl group, and their pharmaceutically acceptable Salts, characterized in that the N ° substituents of a corresponding ^ -substituted N2-arylsulfonyl-L-argininamide of the general formula: HN hn I. r ' / -n - ch2ch2ch2chcor R "HNSOo 2 x CH2) r in which r2, r5, r8, r9, r [0 and ru represent a hydrogen atom and the other symbols have the meanings given in claim 1, but the meanings alkoxycarbonyl group and alkoxycarbonylalkyl group are each replaced by carboxyl group and carboxyalkyl group, and their pharmaceutically acceptable salts, characterized in that the N ° substituents of a corresponding ^ '- substituted N2-arylsulfonyl-L-argininamide of the general formula: hn hn I. r ' • n - c h2 c h2 ch2 chc or Rnsop ir (XX) bin inhibitor to combat thrombosis has been found to be particularly effective are the N2-dansyl-L-arginine cster or amidc (see Applicant's U.S. Patent Application No. 496,939, filed August 13, 1974, assigned to US -PS 3 978 045 5). 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-arylsulfonyI-L-arginine-amidc have an anti-thrombotic effect and, in comparison to the N2-dansyl-L-arginine esters or amides, have an even lower toxicity with the same effect.