DERIVES DE L-ARGININE N.SUP.2-SUBSTITUES ET LEURS SELS D'ADDITION ACIDE POUR USAGE PHARMACEUTIQUE

N.SUP.2-SUBSTITUTED-L-ARGININE DERIVATIVES AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
N2-substituted-L-arginine esters and amides, and the
pharmaceutically acceptable acid addition salts thereof
have been found to be effective as pharmaceutical agents
for the inhibition and suppression of thrombosis.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for preparing an N2-substituted-L-arginine
ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R is selected from the group consisting of C1-C10 alkyl,
C3-C10 cycloalky], C1-C10haloalkyl, C2-C10alkoxyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl, and R' is selected
from the group consisting of <IMG> , wherein R" and
R''' when considered separately are C1-C10 alkyl, or R" and R'''
when taken together are C1-C10 alkylene; <IMG> : <IMG> '
<IMG> ; <IMG> wherein R '''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , comprising:
esterifying an N2-substituted-L-aryinine compound of the
formula: <IMG> wherein R1 is as defined
above with an alcohol of the formula: ROH, wherein R is as defined
above.

2. The N2-substituted-L-arginine
ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R is selected from the group consisting of C1-C10 alkyl,
C3-C0 cycloalkyl, C1-C10haloalkyl, C2-C10alkixyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl, and R' is selected
from the group consisting of <IMG> , wherein R" and
R''' when considered separately are C1-C10 alkyl, or R" and R'''
when taken together are C1-C10 alkylene; <IMG> : <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , whenever prepared by the process of claim 1
or the obvlous chemical equivalent thereof.
56

3. The process for preparing the N2-substituted-L-arginine ester
of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with the process of claim 1 wherein R is selected
from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl,
C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl
and C7-C15 aralkyl and R' is selected from the group consisting
of
<IMG> , wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R''' when taken together
are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , and
wherein the N2-substituted-L-arginine compound is reacted with
alcohol in the presence of a thionyl halide.
57

4. The N2-substituted-L-arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R is selected from the group consisting of C1-C10 alkyl,
C3-C10 cycloalkyl, C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl and R' is selected from
the group consisting of
<IMG> , wherein R" and R''' when
considered separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , whenever prepared by the process of claim 3
or the obvious chemical equivalent thereof.
5. A process for preparing an N2-substituted-L-argininamide of
the formula:
<IMG>
and the pharmaceutically
acceptable acid addition salts thereof wherein R is selected
from the group consisting of (1)
<IMG> , wherein R2
58

and R3 are selected from the group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy; and (2) <IMG>, wherein Z is divalent group which
consists of two or more groups selected from methylene -CH2- and
monosubstituted methylene <IMG> (wherein R4 is selected from the
group consisting of C1-C10 alkyl and C1-C10 alkoxy), and zero
or one or more than one group selected from oxy -0-, thio-S-,
alkyl substituted imino
<IMG>
(wherein R5 is C1-C10 alkyl) and
acyl substituted imino
<IMG>
(wherein R6 is C1-C10 alkyl),
which are combined in an arbitrary order, the number of the
combined groups being up to 20; and R' is selected from the group
consisting of
<IMG> , wherein R" and R'' when
considered separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; IMG>
and <IMG> , comprising:
59

Claim 5 - cont'd ...
reacting an NG-substituted-N2-substituted-L-arginine compound
with an amine of the formula: RH, wherein R is as defined
above, thereby forming an NG-substituted-N2-substituted-
L-argininamide of the formula:
<IMG>
wherein Y and Y' are each hydrogen or a guanidino protective
group with at least one of Y and Y' being guanidino protective
group and Y" is an amino protective group; removing the
N2 protective group of said NG-substituted-N2-substituted-L-argininamide by
hydrogenoloysis or acidolysis; condensing the NG-substituted-
L-argininamide obtained with a sulfonyl halide of the formula:
R'SO2X, wherein R' is as defined above and X is halogen, thereby
forming a second NG-substituted-N2-substituted-L-argininamide of the
formula:
<IMG> , wherein Y, Y', R' and R are
as defined above; and removing the NG protective group from said
second NG-substituted-N2-substituted-L-argininamide by acidolysis
or hydrogenolysis of said second argininamide.
6. The N2-substituted-L-argininamide of formula:
<IMG>
and the pharmaceutically acceptable
acid addition . salts thereof wherein R is selected from the
group consisting of (1)
<IMG> , wherein R2

and R3 are selected from the group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy; and (2) <IMG>, wherein Z is divalent group which
consists of two or more groups seleated from methylene -CH2- and
monosubstituted methylene <IMG> (wherein R4 is selected from the
group consisting of C1-C10 alkyl and C1-C10 alkoxy), and zero
or one or more than one group selected from oxy -O-, thio-S-,
alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and
acyl substituted imino
<IMG>
(wherein R6 is C1-C10 alkyl,
which are combined in an arbitrary order, the number of the
combined groups being up to 20; and R' is selected from the group
consisting of
<IMG>
, wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R'''' when taken together
are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R"" is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , whenever prepared by the process of
claim 5 or the obvious chemical equivalent thereof.
61

7. A process for preparing an N2-substituted-L-argininamide
of the formula:
<IMG> and the pharma-
ceutically acceptable acid addition salts thereof wherein R is
selected from the group consisting of (1) <IMG> , wherein
R2 and R3 are selected from the group consisting of hydrogen,
C1-C10.alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy, and (2) <IMG>, wherein Z is a divalent group which.
consists of two or more groups selected from methylene -CH2- and
monosubstituted methylene
<IMG>
(wherein R4 is selected from
the group consisting of C1-C10 alkyl and C1-C10 alkoxy), and
zero or one or more than one group selected from oxy -O-, thio-
-S-, alkyl substituted imino
<IMG>
(wherein R5 is C1-C10 alkyl),
and acyl substituted imino
<IMG>
(wherein R6 is C1-C10 alkyl),
which are combined in an arbitrary order, the number of the
combined groups being up to 20; and R' is selected from the
group consisting of
<IMG> , wherein R" and R''' when
considered separately are C1-C10 alkyl, or R" and R''' when taken
62

together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R"" is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG> and
<IMG> , comprising:
reacting an N2-substituted-L-arginyl halide with an amine
of the formula: RH, wherein R is as defined above.
8. The N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable
acid addition salts thereof wherein R is selected from the group
consisting of (1)
<IMG> , wherein R2 and R3 are selected
from the group consisting of hydrogen, C1-C10 alkyl, C7-C15
aralkyl, and C1-C10 alkyl substituted with a group selected
from C1-C10.alkoxy, C2-C10 alkoxy carbonyl and carboxy, and
(2) <IMG>, wherein Z is a divalent group which consists of
two or more groups selected from methylene -CH2- and monosubstituted
methylene
<IMG>
(wherein R4 is selected from the group consisting
of C1-C10 alkyl and C1-C10 alkoxy), and zero or one or more than
one group selected from oxy -O-, thio-S-, alkyl substituted
imino
<IMG>
(wherein R5 is C1-C10 alkyl) and acyl substituted
63

imino
<IMG>
(wherein R6 is C1-C10 alkyl), which are combined
in an arbitrary order, the number of the combined groups being
up to 20; and R' is selected from the group consisting of
<IMG> , wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R"" is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , whenever prepared by the process of
claim 7 or the obvious chemical equivalent thereof.
9. A process for preparing an N2-substituted-L-argininamide
of the formula:
<IMG>
and the pharmaceu-
tically.acceptable acid addition salts thereof wherein R is
selected from the group consisting of (1)
<IMG> , wherein R2
and R3 are selected from the group consisting of hydrogen,
C1-Cl0 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy; and (2) <IMG>, wherein Z is a divalent group which
64

consists of two or more groups selected from methylene -CH2-
and monosubstituted methylene
<IMG>
(wherein R4 is selected from
the group consisting of C1-C10 alkyl and C1-C10 alkoxy), and
zero or, one or more than one group selected from oxy -O-, thio-
-S-, alkyl substituted imino
<IMG>
(wherein R5 is C1-C10 alkyl)
and acyl substituted imino
<IMG>
(wherein R6 is C1-C10 alkyl),
which are combined in an.arbitrary order, the number of the
combined groups being up to 20; and R' is selected from the group
consisting of
<IMG> , wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG>> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , comprising:
reacting an N2-substituted-L-ornithinamide of the formula:
<IMG> , wherein R and R' are as defined above with a
guanidylating agent.
10. The N2-substituted-L-argininamide of the formula:
<IMG>
and the pharmaceutically acceptable
acid addition salts thereof wherein R is selected from the group
consisting of (1)
<IMG> , wherein R2 and R3 are selected

from the group consisting of hydrogen, C1-C10 alkyl, C7-C15 ar-
alkyl and C1-C10 alkyl substituted with a group selected from
C1-C10 alkoxy, C2-C10 alkoxycarbonyl and carboxy; and (2)
<IMG>, wherein Z is a divalent group which consists of two or
more groups selected from methylene -CH2- and monosubstituted
methylene
<IMG>
(wherein R4 is selected from the group
consisting of C1-C10 alkyl and C1-C10 alkoxy),
more than one group selected from oxy -O-, thio-S-, alkyl
substituted imino
<IMG>
(wherein R5 is C1-C10 alkyl) and
acyl substituted imino
<IMG>
(wherein R6 is C1l-C10 alkyl),
which are combined in an arbitrary order, the number of the
combined groups being up to 20; and R' is selected from the group
consisting of <IMG> , wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy <IMG> ; <IMG> ; <IMG>
and <IMG> , whenever prepared by the process of
claim 9 or the obvious chemical equivalent thereof.
66

11. A process for preparing an N2-substituted-L-argininamide
of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof
wherein R is selected from the group consisting of (1) <IMG>,
wherein R2 and R3 are selected from the group consisting of
hydrogen, C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substi-
tuted with a group selected from C1-C10 alkoxy, C2-C10 alkoxy-
carbonyl and carboxy; and (2) <IMG>, wherein Z is a divalent
group which consists of two or more groups selected from methy-
lene -CH2- and monosubstituted methylene
<IMG>
(wherein R4 is
selected from the group consisting of C1-C10 alkyl and C1-C10
alkoxy), and zero or, one or more than one group selected.from
oxy -O-, thio-S-, alkyl: substituted imino
<IMG>
(wherein R5 is
C1-C10 alkyl) and acyl substituted imino
<IMG> (wherein R6 is
C1-C10 alkyl), which are combined in an arbitrary order, the
number of the combined groups being up to 20; and R' is selected
from the group consisting of
<IMG> , wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> comprising:
67

reacting an N2-substituted-L-arginine ester of the formula:
<IMG> , wherein R7 is a hydrocarbon radical
with an am ne of the formula: RH wherein R is as defined above.
12. The N2-substituted-L-argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof
wherein R is selected from the group consisting of (1) <IMG>,
wherein R2 and R3 are selected from the group consisting of
hydrogen, C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substi-
tuted with a group selected from C1-C10 alkoxy, C2-C10 alkoxy-
carbonyl and carboxy; and (2) <IMG>, wherein Z is a divalent
group which consists of two or more groups selected from methy-
lene -CH2- and monosubstituted methylene
<IMG>
(wherein R4 is
selected from the group consisting of C1-C10 alkyl and C1-C10
alkoxy), and zero or, one or more than one group selected from
oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is
C1-C10 alkyl) and acyl substituted imino
<IMG>
(wherein R6 is
C1-C10 alkyl), which are combined in an arbitrary order, the
number of the combined groups being up to 20; and R' is selected
from the group consisting of
<IMG> , wherein R" and R''' when considered
68

separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG>
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , whenever prepared by the process of
claim 11 or the obvious chemical equivalent thereof.
13. A process for preparing an N2-substituted-L-arginine ester
or amide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R is selected from the group consisting of (1) -OR1,
wherein R1 is selected from the group consisting of C1-C10 alkyl,
C3-C10 cycloalkyl, C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl; (2)
<IMG>, wherein
R2 and R3 are selected from the. group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected form CC10 alkoxy, C2-C10 alkoxycarbonyl and
carboxyî and (3) <IMG>, wherein Z is a divalent group which
consists of two or more groups selected from methylene -CH2- and
monosubstituted methylene
<IMG>
(wherein R4 is selected from the
group consisting of C1-C10 alkyl and C1-C10 alkoxy), and zero or,
69

one or more than one group selected from oxy -O-, thio-S-,
alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and
acyl substituted imino
<IMG>
(wherein R6 is C1-C10 alkyl),
which are combined in an arbitrary order, the number of the
combined groups being up to 20; and R' is selected from the
group consisting of
<IMG> , wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , comprising:
reacting an L-arginine exteror amide of the formula:
<IMG> , wherein R is as defined above,
with a sulfonyl halide of the formula: R'SO2X, wherein R' is as
defined above and X is halogen.

14. The N2-substituted-L-arginine ester
or amide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R is selected from the group consisting of (1) -OR1,
wherein R1 is selected from the group consisting of C1-C10 alkyl,
C3-C10 cycloalkyl, C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl; (2)
<IMG> , wherein
R2 and R3 are selected from the group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy; and (3) <IMG>, wherein Z is a divalent group which
consists of two or more groups selected from methylene -CH2- and
monosubstituted methylene
<IMG>
(wherein R4 is selected from the
group consisting of C1-C10 alkyl and C1-C10 alkoxy), and zero or,
71

(claim 14 cont'd)
one or more than one group selected from oxy -O-, thio-S-,
alkyl substituted imino
<IMG>
(wherein R5 is C1-C10 alkyl) and
acyl substituted imino
<IMG>
(wherein R6 is C1-C10 alkyl),
which are combined in an arbitrary order, the number of the
combined groups being up to 20; and R' is selected from the
group consisting of
<IMG> , wherein R" and R''' when considered
separately are C1-C10 alkyl, or R" and R''' when taken
together are C1-C10 alkylene; <IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> , whenever prepared by the process of
claim 13 or the obvious chemical equivalent thereof.
72

15. The process for preparing an N2-substituted-L-arginine
ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 1, wherein R is selected from the group
consisting of C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 haloalkyl,
C2-C10 alkoxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl and C7-C15
aralkyl; and R' is
<IMG>
wherein R'' and R''' when considered separately are C1-C10 alkyl,
or R'' and R''' when taken together are C1-C10 alkylene.
16. An N2-substituted-L-arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R is selected from the group consisting of C1-C10 alkyl,
C1-C10 cycloalkyl, C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl; and R' is
<IMG>
wherein R'' and R''' when considered separately are C1-C10 alkyl,
or R'' and R''' when taken together are C1-C10 alkylene, whenever
produced by the process of claim 15 or an obvious equivalent
thereof.
17. The process for preparing an N2-substituted-L-arginine
ester of the formula:
<IMG>
73

and the pharmaceutically acceptable acld addition salts thereof,
in accordance with claim 3, wherein R is selected from the group
consisting of C1 -C10 alkyl, C3 -C10 cycloalkyl, C1 -C10 haloalkyl,
C2 -C10 alkoxyalkyl, C2 -C10 alkenyl, C2 -C10 alkynyl and C7 -C15
aralkyl; and R' is
<IMG>
wherein R" and R''' when considered separately are C1 -C10 alkyl,
or R" and R''' when taken together are C1 -C10 alkylene.
18. An N -substituted-L-arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof, wherein
R is selected from the group consisting of C1 -C10 alkyl, C3 -C10
cycloalkyl, C1 -C10 haloalkyl, C2 -C10 alkoxyalkyl, C2 -C10 alkenyl,
C2 -C10 alkynyl and C7 -C15 aralkyl; and R' is
<IMG>
wherein R" and R''' when considered separately are C1 -C10 alkyl, or
R" and R''' when taken together are C1 -C10 alkylene, whenever produced
by the process of claim 17 or an obvious chemical equivalent thereof.
l9. The process forpreparing an N2-substituted-L-
arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 13, wherein R is OR1 and R1 is
74

selected from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl,
C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl
and C7-C15 aralkyl; and R' is
<IMG>
wherein R" and R''' when considered separately are C1-C10 alkyl, or R" and
R''' when taken together are C1-C10 alkylene.
20. An N2-substituted-L-arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof wherein R is
OR1 and R1 is selected from the group consisting of C1-C10
alkyl, C3-C10 cycloalkyl, C1-C10 haloalkyl, C2-C10 alkoxyalkyl,
C2-C10 alkenyl, C2-C10alkynyl and, C7-C15 aralkyl; and R' is
<IMG>
wherein R" and R''' when considered separately are C1-C10 alkyl, or R"
and R''' when taken together are C1-C10 alkylene, whenever produced by the
process of claim 19 or an obvious chemical equlvalent thereof.
21. The processfor preparing an N2-substituted-L-
arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance. with claim 15, wherein R is selected from the group

consisting of C1-C8 alkyl, cyclohexyl, C2-C6 omega-chloroalkyl,
C2-C6 omega-alkoxyalkyl, C3-C6 alkenyl, C2-C6 alkynyl and C7-C9
aralkyl; and R' is
<IMG>
wherein R" and R''' when considered separately are C1-C5 alkyl, or R"
and R''' when taken together are C1-C5 alkylene.
22. An N2-substituted -L-arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof
wherein R is selected from the group consisting of C1-C8 alkyl,
cyclohexyl, C2-C6 omega-chloroalkyl, C2-C6 omega-alkoxyalkyl,
C3-C6 alkenyl, C2-C6 alkynyl and C7-C9 aralkyl; and R' is
<IMG>
wherein R" and R''' when considered separately are C1-C5 alkyl, or R" and
R''' when taken together are C1-C5 alkylene, whenever produced by the process
of claim 2 or an obvious chemical equivalent thereof.
23. The process for preparing an N2-substituted-L-
arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
76

in accordance with claim 17, wherein R is selected from the group
consisting of C1-C8 alkyl, cyclohexyl, C2-C6 omega-chloroalkyl,
C2-C6 omega-alkoxyalkyl, C3-C6 alkenyl, C2-C6 alkynyl and C7-C9
aralkyl, and R' is
<IMG>
wherein R' and R''' when considered separately are C1-C5 alkyl, or R'' and
R''' when taken together are C1-C5 alkylene.
24. An N2-substituted-L-arginine ester of the formula:
<IMG> and the pharmaceutically acceptab1e acid
addition salts thereof wherein R is selected from the group consisting of
C1-C8 alkyl, cyclohexyl, C2-C6 omega-chloroalkyl, C2-C6 omega-
alkoxyalkyl, C3-C6 alkenyl, C2-C6 alkynlyl and C7-C9 aralkyl; and
R' is
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or R''
and R''' when taken together are C1-C5 alkylene, whenever produced by
the process of claim 23 or an obvious chemical equivalent thereof.
25. The process for preparing an N2-substituted-L-
arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 19, wherein R' is selected from the group
77

consisting of C1-C8 alkyl, cyclohexyl, C2-C6 omega-chloroalkyl,
C2-C6 omega-alkoxyalkyl, C3-C6 alkenyl, C2-C6 alkynyl and C7-C9
aralkyl ; and R' is
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or R''
and R''' when taken together are C1-C5 alkylene.
26. An N2-substituted-L-arginine ester of the formula:
<IMG> and the pharmaceutically acceptable
acid addition salts thereof, wherein R' is selected from
the group consisting of C1-C8 alkyl, cyclohexyl, C2-C6 omega-chloroalkyl,
C2-C6 Q-alkoxyalkyl, C3-C6 alkenyl, C2-C6 alkynyl and C7-C9 aralkyl;
and R' is
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or R''
and R''' when taken together are C1-C5 alkylene, whenever produced by the
process of claim 25 or an obvious chemical equivalent thereof.
27. The process forpreparing an N2-substituted-L-
arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 21, wherein R is selected from the group
78

consisting of propyl, butyl, hexyl, cyclohexyl, 3-chloropropyl,
2-methoxyethyl, 2-butenyl, 3-butynyl and benzyl, and R' is
selected from the group consisting of
<IMG> , <IMG> and <IMG>
28. An N2-substituted-L-arginine ester of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from the group consisting
of propyl, but yl, hexyl, cyclohexyl, 3-chloropropyl, 2-methoxy-
eth yl, 2-butenyl, 3-butynyl and benzyl; and R' is selected
from the group consisting of
<IMG> , <IMG> and <IMG>
whenever produced by the process of claim 27 or an obvious chemical
equivalent thereof.
29. The process for preparing an N2-substituted-L-
arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 23, wherein R is selected from the group
79

consisting of propyl, butyl, hexyl, cyclohexyl, 3-chloropropyl,
2-methoxyethyl, 2-butenyl, 3-butynyl and benzyl; and R' is
selected from the group consisting of
<IMG> , <IMG> and <IMG>
30. An N2-substituted-L-arginine ester of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is selected from the group consisting of prop yl,
butyl, hexyl, cyclohexyl, 3-chloropropyl, 2-methoxyethyl, 2-
butenyl, 3-butynyl and benzyl; and R' is selected from the group
consisting of
<IMG> , <IMG> and <IMG>,
whenever produced by the process of claim 29 or an obvious chemical
equivalent thereof.
31. The process for preparing an N2-substituted-L-
arginine ester of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts
thereof, in accordance with claim 25, wherein R is
OR1 and R1 is selected from the group

consisting of propyl, butyl, hexyl, cyclohexyl, 3-chloropropyl,
2-methoxyethyl, 2-butenyl, 3-butynyl and benzyl; and R' is
selected from the group consisting of
<IMG> , <IMG> and <IMG>
32. An N2-substituted-L-arginine ester of the formula
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is OR1 and R1 is selected from the group
consisting of propyl, butyl, hexyl, cyclohexyl, 3-chloropropyl,
2-methoxyethyl, 2-butenyl, 3-butynyl and benzyl; and R' is
selected from the group consisting of
<IMG> , <IMG> and <IMG>
whenever produced by the process of claim 31 or an obvious chemical
equivalent thereof.
33. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 5, wherein R is
<IMG>
wherein R2 and R3 are selected from the group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with a group
selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and carboxy and R' is as
defined in claim 5.
81

34. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof wherein R is <IMG> wherein R2 and R3
are selected from the group consisting of hydrogen, C1-C10 alkyl, C7-C15
aralkyl, and C1-C10 alkyl substituted with a group selected from C1-C10
alkoxy, C2-C10 alkoxycarbonyl and carboxy and R' is as defined in
claim 33, whenever produced by the process of claim 33 or an
obvious chemical equivalent thereof.
35. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 7, wherein R is
<IMG> wherein R2 and
R3 are selected from the group consisting of hydrogen, C1-C10 alkyl,
C7-C15 aralkyl, and C1-C10 alkyl substituted with a group selected from
C1-C10 alkoxy, C2-C10 alkoxycarbonyl and carboxy and R' is as defined
in claim 7.
82

36. An N2 substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof wherein R is <IMG> wherein R2 and R3 are
selected from the group consisting of hydrogen, C1-C10 alkyl, C7-C15
aralkyl, and C1-C10 alkyl substituted with a group selected from C1-C10
alkoxy, C2-C10 alkoxycarbonyl and carboxy, and R' is as defined in
claim 35, whenever prepared by the process of claim 35 or an
obvious chemical equivalent thereof.
37. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 9, wherein R is
<IMG> wherein R2
and R3 are selected from the group consisting of hydrogen, C1-C10 alkyl,
C7-C15 aralkyl, and C1-C10 alkyl substituted with a group selected from
C1-C10 alkoxy, C2-C10 alkoxycarbonyl and carboxy and R' is as defined in
claim 9.
38. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof wherein R is <IMG> wherein R2 and R3 are selected from
the group consisting of hydrogen, C1-C10 alkyl, C7-C15 aralkyl, and C1-C10
alkyl substituted with a group selected from C1-C10 alkoxy, C2-C10 alkoxy-
carbonyl and carboxy and R' is as defined in claim 37 whenever
produced by the process of claim 37 or an obvious chemical
83

equivalent thereof.
39. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 11, wherein R is
<IMG> wherein R2
and R3 are selected from the group consisting of hydrogen, C1-C10 alkyl,
C7-C15 aralkyl, and C1-C10 alkyl substituted with a group selected from
C1-C10 alkoxy, C2-C10 alkoxycarbonyl and carboxy and R' is as defined
in claim 11.
40. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof wherein R is <IMG> wherein R2 and R3 are selected from
the group consisting of hydrogen, C1-C10 alkyl, C7-C15 aralkyl, and C1-C10
alkyl substituted with a group selected from C1-C10 alkoxy, C2-C10 alkoxy-
carbonyl and carboxy and R' is as defined in claim 39 whenever
produced by the process of claim 39 or an obvious chemical
equivalent thereof.
41. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 13, wherein R is
84

<IMG> wherein R2 and R3 are selected from the group consisting
of hydrogen, C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and carboxy and
R' is as defined in claim 13.
42. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is <IMG> wherein R2 and R3 are selected from
group consisting of hydrogen, C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl
substituted with a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl
and carboxy and R' is as defined in claim 41, whenever produced
by the process of claim 41 or an obvious chemical equivalent
thereof.
43. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 33, wherein R is selected from the group
consisting of C1-C9 alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8 omega-
alkoxycarbonylalkylamino, C7-C10 aralkylamino and C2-C10 dialkylamino;
and R' is selected from the group consisting of
<IMG>
wherein R'' and R''' when
considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG>; 85

<IMG> ; <IMG>
wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> .
44. An N2-substituted-L-argininamide of the formula:
and the pharmaceutically acceptable acid addition
<IMG>
salts thereof, wherein R is selected from the group consisting of C1-C9
alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8 omega-alkoxycarbonyl-
alkylamino, C7-C10 aralkylamino and C2-C10 dialkylamino; and R' is
selected from the group consisting of
<IMG> wherein R'' and R''' when
considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
<IMG> ;<IMG> wherein R'''' is C1-C5 alkoxy,
86

<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 43 or an
obvious chemical equivalent thereof.
45. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 35, wherein R is selected from the group
consisting of C1-C9 alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8
omega-alkoxycarbonylalkylamino, C7-C10 aralkylamino and C2-C10 dialkylamino;
and R' is selected from the group consisting of
<IMG>
wherein R'' and R''' when
considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> .
87

46. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is selected from the group consisting of C1-C9
alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C6 omega-alkoxycarbonylalkylamino,
C7-C10 aralkylamino and C2-C10 dialkylamino; and R' is selected from the
group consisting of
<IMG> wherein R'' and R''' when
considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> ; whenever produced by the process of claim 45
or an obvious chemical equivalent thereof.
88

47. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 37, wherein R is selected from the group
consisting of C1-C9 alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8 omega-
alkoxycarbonylalkylamino, C7-C10 aralkylamino and C2-C10 dialkylamino;
and R' is selected from the group consisting of
<IMG> wherein R'' and R''' when
considered separately are C1-C5 alkyl; or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> .
48. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is selected from the group consisting of C1-C9
89

alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8 omega-alkoxycarbonylalkylamino,
C7-C10 aralkylamino and C2-C10 dialkylamino; and R' is selected from the
group consisting of
<IMG> wherein R'' and R''' when
considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 47 or an
obvious chemical equivalent thereof.
49. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 39, wherein R is selected from the group
consisting of C1-C9 alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8
omega-alkoxycarbonylalkylamino, C7-C10 aralkylamino and C2-C10 dialkylamino;
and R' is selected from the group consisting of
<IMG> wherein R'' and R''' when

considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> .
50. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is selected from the group consisting of C1-C9
alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8 omega-alkoxycarbonylalkyl-
amino, C7-C10 aralkylamino and C2-C10 dialkylamino; and R' is selected
from the group consisting of
<IMG> wherein R'' and R''' when
91

considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
<IMG> ;<IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 49
or an obvious chemical-equivalent thereof.
51. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 41, wherein R is selected from the group
consisting of C1-C9 alkylamino, C2-C6 omega-alkoxyalkylamino,
C3-C8 omega-alkoxycarbonylalkylamino, C7-C10 aralkyl-amino and
C2-C10 dialkylamino: and R' is selected. from the group consisting
of
<IMG>
wherein R'' and R''' when
considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
92

<IMG> ; <IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> .
52. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is selected from the group consisting of C1-C9
alkylamino, C2-C6 omega-alkoxyalkylamino, C3-C8 omega-alkoxycarbonylalkyl-
amino, C7-C10 aralkylamino and C2-C10 dialkylamino; and R' is selected
from the group consisting of
<IMG> wherein R'' and R''' when
considered separately are C1-C5 alkyl, or R'' and R''' when taken
together are C1-C5 alkylene;
<IMG> ; <IMG> ;
93

<IMG> ; <IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 51
or an obvious chemical equivalent thereof.
53. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 43, wherein R is selected from the group
consisting of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino,
2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R'
is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> .
94

54. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof wherein R is selected from the group consisting
of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-
ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is
selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> , whenever produced by the process of claim 53
or an obvious chemical equivalent thereof.
55. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 45, wherein R is selected from the group
consisting of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino,
2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R'
is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,

<IMG> , <IMG> , <IMG> , <IMG>
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> .
56. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is selected from the group consisting of butylamino,
2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino,
benzylamino and N-methyl-N-butylamino; R' is selected from the group con-
sisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
and <IMG> , whenever produced by the process of claim 55
or an obvious chemical equivalent thereof.
96

57. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 47, wherein R is selected from the group
consisting of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino,
2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is
selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> .
58. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from the group consisting
of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-ethoxy-
carbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is selected
from the group consisting of
97

<IMG> , <IMG> , <IMG>,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> , whenever produced by the process of claim 57
or an obvious chemical equivalent thereof.
59. The process for preparing an N -substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 49, wherein R is selected from the group
consisting of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino,
2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R'
is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> .
98

60. An N2-substituted-L-argininamide of the formula:
and the pharmaceutically acceptable acid
<IMG>
addition salts thereof, wherein R is selected from the group consisting
of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-ethoxy-
carbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is selected
from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> , whenever produced by the process of claim 59
or an obvious chemical equivalent thereof.
61. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salt thereof,
in accordance with claim 51, wherein R is selected from the group
consisting of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino,
2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is
selected from the group consisting of
<IMG> , <IMG> , <IMG> .
99

<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> .
62. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from the group consisting of
butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-ethoxy-
carbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is selected
from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG>
and <IMG> whenever prepared by the process of
claim 61 or an obvious chemical equivalent thereof.
100

63. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 5, wherein R is <IMG>, wherein Z is a
divalent group which consists of two or more groups selected
from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20, and R'
is as defined in claim 5.
101

64. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is
<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from ox -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20, and R'
is as defined in claim 63, whenever prepared by the process of
claim 63 or an obvious chemical equivalent thereof.
65. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 7, wherein R is
102

<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20, and R'
is as defined in claim 7.
66. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is
<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -0-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20, and R'
is as defined in claim 65, whenever produced by the process of
claim 65 or an obvious chemical equivalent thereof.
103

67. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 9, wherein R is
<IMG> wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20, and R'
is as defined in claim 9.
68. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof wherein R is
<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
104

<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20 and R'
is as defined in claim 67 whenever produced by the process of
claim 67 or an obvious chemical equivalent thereof.
69. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 11, wherein R is
<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20 and R'
is as defined in claim 11.
105

70. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is
<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20, and R'
is as defined in claim 69, whenever produced by the process of
claim 69 or an obvious chemical equivalent thereof.
71. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 13, wherein R is
<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
106

<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20 and R'
is as defined in claim 13.
72. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is
<IMG>, wherein Z is a divalent group which consists of two or more
groups selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the group consisting of
C1-C10 alkyl and C1-C10 alkoxy), and zero or, one or more than one
group selected from oxy -O-, thio-S-, alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and acyl substituted
imino
<IMG> (wherein R6 is C1-C10 alkyl), which are combined in an
arbitrary order, the number of the combined groups being up to 20, and R'
is as defined in claim 71, whenever prepared by the process of
claim 71 or an obvious chemical equivalent thereof.
73. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 63, wherein R is selected from
107

the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneinlinyl substituted with a group selected from
C1-C5 alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin -n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> .
74. An N2-substituted-L-argininamide of the formula:
and the pharmaceutically acceptable acid
<IMG>
108

addition salts thereof, wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 73 or an
obvious chemical equivalent thereof.
75. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 65, wherein R is selected from
109

the group consisting of C3C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> .
76. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
110

an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alky1 and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG>, whenever prepared by the process of claim 75 or an
obvious chemical equivalent thereof.
77. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 67, wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
111

selected from the group consisting of
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> .
78. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid addition
salts thereof, wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
112

selected from the group consisting of
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 77 or an
obvious chemical equivalent thereof.
79. The process for preparing all N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 69, wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; 1-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
113

wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> .
80. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l,n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-1, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
114

wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy,
<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 79 or an
obvious chemical equivalent thereof.
81. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 71, wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected fronl C1-C5alkyl and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
wherein R'' and R''' when considered separately are C1-C5 alkyl, or
115

R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> .
82. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from
the group consisting of C3-C10N, N-polymethyleneiminyl; C3-C10
N,N-polymethyleneiminyl substituted with a group selected from
C1-C5alkyl and C1-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl, wherein n is
an integer of 2, 3 or 4; tetrahydro-l, n-thiazin-n-yl, wherein
n is an integer of 2, 3 or 4; l-piperazinyl substituted with
a group selected from C1-C5alkyl and C1-C5acyl; and R' is
selected from the group consisting of
<IMG>
116

wherein R'' and R''' when considered separately are C1-C5 alkyl, or
R'' and R''' when taken together are C1-C5
alkylene; <IMG> ; <IMG> ; <IMG> ;
<IMG> wherein R'''' is C1-C5 alkoxy;
<IMG> ; <IMG> ; <IMG> and
<IMG> , whenever produced by the process of claim 81 or an
obvious chemical equivalent thereof.
83. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 73, wherein R is selected from
the group consisting of piperidino, hexamethyleiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
l-piperazinyl; and R' is selected from the group consisting of
117

<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
84. An N2-substituted-L-argininamide of the formula
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
l-piperaziny1; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> when-
ever produced by the process of claim 83 or an obvious chemical
equivalent thereof.
118

85. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 75, wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
119

l-piperazinyl; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
86. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable
acid addition salts thereof,wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-l-piperazinyl and 4-acetyl-
l-piperazinyl; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
120

<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
whenever produced by the process of claim 85 or an obvious chemical
equivalent thereof.
87.. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 77, wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
l-piperazinyl; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
121

88. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
l-piperazinyl; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
whenever produced by the process of claim 87 or an obvious chemical
equivalent thereof.
89. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 79, wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4 methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
l-piperazinyl; and R' is selected from the group consisting of
122

<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
90. An N2-substituted-L-argininamide of the formula:
<IMG> and the pharmaceutically acceptable acid
addition salts thereof, wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
l-piperazinyl; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
123

<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
whenever produced by the process of claim 89 or an obvious chemical
equivalent thereof.
91. The process for preparing an N2-substituted-L-
argininamide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
in accordance with claim 81, wherein R is selected from
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
1-piperazinyl; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
92. An N2-substituted-L-argininamide of the formula:
and the pharmaceutically acceptable acid
<IMG>
addition salts thereof, wherein R is selected from
124

(claim 92 cont'd)
the group consisting of piperidino, hexamethyleneiminyl, 4-methyl-
piperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,
tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl and 4-acetyl-
l-piperazinyl; and R' is selected from the group consisting of
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and <IMG> .
whenever produced by the process of claim 91 or an obvious chemical
equivalent thereof.
125

93. A process for preparing an N2-substituted-L-arginine
ester or amide of the formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R' is selected from the group consisting of
<IMG> , wherein R" and
R''' when considered separately are C1-C10 alkyl, or R'' and R'''
when taken together are C1-C10 alkylene;
<IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R"" is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> ,
and R is selected from the groups represented by the formula
(1) -ORl'
(2) <IMG> ; or
(3) <IMG>
wherein
- R1 is selected from the group consisting of C1-C10 alkyl,
C3-C10 cycloalkyl, C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl;
126

(claim 93 cont'd - Page 2)
- R2 and R3 are selected from the group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy; and
- Z is a divalent group which consists of two or more groups
selected from methylene -CH2- and-monosubstituted methylene
<IMG> (wherein R4 is selected from the
group consisting of C1-C10 alkyl and C1-C10 alkoxy), and zero or,
one or more than one group selected from oxy -O-, thio-S-,
alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and
acyl substituted imino
<IMG> (wherein R6 is C1-C10 alkyl),
which are combined in an arbitrary order, the number of the
combined groups being up to 20;
comprising:
(a) when R is
(1) -OR1 wherein R1 is as defined above;
and R' is as defined above
- esterifying an N2-substituted-L-arginine compound of the
formula:
<IMG> wherein R' is as defined
above with an alcohol of the formula: R1OH, wherein R1 is as
selected and defined in (1) above;
(b) when R is selected from the group consisting of
127

(claim 93 cont'd - Page 3)
(2) <IMG> wherein R2 and R3 are as defined above,
and
(3) <IMG> wherein Z is as defined above; and R' is as
defined above:
- reacting an NG-substituted-N2-substituted-L-arginine compound
with an amine of the formula: RH, wherein R is as defined above
in (2) and (3), thereby forming an NG-substituted-N2-
substituted-L-argininamide of the formula:
<IMG>
wherein Y and Y' are each hydrogen or a guanidino protective
group with at least one of Y and Y' being guanidino protective
group and Y" is an amino protective group;
removing the N2 protective group of said NG-substituted-
-N2-substituted-L-argininamide by hydrogenolysis or acidolysis;
condensing the NG-substituted-L-argininamide obtained
with a sulfonyl halide or the formula: R'SO2X, wherein R' is as
defined above and X is halogen, thereby forming a second
NG-substituted-N2-substituted-L-argininamide of the formula:
<IMG> , wherein Y, Y' and R' are as
defined above and R is as selected and defined in (2) and (3)
above; and
128

(claim 93 cont'd - Page 4)
removing the NG protective group from said second NG-
-substituted-N2-substituted-L-argininamide by acidolysis or
hydrogenolysis of said second argininamide;
(c) when R is selected from the group consisting of
(2) <IMG> wherein R2 and R3 are as defined above,
and
(3) <IMG> wherein Z is as defined above; and R' is as
defined above:
-reacting an N2-substituted-L-arginyl halide with an
amine of the formula: RH, wherein R is as selected and defined
in (2) and (3) above;
(d) when R is selected from the group consisting of
(2) <IMG> wherein R2 and R3 are as defined above,
and
(3) <IMG> wherein Z is as defined above; and R' is as
defined above:
- reacting an N2-substituted-L-ornithinamide of the formula:
<IMG> , wherein R is as selected and defined in (2)
and (3) above and R' is as defined above with a guanidylating
agent;
(e) when R is selected from the group consisting of
(2) <IMG> wherein R2 and R3 are as defined above,
and
(3) <IMG> wherein Z is as defined above; and R' is as
defined above:
129

(claim 93 cont'd - Page 5)
- reacting an N2-substituted-L-arginine ester of the formula:
<IMG> , wherein R7 is a hydrocarbon radical
with an amine of the formula: RH wherein R is as selected and
defined in (2) and (3) above;
and
(f) when R is selected from the group of
(1) -OR1 wherein R1 is as defined above;
(2) <IMG> wherein R2 and R3 are as defined above,
and
(3) <IMG> wherein Z is as defined above; and R' is as
defined above:
reacting an L-arginine ester or amide of the formula:
<IMG> , wherein R is as selected and
defined in (1), (2) and (3) above, with a sulfonyl halide of the
formula: R'SO2X, wherein R' is as defined above and X is halogen.
130

94. An N2-substituted-L-arginine ester or amide of the
formula:
<IMG>
and the pharmaceutically acceptable acid addition salts thereof,
wherein R' is selected from the group consisting of
<IMG> , wherein R" and
R''' when considered separately are C1-C10 alkyl, or R" and R'''
when taken together are C1-C10 alkylene;
<IMG> ; <IMG> ;
<IMG> ; <IMG> wherein R"" is C1-C10
alkoxy; <IMG> ; <IMG> ; <IMG>
and <IMG> ,
and R is selected from the groups represented by the formula
(1) -OR1;
(2) <IMG> ; or
(3) <IMG>
wherein
- R1 is selected from the group consisting of C1-C10 alkyl,
C3-C10 cycloalkyl, C1-C10 haloalkyl, C2-C10 alkoxyalkyl, C2-C10
alkenyl, C2-C10 alkynyl and C7-C15 aralkyl;
131

(claim 94 cont'd)
- R2 and R3 are selected from the group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and C1-C10 alkyl substituted with
a group selected from C1-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy; and
- Z is a divalent group which consists of two or more groups
selected from methylene -CH2- and monosubstituted methylene
<IMG> (wherein R4 is selected from the
group consisting of C1-C10 alkyl and C1-C10 alkoxy), and zero or,
one or more than one group selected from oxy-O-, thio-S-,
alkyl substituted imino
<IMG> (wherein R5 is C1-C10 alkyl) and
acyl substituted imino
<IMG> (wherein R6 is C1-C10 alkyl),
which are combined in an arbitrary order, the number of the
combined groups being up to 20; whenever prepared by the process
of claim 93 or an obvious chemical equivalent thereof.
132

Description

N -SUBSTITUTED-L-ARGININE DERIv~TIvEs AND THE PHARMACEUTICALLY
ACCEPTABLE ACID ADDITION S~LTS THEREoF
_ .
BACKGROIJND OF TEIE INVENTIO_
Field of the Invention
This invention relates to the discovery of certain new and use-
ful N2-substituted-L-arginine derivatives and the pharmaceuti-
cally acceptable acid addition salts thereof, which are of es-
pecial value in view of their outstanding antithrombotic
properties.
Description of the Prior Art
In the past, there have been many attempts to obtain new and im-
proved agents for the treatment of thrombosis. Of these,
N2-(p-tolylsulfonyl)-L-arginine esters are known to be effective
in dissolving blood clots. (U. S. Pat. No. 3,622,615, issued
Nov. 23, 1971)
However, there is a continuing need for a highly specific inhi-
bitor of thrombin for the control of thrombosis. Accordingly,
we have discovered novel N2-substituted-L-arginine derivatives
which exhibit antithrombotic activity.
SUMMARY OF THE INVENTION
The invention comprehends N2-substituted-L-arginine ester or
amide compounds and the process of preparing such compounds of
the formula (I):
HN
/ C-NH(CH2)3-CHCR (I)
H2N
HN- SO 2
R'
and the pharmaceutically acceptable acid addition salts thereof,
wherein R' is selected from the group consisting of
~ OR , wherein R" and
R''' when considered separately are Cl-C10 alkyl, or R" and R'''
-1- ~

851
when taken together are Cl-C10 alkylene;
~ ~ ; ~ Rn~ wherein R"" is Cl-C10
alkoxy; ~ ; ~ ;
and ~ ~
and R is selected from the groups represented by the formula
(1) -ORl;
/R2
(2) - ~ ; or
R3
~3) -N Z
wherein
Rl is selected from the group consisting of Cl-C10 alkyl,
C3-C10 cycloal~yl, Cl C10 halalkYl~ C2-C10 alkXYalkYl~ C2-C10
alkonyl, C2-C10 alkynyl and C7 Cls Y
R2 and R3 are Yelocted from the group consisting of hydrogen,
C1-C10 alkyl, C7-C15 aralkyl, and Cl-C10 alkyl substituted with
a group selected from Cl-C10 alkoxy, C2-C10 alkoxycarbonyl and
carboxy; and
Z is a divalent group which consists of two or more groups
selected from methylene -CH2- and monosubstituted methylene
. 14
-Cl- (wherein R4 is selected from the
group consisting of Cl-C10 alkyl and Cl-C10 alkoxy), and zero or,
one or more than one group selected from oxy -O-, thio-S-,
alkyl substituted imino R5
-N- (wherein R5 i9 Cl-C10 alkyl) and
-2-

6~ilS3~
acyl ~ubstituted imino O-C-R5
-N- (wherein R6 is Cl-C10 alkyl),
which are combined in an arbitrary order, the numbex of the
co~ined groups being up to 20.
When R in Formula (I) is
(1) -ORl wherein Rl is as defined above;
and R' is as defined above, the process comprises
esterifying an N2-substituted-L-arginine compound of the
formula: HN~
/ C NH(cH2)3-cHco2H
H2N ¦ wherein R' is as def~l
HN-S02R '
above with an alcohol of the formula: RlOH, wherein Rl is as
selected and defined in (1) above.
When R in Formula (I) is selected ~rom the group consisting of
~2) -N \ wherein R2 and R3 are as defined above,
R3
and
(3) -N ~ wherein Z i5 as defined above and R' is as
defined above r the process comprises
reacting an NG-substituted-N2-substituted-L-arginine compound
with an amine of the formula: RH, wherein R is as defined above
in (2) and (3), thereby forming an NG-substituted-N2-
substituted-L-argininamide of the formula:
HN~
, 7 (C~ 2)3 -f HCOR
y NI~Y 1~
wherein Y and Y' are each hydrogen or a guanidino protective
30 group with at least one of Y and Y' being guanidino protective
group and Y" is an amino protective group;
removing the N2 protective group of said NG-~ubstituted-
-N2-~ubstitut~d-L-argin~amid~ by ~ydrogenoly~i~ or acidolysi~;
-3-

~68~1
conden~ing the NG-substituted-L-argininamide obtained
with a sulfonyl halide or the formula: R'SO2X, wherein R' is as
defi.ned above and X is halogen, thereby forming a second
NG-substituted-N2-substituted-L-argininamide of the formula:
HN ~
C-N-~CH2)3-CHCR
HN./ Y' 1 ' wherein Y, Y' and R' are as
defined above and R i8 as ~elected and defined in (2) and (3)
above; and
removing the NG protective group from said second NG-
-substituted-N2-substituted-L-argininamide by acidolysis or
hydrogenolysis of said second argininamide.
When R in Formula (~) is selected from the group consisting of
/R2
(2) -N wherein R2 and R3 are as defined above,
R3
and
(3) -N Z wherein Z is as defined above; and R' is as
defined above, the process comprises
reacting an N2-substituted-L-arginyl halide with an
amine of the formula: RH, wherein R is as Relected and defined
in (2) and (3~ above.
When R in Formula .~I) is selected from the group consisting of
/ R2
(2) -N wherein R2 and R3 are as defined above,
R3
and
(3) -N~_,Z wherein Z is as defined above; and R' is as
defined above, the process comprises
reacting an N2-substituted-L-ornithinamide of the formula:
H2N-(CH2)3-CHCOR , wherein R is as selected and defined in (2)
HNS02R '
-3a-
.

8S~
and (3) above and R' is as defined above with a guanidylating
age.nt.
When R in Formula ~I) is selected from the group consisting of
/R2
(2) -N ~ wherein R2 and R3 are as defined above,
and
(3) -N Z wherein Z i8 as defined above; and R' is as
defined above, the process comprises
reaGting an N2-substituted-L-arginine ester of the formula:
HN~
C-NH(CH2)37HCO2R7 , wherein R7 i8 a hydrocarbon radical
HNSO2R'
with an amine of the formNla: RH wherein R i9 as selected and
defined in (2) and (3) above.
When R in Formula (I) is selected from the group of
ORl wherein R1 is as defined above;
/R2
(2) -N wherein R2 and R3 are as defined above,
and
-
(3) -N Z wherein Z is as defined above; and R' is as
defined above, the process comprises
reacting an L-arginine ester or amide of the formula:
C-NH(CH ) fHCOR , wherein R i8 as selected and
NH2
defined in (1), (2) and (3) above, with a ~ulfonyl halide of the
formula: R'SO2X, wherein R' is as defined above and X is halogen.
-3b-

8~;~
1,13L) Dl~ :1'1"1`ION Ol~` '1`111;` 1'1~1~1i`131~ 11301)1i'1EN'l`S
As summarized abo~e, this inventioll rela-tes to a group of
N -substit;utecl-L-arginille es ters and arnides of -the formula
(I)
~IN i~ 1l
/C~N~(cll2 ) 3 - lcHcoR ( I )
2 f lN -S 2
wherein R is represented by the formula (l)-ORl, (2)-N\
or ( 3)-N ~, each of which wi Ll be described below in detail .
10 (1) In case where R is -ORl
Rl i9 seleeted I`rom the group CollsiS ting of Cl-C10 alkyl
sueh as methyl, ethyl, propy:L, iso~ropyl, bulyl, tert-butyl,
pentyl, hexyL or -the like; C3--ClO cyc:loal~{yl such as eyelo-
propyl, eyelohexyl or the like; Cl--C10 haloalkyl sueh as
15 2-ehloroethyl, 3-chloropropyl, 4-chlorobutyl or the lilce;
C2--C10 alkoxyalkyl such as 2-methoxyetllyl., 2-ethoxyethyl or
the like; C2-C10 alkenyl such as allyl, 2-bute~lyl or tlle
like; C2--C10 alkynyl such as 3--I)~ltyIly.L or tlle lilce; and
C7-C15 aralkyl such as ben~yl, phellethyl or the li]ce.
_ - ... _
. ,
." . . ',
. .' ' ' ~ , .

68~
(2) In case wllere R is -N \
R3
R2 and R3 are selected from the group consisting Or hydrogen;
Cl-ClO allcyl such as methyl, ethyl, propyl, isopropyl, bu-tyl,
iso~utyl, pentyl, llexyl, lleptyl or -the like; C7-C15 aralkyl
such as benzyl, phenethyl, 3-phenylpropyl or the like; and
Cl-ClO alkyl su~sti-tuted with a group se:Lectcd i`rom Cl-ClO
alkoxy, C2-ClO alkoxycarbollyl and carboxy such as 2-methoxy-
ethyl, 3-methoxypropyl, 2-ethoxyethyl, ethoxycarbonylmethyl,
2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-ethoxy-
carbonylpropyl, carboxymethyl, 2-carboxycthyl or the like.
(3) In case where R = -N G
Z i9 a divalent group which consists of two OI` more groups
selected from methylene -C~2- and monosubstituted methyLelle
I l~
-C- (wllerein R~ is selected from the group consisting of
Cl-ClO alkyl and Cl-C10 alkoxy), and ~ero or one or nlore than
one group selected from oxy -O-, tllio -~-, a].kyl su~s-ti-tuted
R5
imino -N- (wherein R5 is Cl-C10 a:Lkyl) alld acyl substituted
0~-~;
imino -N- (wherein R6 is Cl-C10 alkyl), wl~ch arc combined
in ~l ar~itIaly ordor, ~hQ IIUIIIL)Cr 01` t11C COIIIbillO~ groups L)e:illg
normally up to 20.
~ ~. .. ....... . . ~
..
, . '''-:,
.

68$~
More particularly, R includes l-polymethyleneimillyl groups
or the derivati~es thereof, such as l-aziridinyl, 1-
azetidinyl, 3-methoxy-1-aZetidi.nyl~ 3-etlloxy-l-aze-ticlinyl,
l-pyrrolidillyl, piperid:ino~ 4-nletl:~ylpipcricl:illo, 4-ethyl-
piperidirlo, 4-1~ropy:lpiperidino, 4-isopropyLpiE)eridillo~ 2-
methylpiperidino, 3-methylpiperidino, 4-nletlloxypiperidino~
l-hexamethy].eneiminyl, l-oc-tame-thyleneirninyl, an~ the like;
an oxazole or tl~iazole series sucll as 3-oxazo:Lidillyl, 3-
thiazolidinyl, ~Id the like; an lsoxazole or isothiazole
series such as 2-isoxazolidinyl, 2-isothiazolidinyl, and
the like; an oxazine series such as morpholino, 2,6-dimethyl-
morpholino, tetrahyclro-1,3-oxazin-3-yl, and the likb; a
thiazine series such as tetrahydro-1,4-thiazirl-ll-yl, and
the like; 4-methyl-1-piperazinyl, 4-acetyl-1-piperazinyl,
and the like.
The prererrecl R groups are the rollowing:
(1) In case wllere R is -~1
Cl-C8 alkoxy, cyclohexyloxy, C2-C~ omega-chloroall;oxy,
C2--C6 omega--alkoxyalkoxy, C3-C6 allcellyloxy, C2-C6
alkynyloxy, C7-C~ aralkyloxy
/R2
(2) In case where l~ is -N \
Cl--Cg alkylallLirlo, C2-C6 omega--alkoxyallcy:LanLino, C3--C8
. ~
.. ' ' ' . ' ..
.. ' ' . ' ' ' .
, ~ . '

6~
onlo~a~al.]~oxycar~o1~ylalkyl~n~ o, C7-C~ rall~yl~nlillo~
C2-C10 dialkylamino
(3) In caYie wllere X is -N~_~
C3--Clo N,N-polynletllyleneinlillyl; C3-Clo N,N-polymetllylelle-
iminyl substituted wlth a group selected from Cl-C5
alkyl and Cl-C5 alkoxy; tetrahydro-l, n-oxazin-n-yl
(n=2, 3 or 4); te-trahydro-l, n-thiazi11-11-y1 (n=2,3 or 4);
l-piperazinyl substituted with a group selected from
Cl-C5 alkyl and Cl-C5 acyl
The most preferred R groups are the ~ollowing:
(l) In case where R is -ORl
propoxy, butoxy, hexyloxy, cyclohexyloxy, 3-chloro-
propoxy, 2-methoxyethoxy72-butenyloxy, 3-butynyloxy,
benzyloxy
(2) In case where R is -N /
1~3
butylamino, 2-methoxyethylamir1o, 2-me-thoxycarbonyl-
ethylamino, 2-ethoxycarbonylethylamino, benzylamino,
N-methyl-N-butylami11o
(3) In case where R i9 -h ~.
piperidino, hexamethyleneiminyl, 4-metllylpiperidi1lo,
4--ethylpiperidino, 4-metlloxy~iperidillo, mor~>llolino,'
.. . , ' ', . . " ' : ' ' ''' ' ' . ' '.' - '`^' " . , ' .. ~, ;. -

68~i~
tetrahydro-1,4-thiazin-4-yl, ~I-metl-yl-l-piperazinyl~
4-acetyl-1-piperazinyl
In the above formula (I), R' is a member selec-ted from the
group consisting~ of (d) substi-tuted naphthyl ~
OR"'
wherein R" and R"~whell considered separately are respec-
tively Gl-~lo (preierably Cl-C5) alkyl such as methyl, e-thyl,
propyl, isopropyl, ~utyl, isobutyl~ tert-butyl or -the like;
or R" and R"'when taken together are Cl-C10 (preferably
Cl-C5) alkylene such as methylelle~ ethylene, trimethylene
or the li]ce; the alkoxy (-O~", -OR"~) or the alkylenedioxy
(-OR"-R"~O-) groupc~ d the sulfonyl group may be located a-t
any of the 1- to 8- position of the naphthalene nucleus;
normally, the sulfonyl group is locatecl at 1- or 2- position,
~md the alkylelleclioxy group is a 6,7-allcylenedioxy group;
(b) 6-chromanyl ~ ~ , (c) 1,4-bell~odiox~l-6-yl
) , (d) Zll-3,11-dillydro-1,5-b~ oclioxepill-7-yl
, (e) derivatives of` (d) llaving a subst:ituent a-t
the 3-position ~ } R"~ wherein R"" i~ Cl-C10 (preferably
.
~ ~ ~ ' . .
. : ' ; ,, ,' , .

68~1
Cl-C5) alkoxy, (f) 2-diberl~,ofur~lyl . ~ , (g)
4-dibellzofuranyl ~ ~ , (h) 2-xan~hellyl
and (i) dibenzo-p-dioxirl-2-yl ~ ~ .
'rypical Or the ~ group are the following:
~OCH3 ~ . ~ 'C2H5 ~ ~
C~3 ~1 OC~13 ~ OC 11 ' ~ J
~o~ ~7 ~ ~ OCH3 ,
~~
Illustrative of the typical N -substituted-L-argilline esters
and amides o r thii~ inventiorl are the followirl~:
~ 11 tlle CaSQ ol` the esl;~r dorivativoi~
N -(6,7-dillletlloxy-2-l1aplltllalellesulrollyl)-L-arginine propyl
ester
~ ' . ' ~ , ' ' ' .

N -(6,7-clilnctlloxy-2-llapl~ aLellesulL`olly.L)-L-ar~ e
butyl ester
N -(6,7-~1inlctlloxy-2-lla~lltllalcl-lesulronyl)-L-arg:illine
benzyl ester
N -(6,7-dimethoxy 2-naph-thalenesulronyl)-L-arginine
3-chloropropyl ester
N -(6,7-dimethoxy-2-llaphtllalellesulfollyl)-L-argilline
2-methoxyetllyl ester
N -(6~7-dimethoxy-2-naphthalenesulronyl)-L-arginine
3-butynyl ester
N -(6,7-dime-thoxy-2-naphthàlenesul~onyl)-L-arginine
2-butenyl ester
/R2 ' ' ' '
(2) In the case Or the amide derivatives wherein R is -N
N -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-
(2-methoxyethyl)-L-argininamide
N -(6,7-dimethoxy-2-1laphthalenesulfonyl)-N-
benzyl-L-argininamide
N -(2-xanthellesulronyl)-N-metllyl-N-butyl-L-
argininamide
.
-- 10 --
. ~ ` ": ' ' . '~ . '~; ' . ., ',,
~ . . , ~ .
. ' " ' "'
... ~

~68$~
(3) In the case Or the alllide ~erivatives wllerein R is -N
4~methyl-1-(N -(6,7-dimethoxy-2-naphtllalenesll~fonyl)-
L-arginyl)pi.perldine
y.L--.l.--(N --(G,7--~lilllcl,l~o,Yy--~ l,ll~Lc~ u.Ll`o~lyL)--
L-arginyl)piperidine
l~N -(G,7~ o~y-2-~ l~lc~ `ollyl)-L-
<I.l'~,';i.lly L) 11(!.`;.~1111(~ ~.llyloll(~ .Ju~
: 4-~N2-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-
arginyl~morpholine
4-me-thoxy-1-(N -(6,7-dirnethoxy-2-napllthalellesulfonyl)-
L-arginyl~ piperidine
4-methyl-1-(N -(4~6-dinletlloxy-2-rlaplll;llalerle~ulf'ollyl)-
L--ar~,riny:l.)pi.peridille
l~--ethyl--l--~N --(4,6--dinlettloxy--2--napllthalellesulronyl)-
L-argillyl~pipe:ridille
4-ethyl-1-(N -(21~-3,4-dilly~ro-1,5-bell~,odioxepin-7-
SulrOllyl )-L-argilly:L)piperi~ille
4--mcthyl~ N --(2~1--3~4--dillydro--1,5--L)en~odioxepill--7--
sulfonyl)-L-arginyl~piperidine
-- 1 1 --
; ~ ``' ~ ~ . '.
. . .. . .. ., __,_ _ __
~ , .

8Sl - :
4-ethyl-1-(N -(3-metlloxy--(211-3~4-dillydro-1,5-
bell~odioxepill)-7-sulro3lyl)-L-argillyl3piperidille
4-etllyl-1-~N -(2-x~ltllenesulrollyl)-L-argillyl~pipericlille
4-ethyl-1-~N -(2-dibenzofurallsu.l.:`ollyl)-L-arginyl~
piperidine
4-ethyl-1-~N -(4-dibenzofuransulfollyl)-L-argillyl~
pip ericline
4-ethyl-1-(N -(dibenzo-p-dioxin-2-sulfonyl)-L-arginyl)
piperidine
l-~N -(4-dibenzoruransulfonyl)-L-aJ-gillyl~llexametllylene-
imine
The following compo-~lds are mos-t preferrecl due ~o tlleir
high level of ~?I;ithronibotic activity.
N -(6,7-climethoxy-2-llapllthalenesulfonyl)-L-argilline butyl
ester
N -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methoxyethyl)-
L-argininamide
~-methyl-l-~N -(6,7-dimethoxy-2-1laplltl}a,lellesull'onyl)--L-
arginyl1piperidine
- 12 -
.~, ... .. .
r' . :

~6~51
4-ethyl~ N -(6,7-dilllethoxy-2-1laplltha.lcnesulI`ollyl)-L-
arginy.l~ piperidine
4-methoxy-1-~N2--(6,7-dimetlloxy-2-1laphtllalenesulfonyl)-L-
a;rginyl~piper.i(l:ille
4 methyl-l-~N -(I~,G-dinletlloxy-2-r~llLllLllellcsulrollyl)-L-
àrginyl~piperidine
4-etllyl-1-~N -(4,~-(linletlloxy-2-1laplltllalcllesull'orlyl)-L-
arginyl1 piperidine
4--ethyl~ N2-(2-xanthenesulfonyl)-L-arginyl)piperidine
4-ethyl-1-~N -(4-dibenzofurarlSulfonyl)-L-arginyl)piperidine
4-ethyl-1-~N -(di.ben~o-p-dioxin-2-sulronyl)-L-arginyl)
pipericdine
The pharmaceutica.Lly acceptable acid acldit:ion saLts of the
above compounds are Or courSe also included within the
scope of this invention.
The above compounds are inteJlcled only to illustrate the
variety of structures which can be used in the process of
this invention, and the above llsting is not to be con-
strued as limiting the scope-of thc inven~:iol:l.
These typical compounds are highLy potent in their anti-
~ thrombotic activity.
., ~
. , '' ' .
.
' ' ' ~ , ....... ~

6851
For the preparation of the compo~lds Or tlli~ invention,
VaJ'.i.OllY 1110 tllO(Is Ca]~ bc enlployo(l dcl~ell~iug ul~oll tl~ ~Ul'ti.CU-
lar starting maLerials and/or inLermediates i~lvolved.
';uccessful preparation of these com~ourlds is possible by
way of several syllthetic routes whicll are outlined below.
(1) Preparation of N -substi-tuted-L-arginiIIe esters
a) Esterirication of an N2-subsLituted-L-arginine
i) Reaction ol` an N -substituted-L-argilline and
all alcohol
This process may be illus-tra-ted as rOllOwS: -
~C-N-(CHz)3~C~lCOOll Rll (~1) ~C-N-(CH2)3-CHCOR
12 }~-S2
R' R'
(II) (I)
ln the above ~ornlu:Las, ll is -ORL, in which
Rl is as derined here:in above, and R~ is as
defined herein above.
The N -substituted-L-arginine esler (I) is
prepared by esterifying an N2-substituted-L-
arginine (II) witll ~UI alcohol (:~).
Tlle estoriricatio~l cau be cr~octc(l ~y reac-tillg
; the N -substi-tuted-L-argirlirle witll at least 5
equivalents of the alcohol in -the presence Or
. . '
.. ,, ,. . ~; .. , . , __, . , __ .. _. ~
. ~ ~ ' '''' '
'`~ , ' , ~ ,.
'

85~
at Leas-t an equimolar amoun-t of an acid catalyst
such as hydrogen chloride, sulfuric acid,
toluenesulfonic acid or the like
The reac-tion is generally carried out without
an added solvent or in a suitable reaction-
inert solvent at a temperature of 0C to the
boiling temperature of the alcohol or the
solvent for a period of 10 minutes to 15 hours.
Tlle preferred solvents are those which form
an azeotropic mixture with water and facili-
tates the removal o~ water formed during -the
reaction.
EXalllp1eS of such solvents are berl~erle, toluene,
xylene, cyclohexalle, carbon te-trachloride and
dichlorome-thane.`
After the reaction is comp:l.ete, the alcohol
alld/or the solvent is distilled off to give
the N -subStitu-ted-L-argilline es-ter (I) or
an acid addition salt thereof~ WiliCh can be
purified by recrystalli~iation from a combi-
na-tion of solvents such as ethyl ether, alcohols
and ace-tone, or ~y reprecipita-tion by adding
e-tller -to the alcohol solution thereor.
The acid addition salt of the N -substituted-L-
arginine es-ter can be easily converted to the
.
. - 15 -
l ~ .t,~,,'., .,~", ~
. .~ ,. ' '.'. .
. ~_ ;; ... .. , _
. . '' ' "' , ''' , ' , '

6B~l
correspo~ g ester by adjustillg tlle pll Or
the solution,
ii) Reactioll Or all N -sul)stiLuted-L-arg:~ninc, ar
alcoho.l. ~Id a Llliolly.L llalido.
5 , 'l`he N -substitul;ed-L-argin:illo ester (1) can
be prepared by reacting an N -substituted-L-
arginille (~ UI a.l.col)ol (I~) alld a ~llionyl
h.alide such as tl~.ionyl cllloride or tll:ionyl
bromide.
The thionyl halide is preferably used in an
amount not less than 2 moles per mole o~ the
N -substituted-L-arginine.
The other reaction conditions sucll as reaction
temperature, reaction time, amount o~ tlle
a:Lcohol -to be used; and the procedures of
separal;ion and purificatioll o.~ tlle product are
as described above in the esteriricatio~ itl
an acid catalyst.
According to this method, the product is
20 usurllly a halogeno acid salt of the N -
substituted-L-arginine ester.
Tlle N -subs-titllted-L-ar~illinc (:LI) can be
esteri.fied by mally otllc:r ~rocedurcs.
. Tlle N -s~ll)stil;~lted-L-argin:illcs (II) stilrtillg
materials are readil.y obtained by reacting
- 16 -
. .
. ~ .
. ,. "`' .. .
. _ _~. _. .. __ _ .. .. _ _ .

68Sl
argi~ e alld a su ~fo~yl ha:Li(le (pror~rably a
ch:Lori(le) of the rormula (IV): :
5 ~ wherei~ is as defined herein above and X
is halogen, in -the presence Or a base such as
K2C03, KOH, NaOH, triethy1amine or pyridine.
b ) Condensa-tioll of` an L-arginille ester wi Lh a s
halide
This process may be illustrated as :L'ollows:
--N--(cl-l2)3 - c~coR (V) R 902X (~
NH2
HN ~ ll
s,~ N ~C N ( C~12 ) 3--CrlCOR ( I )
l-lN-S 2
R '
In the above formu1as, R is -ORl wherein R1 is
as defined herein above; R ' is as defined herein
above; and X is halogen.
The N --subs ti -tu t ed--L-arginine es -t er ( I ) i s prepared
by the condensation of an L-arginine ester ( V) wi-th
a substantially equimolar amount of a sul:L`onyl
.
-- 17 --
~ ' .. ' ..
~ _ . . ~ --, -- ------- ---------- -_ .__ _._____,_ .
.
.' , ' ~' ' '

~68Sl
alide (lV), pre~`eral-ly a cllloricle.
'rllc condcllsatioll reactiol~ ; gollerally erf`ecto(:l
in a suitable reactio~ lcrt solvellt in the
pre~ence Or all excess Or a basc, such as all organic
5 ~ase (triethylanulle, pyrid:ille) or a solutio2l of
an inorganic base (sodium hydroxicle, potassium
r carbonate), a-t a temperature Or 0C to the boilingtemperature Or the solvellt for a pcriod of 10
mirlutes to 15 hours.
The preferred solvents for the condensation include
- dichloromethane~ diethyl ether-water and dioxane-
water.
After the reaction is con-pletc, the formed salt is
extracted with water, and tlle solvcnt is rcnloved
by such standard means as evaporation under reduced
pressure to give the N -substitutcd-L-argir~ o ester
(1), wh:Lcll call ~e puriric(l ~y tritur;ll;ioll or re-
crysta~ at:ioll rrOm a suitable solvellt, such as
diethyl ether--te-trahydrorurarl, diethyl ether-
metharlol alld water-methanol, or nlay be cllronlato-
graphed on silica gel.
The L-arg~ le ester (V) startillg Illaterials are
most generally prepared by reactillg L-arginine with
an alcohol in the presence Or an acid catalyst.,
- 18 -
.. . . . .. .. ... . _ _ _ _ . _ .. _ _ _ . _ _ . .
~-- .
;. . , ', ..
. .. . ...
: , .

68S~
(2) 1'rc~ N -~ul)~ L-~
a) Conde1lsatio11 of au L-argillir1anlide witl1 a sulronyl
l I J, ~ 0
'l`his process may be i1.:1ust:rated as rOllOws:
H /C-N-(Cll2)3-lllcOR (V) R'50~ (lV)>
N112
~LN ~ 11
C-N-(C11 ) -CllCOR (I)
H2N ~ 2 3
2
R'
In the above formulas, R is -N\ or -N
wherein R2, R3 and Z are as defined herein above;
R~ is as defined herein above; and X is halogen.
The N -substituted-L-argininamide (:C) is prepared
by condensing an L-argininamide (V) with a sub-
stantially equimolar amount of a sulfonyl halide
(IV), preferably a chloride, in the presence of
a base.
The reac-tion conditions are tlle sarne as those
described in the Process (l) b) (corlde1lsation of
an L-àrgi~:ine ester with a sulronyl l1alide).
. _ . . .
., ~ ,, , , ""' ':.
., . ' ', ' ` " , '. '.
: . :
. '.... - ' ~ ~' ' '' .

6~51
'l`he L-argi~ lamides (V) start~ g matcr:ials
required for the condensation reactioll C~l be
prepared by protecting the guanidillo and ~ -amino
grollp o~ the arg;inine via ~litratio~l, acetylation,
rormylatioll, plltllaloylatioll, trifluoroacetylatioll,
p-metlloxyben~,yloxycarbonylatioll, benzoylatioll,
ben~yloxycarbonylation, tert-butoxycarbonylatioJI
or tritylatioll and tllen condel~:irlg the formed NG-
substitute~-N -substituted-L-argilline witll a
correspondillg amine by sucll a conventional process
as the acid cllloride method, a~ide me1;hod, mixed
anhydride method, activated ester method or
carbodiimide method, and therea~-ter selectively
removing the protective group.
b) Removal of the NG-substituent from an NG-subs~ituted-
N -substituted-L-argirlillamide
Tllis process may be illustrated as follows:
HN~
~C--~--(C}12)3--IcllcOO~I (VI) 1
2 O I Y ' HN
Y~-
. .
~C--N--( C 112 ) 3 -C}lC OR ~C--N--( C 112 ) -Cl IC OR
llN ~ I llN (VII)~ llN ~ yl 3 N~2 (V:t[L)
Y I . Y
- 20 -
. .
.~ ' , . ...

68Sl
r~so~x ( LV) IIN;~
, . ~ ~C l ( Cl 2 ) 3 1 ( IX )
Y ' I-IN--S02
R'
5IIN ~ ~1
C--N--( Cl l ) --C l-IC OR ( I )
~IN - S 2
R
In the above ~ormulas, R is -N ~ R or -N Z,
10 wherein R2, R3 and Z are as defined herein above;
R~ is as defined herein above; X is halogen; Y"
is a protective group for the amino group, such
as ben~yloxycarbonyl or tert-butoxycarbonyli and
Y and Y~ are hydrogen and protective groups for
the guanidino ~roup, such as nitro, tosyl, trityl, .
oxycarbonyl or the like.
At least one o~ Y and Y' is a protec-tive group for
the guanidino group.
The N -substituted-L-argillinamide (~) is prepared
by renloving the N -sub.stituent ~rom ~l N -substituted-
N - SlJb.S t:itu~e-l-L-argiu:i.tl.~ ) I)y m~alls or
acidolysis or hydrogenolysis.
.
;: ' ' ' '
. - .
~ ~ ' ' ' ' ' ,.

l`he acidolysis is generally effected by contact-
ing the NG~substitutecl-N -substituted-L-argininamide
(IX) an(l ~l excess of an acid such as hydrogen
fluoridc" hydrogell cllloride, hydrogeJI bromide or
5 trifluoroacetic acid, without a solvent or in a
solvent, such as an ether (-tetrahydro~uran,
dioxane), an alcohol (methanol, ethanol) or acetic
acid at a temperature of -lO C -to 100C, and
preferably at room temperature for a period of lO
minutes to 24 hours.
The produc-ts are isolated by evaporation of the
solvent and the excess acid, or by -tri-turation
with a suitable solvent followed by filtration
and drying.
1~ Because of the use of the excess acid, the products
are gerlerally the acid additiorl salts of the N -
substituted-L-argininamides (I), which can be easily
converted to a free amide by neu-tralization.
The rernoval Or the nitro group and the oxycarbonyl
group, e.g., benzyloxycarbonyl, p-nitrobenzyloxy-
carbonyl, is reaclily accomplished by the hyclro-
genolysis.
The hydrogenolysis is efrected in a reaction-inert
solvent, e.g., methallol, e-thallol, tetrahy~rof`uran
.
: "~ -
. ~
_
.

or dioxane, in the prcsetlce of a hydrogen-activat-
ing catalys-t, e.g., Raney nichel, palladium, or
platinum, in a hydrogell atmospllerc at a tenlpcrature
ol` ~ to l;lle boili~lg telll~erature ol` Llle so:Lvellt
5 ` for a ~eriod of 2 hours to 120 hours.
The hydrogen pressure is not critical, an~ atnlos-
pllcric prossure is sur~icient.
~rhe N -bu~stituted-L-argi~ lllides (L) arc isolated
by filtration of the catalyst followed by evapora-
tion of the solvent.
The N -substituted-L-argininamides can be purified
in the same manner as described above.
The N -substituted-N -substituted-L-argininamides
(IX) starting materials can be prepared by condens-
ing an NG-substituted-N -substituted-L-argilline
(VI) (gellera:lly the N -substituerlt is a protective
group for the amillo group, such as ben~yloxycarbonyl,
ter-t-butoxycarbonyl, or the like) and a corresponding
amille (LI) via the a~ide method, mixed anllyclride
metllod~ activated ester method, carbodiimide method
or -the like, seLectively removing only the N -
substituent of all NG-substitutecl-N2-substituted-L-
argininamide (VII) by means Or cata:Lytic hyclro-
genolysis or acidolysis, and tllen condensillg the
.'~' ,
~ _ ' ' ' ' , ' ,'.

11~6~Sl
tllUs Obl.aillCd N --sub~til;ul;ecl--L--argillinumide (V
with a sulfonyl halide (l:V), preferal~ly a
chloride ill the E)resellcc Or a base in a solvent.
TllC'Se l`e1Cti OIl COrl(li t:i.Olls are as ~lcscri.l)ed al~ove
in l;lle condeJlsatiotl Or an L-argininanlide with a
sulronyl halide, and l;he renloval of the N -
substituent from an NG-substituted-N -subs-tituted-
L-arginiIlatlli de .
c) Condensation of an N -substituted-L-arginyl halide
wi th an amine
This process may be illustrated as foll.ows:
Il N/C N (c~l2)3 - cl-lcox (X) ._~
~IN--S 2
R'
HN ~ ll
~C--N ~ ( Cll2 ) 3 -Cl-lCOR ( I )
HN--S 2
R'
In -the above formulas, R is --N 2 or -N Z,
wherein R2 R3 and Z are as ciefinecd ll.ereill above;
R ~ lS as clerined hereill above; allù X is halogell .
-- 24 _
. . . ....
~` . . . , ' '- , ' .
~ . , -- -- -- - . __._
.

~ ~685~
The N -substituted-L-argi~ anlide (I) is prepared
by the condensation of an N -substituted-L-
arginyl halide (X), preferably a chloride with at
least ~n equimolar amount of atl anlille (I~).
The condel-lsation reaction can be carried out
without an added solvent. However, satisfactory
results will be obtained with the use of a solvent
such as basic solvents (dimethylformamide, dimethyl-
acetamide, etc.) or halogenated solvents (chioro-
form, dichloromethane, e-tc.)
The amount of the solvent to be used is not critical
and may vary from about 5 to 100 times the weight
of the N -substituted-L-arginyl halide (X).
Preferred condensat:ion reactioJl tenlpe~ratures are in
the r~nge of from -10 C to room temperature. The
reaction time is not critical, but varies with the
amine (II) employed. In general, a period of from
5 minutes to 10 hours is operable.
The obtained N -substitu-ted-L-argininanlide can be
isolated and purified in -ttle same ma~uler as de-
scribed above.
Tlle N -substituted-L-argillyl halidc (X) startillg
materials required for the condonsation reaction
can be prepared by reacting an N -substituted-L-
arginine (II) with at least an equimolar amount of
- 25 -
F~
~ .~ ,,: "' . '''. '
' . _. . . _ _ ___ ___.. _ . _ _~ ' ' _
_-, ' '.. '' ' ' " .

68Sl
a halogenating agellt sucll as thionyl chloride,
phosphorous oxychloride, phosphorus trichloride,
phosl)llorous pelltacll.lori(le or phospllolus tribromide.
rJle halogenatiorl carl be carriecl Ollt with or without
an added solvent.
The preferred solvents are chlorinated hydrocarbons
such as chloroform and dichloromethane, and ethers
such as tetrahydro~urarl and dioxane
The amount of the solvent to be used is not criti-
cal and may vary from about 5 to 100 times the
weight of the N -substituted-L-arginine. Preferred
reaction temperatures are in the range Or -10 C to
room tempera-l:ure. rhe reactioll time is not criti-
cal, but varies with tlle halogerlat~ gr agent and
reaction temperature. In gerleral, a period Or 15
minutes to 5 hours is operable.
d) Guanidylation Or arl N2-s~l~stitutcd-L-orllithillanlide
or an acid additioll salt thereor
This process may be illustrated as follows:
H2N--(C1~2)3--C~CR i~ }I
l > C-N-(CH2)3-CHC0R
HN-S0 ll2N
l ~-S2
R' I :
R'
(Xl) ( )
.
- 2~ -
., ~
.. ' ,.~ .
. ' : , ., .~'
. ,. ~. . .
'

68S~
ln tllc a~ove f`orm-llas, l~ is -N / or -N~
R3
wherein R2, R3 and Z are as defined herein above;
al-ld R ' is as derille(lllerei.n al)ove.
The N -~u~stituted-L-argillinamide (I) is prepared
by gu~lidyla-ting an N -substituted-L-orllithinamide
(XI) with an ordinary guanidylatillg ag~lts such as
an O-alkylisollrea, S-all<y:lisotlliourca, 1-guallyl-
3,5-dimethylpyrazole or carbodiimide. The preferred
guanidyla-ting agents are the O-alkylisourea and
the S-alkylisothiourea.
The guanidylation of the N -substituted-L-
oInitllillamide (XI) with the O-alkylisourea or S-
alkylisothiourea is generally effected in A solvent
in the presence of a base at a temperature of from
0 C to the boiling temperature of the solvent for a
period of fronl 30 minutes to 50 hours.
Examples of the preferred base are triethylamine,
pyridine, sodium hydroxide and sodium methoxide.
The base is used in an amount of O.Ol to O.l
equivalent to the N -substituted-L-ornithinamide.
Examples of the preferred solvent are water~ watar-
ethanol and water-dioxane.
. ~
. ,.. ~ ', .
.'
., . ' ' . '

~61~5~
~fter the react;ion is conlplete, tlle N --sUI)~'; ti tuted--
L-arginirlanlide (I) is isolated by evaporation of
the solvent followed by removal of t1le excess
base ~lld tlle forn1(?d sa:Lt by a water was1~.
5 e) Reactio~l oP an N -substil;uted-L-argi~ e ester and
a p ri ma ry amin e
This process may be illustrated as rOllOws:
~lN ~ I I .
~C--N--(CH2)3-CHCOOR7 . (XII) 2
IIN--S02
R '
2 ) 3
~2N / ¦ R2 (XIV)
~lN -S 2
R '
In tlle above form1t:Las, R2 arld R ' are as defined
herein above; and R7 is Cl-ClO al:kyl.
. The N -substituted-L-argininarnide represented by
the forn1ula (XIV) can be prepared by the reac tion
of an N -substituted--L-arg-inine ester (YII) and
about 2 to .L0 equivalenl;s Or a ~rimary an1ille (`Clll).
The reaction i9 gencrally Carrie(l out Wi thOllt an
aclded solvent or in a solvent such as an alCOllO
_ 28 ~
. _ . _ . . . ~
.
~ . . ' . ~ ',, !
. . . ' ' ' , ,' .
' ~ . :

~6851
(methallol, ethanol), arl ether (etllyl ether,
tetrallydroruran), a hydrocarboll (bellzelle, -toluene)~
a halogellated hyd:rocalboll (chloloforlll, dicllloro-
metharle) or water at room temperature for a
5 period of several hours to several days.
In order to accelerate the reaction, the reaction
mixture may be heated to a temperature of up to
the boiling point of the amine or the solvent
Alternatively, a basic catalyst such as sodium
methoxide or pyridine may be added to the reaction
mixture .
After the reaction is complete, -the formed ~ -
substituted-L-argininamide (XIV) is isolated by
filtration or by evaporation of the excess amine
and/or the solvent, washed Wit}l water, and then
purified by recrystallization from a suitable
solvent such as water-methanol.
The N -substituted-L-arginine esters or amides (I)
of this invention form acid addi.tion salts with
any of a variety of inorganic and organic acids.
The product of the reactions described above can
be isolated in the free form or in the form of
acid addition salts ln addition, tlle ~roduct can
be obtailled as ~llarnlaceutically acccptable acid
- 29 -
.. _ _ . _ _ _ .. . .
.~
r
. .` . ',

851
addition salts by reacting one of the free bases
with an acid, such as hydrochloric, hydrobromic~
hyclroiodic, nit:ric, su:Lt`uric, phosplloric, acetic,
citric, nlale:Lc, SUCC:illiC, lacti c, tart-lriC~
5 glucollic, benzcic, meth~lcsulrollic, e-thatlesulfollic,
benzenesulfonic, p-toLuenesulfonic acid or the like.
Likewise, treatment of the acid addition sal-ts with
a base results in a regeneration Or the ~ree ami~e
or ester.
As stated above, the N2-substituted L-arginine
esters and amides, and the sal-ts thereof of this
invention are characterized by highly specific
inhibitory activity against thrombin, and therefore,
these compounds are usefu:l in the deterrllination Or
t;hronlbill in blood as diagnost;ic reagents, and/or
for the medical control or prevention of thrombosis.
The antithrombotic activities of the N -substituted-
L-arglnine esters and amides of -this invention were
compared with that of a known antithrombotic agent,
N -(p-tolylsulfonyl)-L-arginine methyl es-ter, by
determining the fibrinogen coaguLa-tion time. The
measurenlellt of -the fibrinogen coagu:Lation time was
conclucted as follows:
- 30 -
.~
. '"` ''
,

685~1
An 0.8 ml aliquot of a fibrinogen solution, which
had been prepared by dissolving 150 mg of bovine
fibrinogen (Cohn fraction 1) supplied by Armour
Inc. in 40 ml of a borate saline buffer (pH 7.4),
was mixed with 0.1 ml of a borate saline buffer,
pH 7.4, (control) or a sample solution in the
same buffer, and O.q ~l Qfa thrombin solution
(5 units/ml) supplied by Mochida Pharmaceutical
Co., Ltd. was added to the solutions in an ice
bath. Immediately after mixing, the reaction
mixture was transferred from the ice bath to a
bath maintained at 25C. Coagulation times were
taken as the period between the time of trans-
ference to the 25C bath and the time of the first
appearance of fibrin threads. In the cases where
no drug samples were added, the coagulation time
was 50-55 seconds.
The experimental results were summarized in TABLE
1. The term "concentration required to prolong
the coagulation time by a factor of two" is the
concentration of an active ingredient required to
prolong the normal coagulation time of 50-55 seconds
to 100-110 seconds.
The concentration required to prolong the coagulation
X

tinle by ~ I`ac-tor of` two .t`or tlle k]lowll allti-
throml~oti.c agcllt, N -(~-tolylslllfollyl)-L-argil~ e
meSlly:L ester, was l,.lOO,~M.
Tlle ilLll:i bi tors are ~llown :i.n 'l`~l~L,l~ 1 by indicatil-lg
1~ an~ 1~' in the fornlula (1) and tlle addi tiOIl
moiety.
When a solution containing an N -substituted-L-
arginille ester or amide Or th:is invellt:ion was
admini.stered intravenously illtO aninlal bodies, the
high antithrombotic ac-tivity in the circulating
blood was maintained for from one to three hours.
The half-life for decay of the antithrombotic
compounds Or ~;his invellt.ion in circulating blood
wa9 sllowil to be al~proximatelr 30 millute9; khe
physiological conditiorls Or the host animals (rat,
rabbit, dog and chimpanzee) were well main-tained.
The exper:illlelltal decrease of fibrillogen in animals
caused by infusion of throlllbin was satisfactorily
controlled by simultalleous infusion of the com-
pounds of this invention.
The acute toxicity values (LD50) d~ermined by
ora:l. adm:illi.stration of su~stal-lccs of f`ormula (I)
in mice (male~ 20 g) Fange from about 1,000 to
10,~00 milligrams pcr kilogranl of body weigllt.
32
.
_ . , _. .. ,. ____ . .. _.. __ ..... .. _ _ _ _ . ..
.
'.' ~ , '' '. .

68~
The therapeutic agen-ts of this invention may be
administered alone or in combination with pharma-
ceutically acceptable carriers, tlle proportion of
which is cletermined by the solubility and chemical
5 nature of the con-pound, cl30sell routo of admillis-
tratiorl hll(l stalldArd pharmaceutical l~ractice.
For example, the compounds may be injected
parenterally, -that is, intramuscularly, intravenously
or subcutarleously. For parenteral adnlinistratioll,
the conlpounds may be used in the form of sterile
solutions containing other solutes, for example,
sufficient saline or glucose to make the solutioll
iSOtO}lic. The compounds may be administered orally
in the form of tablets, capsules, or granules
corltaining suitable excipients such as starch~
lactose, white sugar and the like. The compounds
may be administered sublingually in the form of
troches or lozenges in which each actïve ingredient
is mixed with sugar or corn syrups, flavoring
agen-ts and dyes, and then dehydrated sufflciently
to make the mixture suitable for pressing into
solid rOl~l. The compounds may be administered
orally in the form of solutions which may contain
coloring and flavoring aFents.
- 33 ~
.
~,'. , '. `- ',, " , .
: .

~1~!6~51
Physicialls will deteln~ e the dosage ol` ~lle
present therapeu-tic agents which will be most
suitable, an(l dosages vary with tlle mode of`
aclministratioll alld tlle partlcuLar compo~ l cllosen.
:tn a~dition, the dosage will vary with the par-
-ticular patient under treatmellt.
When the composltion is administered orally, a
larger quarltity Or thc active agent will be
required to produce the same effect as caused
10 - with a snlaller quantity given parenterally. The
- therapeutic dosage is generally 10-50 mg/kg of
active ingredient parenterally, 10-500 mg/kg
orally per day.
Having generally described the invention, a more
complete understanding c~n be obtairled by reference
to cer~ain speciric examples, which are included
for purposes of illustration only and are not
intended to be limi-ting unless otherwise specified.
_ 34 _
. _ .. .... _ . _ . .. . , . . __ .. . .. _ __ __
~ ;;,;, ~ - ,
' . ' . . . .
' " : ' ' ' '',
7 F~
.
'

68Sl
To 1.0 g (0.0018 mole) of 4-ethyl-l~(NG-llitro-N -(6,7~
dimetlloxy-2-na~ tl~ lollc~ulrollyl)-L-argilLyl)pipelicline were
adde~ 5.7 ~ (0.0053 mole) oL' anist).le and 3 mL of hydrogrell
fluoride whi.Le cooling with Dry-ice/acetolle, and -the mix-
ture was stirred for 30 minutes in an ice ~ath. The anisole
iInd the e.~cess hydrogen fluoricle were evapolated at reduced
pressure with cooling to afford all oily product, which ~as
slurried with 100 ml of dry ethyl ether. The ether layer
was separated by decanta-tioIl, and the ol~tained powder was
dissolved in methanol, reprecipi-t~ted with ethyl e-ther,
and then filtercd to give l~-etllyl-l-(N -(6,7-diilletlloxy-2-
naphthalenesulrorlyl)-L-ar6rillyl1l>i~eridille hydlofluoride in
the powder form in a yield of 75%.
Elemental analysi.s:as C25l1,~705N5S-lll?
C ~l N
Calculated (~0) 55.6l~ 7.1~ 12.98
Found (%) 55.50 7.1212.87
]~ 2
Into a suspellsioll of l.0 g (0.00186 mole) Or 4-~NG-ni~ro-~ -
(6,7-dimetho~y-2-1lapllthalerlesulfonyl)-L-arginyl~ morpholine
and 0.1 g of pallad~um ~lack in 30 ml of ethallol and 10 ml
.. . ............................................... ..
' , ' ,

8Sl
of acetic acid was passed hyclrogcll gas for 6~ llours at room
temperature. Upon completion of tlle reaction, the catalyst
was filtered Orr, ~ld tlle solvent was evaporated un~er
reducecl pressu.re to g.i.vo a viscous oily resi~ue, wlLicll was
talcerl up in metllallol and reprccip~ ated witll e~her to
~ af`ford 4-(N -(6,7-dimel;lloxy-2-llaplll,llalelle9ulI`ollyl)-L-arginyl~
morpholine acetate in tlle powcler form in a yie~Ld of 82%.
Elemental ana:Lysis: as C22113L 6 r~ 3
~ Il N
10 Calculated (%) 52.07 . 6.37 12.65
Found (yO). 51.99 6.28 12.41
~ l'L]3 3
Into a suspension of 2 0 g (0.0027 mole) o~ NG,NG-dibenzyloxy-
carbonyl-N -(6,7-d:inletlloxy-2-1la~4tllcllellesulronyl)-N-butyl-L-
argininanlide alld 20'~ L)alladiunl-carboll in 50 ml Or ethallol
and 10 ml of acetic acid was ~assed hyd:rogell ~as for 10
hours at room tempcra-ture. Upon completion Or the reaction,
the ca-talyst was fil-tered off, and -the solvent was evapo-
rat.ecl under.reduced pressure to give an oily residue, which
. . was reprecipitated with metllallol-etllcr to givc N -(6,7-
dime.thoxy-2-naplltllalellesu If onyl )-N-l~utyl-L-a~ ininamide
acetate in the powder form ln a yield Or 7~.
,
. - 36 -
.
.. . .... ..
1` - - . . .. . .
~!1_ . . , ,, ,, ~ _ _ -- ___

1~6~S~
Elenlenta1 alI~Lysis: as C22I1~3~5N5$.CII3CoolI
C H N - .
CaJculated (~0)53.1l2G.gl 12 .98
l?ound (~') 53 .Gl 6.87 12.71
~X~ LI~ /~
rO 5.0 ml (0.069 nlole) o~ cold tl~onyl chl.olide was ad~ed
witll vigorous stirrillg 1.0 g (0. 002 36 ,,,01 e ) 0 r N -(6, 7 -
dimetlloxy-2-rlaphthalellesulroIlyl)-L-argilline, and the
reaction mixture was allowed to react.at room Lemperature
for 1 hour. ~fter the reaction was conlplete, 100 ml of
dry ether was adcIed t;o the reactioll mixture, aIld tlle formed
precipitate was collected and waslled well with 5~ nll Or cIry
ether.
The thus obt~inecl powdery N -(G,7-cli.metIloxy-2-Ilaphthalene-
sulfonyl)-l,-ar~rinyl chloride clihydrochloride was added with
stirrirlg to a solutioll of l.2 g (0.012 mole) of L~-methyl-
piperidine in 10 nLL of chlorororm, and the mixture was
allowed to stand for 3 hours at room temperature. After the
reaction was com~lete, the solvcnt and tle excess 4-nIethyl-
piperidine were distilled uncIer recluced pressure, and the
residue.was cIissolved ill 20 m.L of chlororolllI. rhe chlorofor
layer was wasI.lcd wcll witll sAtuJated NaC1 a<Iuoous ~olutiolI
and dried over sodiunI sulfate, ~ld ~llelI~ tlle chlororol~lI was
.
- 37 -
~1 ... .
.
' ~ ' '
_ _ . . _ =_ _ _ . _ _ ._
` ' , ' '
.

~6~51
distilled under reduced pressllre. ~ddi tiO.II of 10 ml of
acetic acid and 100 ml of dry ether to the reSidue resulted
in deposition of all oily product. l`he ether was removed by
decantatioll, ~Id the oily product was washed wel:L with dry
et;her to ~,ive powdery 4-metllyl-1-(N -(6,7-dilllethoxy-2-
naphthalenesulfollyl)-L-arginyl~piperidine monoacetate.
Yield 1.1 g (84~).
Elemental analysis: as C2l~H35N505$-CI-I3C001l
. C 11 N
Calculated (~0) 55.21 6.95 12.38
Found (a~) 55.11 6.74 12.01
~ L~]~ r~
To a.suspensioll Or 1.00 g (0.00236 mole) of N -(6~7-
dimethoxy-2-naphtllalenesulrorlyl)-L-ar~ ille in 20 ml of
tetrahydrofurall was added little by liLtle o.y8 g (0.0047
mole) of phospllorus pentachloride wllile cooling with ice
water. The mixture was stirrcd for 1 llour at 0-5C, alld
then, for 2 hours at room temperature.
To this reaction mixtuIe was ad-led 100 ml ol` dry ether, and
the superllatallt was removed by decanta~ioll. The residual
oily product was washed with 50 ml Or clry etller -~o give
powdery N --(G ,7-dimetlloxy--2-na~ Lllaloll(?su Lronyl )--L--argillyl
cl~oride dillydroclllolide~ wl~ch was added with stirring to
_ 3~ _
. " . . _ _ . __ _ _ _ _ .. , .. .. _. . .. . .. _. _ _ . __ ___ _ .. .. ._
~ .. ....
. , . .. " . ,.~
'' ' ,', ' ' ''' ' , ' ' ,' ' '" ," ' ': ' '
. - . _ _ _ _ _
. .. ,. . . . ... _

s~
a solution of 1.31 g (0.015 mole) of N-methyl~N-butylamine
in 10 ml of chloroform. Thereafter, following the same
procedures as described in Example 1, N2-(6,7-dimethoxy-2-
naphthalenesulfonyl)-N-methyl-N-butyl-L-argininamide
monoacetate was obtained. ~ield 0.76 g (58~).
Elemental analysis: as C23H35N5O5S-CH3COOH
C H N
ralculated (~) 54.24 7.10 12.65
Found (%) 54.00 7.21 12.46
EXAM~LE 6
To a solution of 1.0 g (0.004 mole) of L-arginine ethyl
ester dihydrochloride in 50 ml of dichloromethane and 1.15 g
(0.012 mole) of triethulamine was added 1.14 g (0.004 mole)
of 4,6-dimethoxy-2-naphthalenesulfonyl chloride with stir-
ring at room temperature.
After stirring for 5 hours at room temperature, the reaction
mixture was washed with water to remove the formed triethyl-
amine hydrochloride. After the solution was dried over
sodium suIfate, the dichloromethane was evaporated under
reduced pressure, to give N2-(4,6-dimethoxy-2-naphthalene-
Sulfonyl)-L-arginine ethyl ester.
To this product was added ethyl ether, and then hydrogen
chloride was passed. The formed precipitate was filtered to
- 39 -
.

~6~5~
give N ~ ,G-dinletlloxy-2-]1a~ tllaLerlesul~olly.L)-L-argirlille
ethyl ester hydrocll:loride in the rorm of a powcler.
Yield 84%.
~.e~lellt~ aly~ as C2ul~2(~()Nllscl
C 1{ N
r ~alculated (%) l~.l3 5-~7 .11.46
Found (~)48.~G 6.15 11.52
~,YA~II'LI3 7
To a suspension of 1.50 ~r (o,005 mole) Or L-ar6irline butyl
l.0 ester dihydrocllloride in a solution conSisting of 1.4 g
Or potassium carbollate and 10 ml Or water, wl~ch had been
cooled to 0-5C, was added dropwise a solution Or 1.43 g
(0.005 mole) Or 6,7-dimethoxy-2-naphthalerlesu.Lrorlyl cllloride
in 10 ml Or ctllyl e-tller witll vi.gorous s tirrillg OVel' a pe~riod
Or 30 minutes,
The mixture was stirred ro:r rurtller 10 minutes and a viscous
deposit was obta:ined. The solverlt was removed by decan-
tation, and tlle residucLl del~osit was waslled wi-th water and
ether.
To a suspensioll Or tlle resul tin~r product iII 20 nll of ethyl
ether was addecl 2 g of p--tOlUell(?sUlrOlliC acid nlOllOllyClrate
with stirrin~r to yield a crystal, whicll was ri ltercd and
washed several times with e-thyl e-ther to give N -(6,7-
1
:~. . . ' , . , . ' s
: . ', . ' ' . ....
_ . . _ _ . . _ . _ .. , . . . _ _ _
~ . . , , _ .. _ ... _ ... .. _ ._ ._ ... ... _ . _

s~ ~
dimethoxy-2-naphtll.llenesulrollyl )-L-argillirle l~uty1 ester
p-toluerlesulrollate in 92% y:ielcl; m.p. 113-115C.
I~lemellta1 analysis: as C2~Jl~ ~~N/ ~2
. C 1I N
Ca:Leulatecl (~) 53 ~36 6.1~ ~3.59
~r li~ound (%) 53.23 G.l/l 8.70
To a mixture ol` l.U0 g (0.0()37 mo1e) of 4-etllyl--l--(L--argirlyl)
piperidine and 0.61 g (0 0044 mole) of potassium earbonate
10 in 10 ml of water, wl~ eh had been eooled ll~o 0C, was adcled
dropwise a solut.ion oI` 1.25 g (0 ooll4 mole) of 6,7-
dime-thoxy-2-naplltllalenesul:t`olly1 ehloride in 3V ml of` clioxane
with vigorous s tirrin~ over a l)eriod of 30 minutes .
The reaetion mix ture was .s tirrecl . for atlcl:i tional 5 hours at
15 room t;emperature allcl the formed preeipi l;ate was removed l~y
fi1tral;iorl. rhe solvent was evaporateci wlder redueed
pressure, ancl -to l:he residue was acldecl 50 ml Or elllorororm.
The undissolved material was filterecl off an(l the solu-tioll
was dried over socdium su:Lfate. Ikidition of` 10 ml of aeetie
20 aeicd to this sol.ution followed by evaporatioll of` the so1vent
gave a viseous oily procluet, whieh was reprc eipit~ted with
methano1--ethyl ether to a.t`rorcd 4--etbyl--l-(N ~((i,7-dimcthoxy--
2-naphtllalenesul:t`olly1)-L-arginyl3 piperidine aeetate in a 62%
yield .
-- 1~
. ~__.. _.. __~__._ ._ ,.. .. ... __._ _ ._. ......... ._ _ __ .. _
! ~
.;
:~ , . , . _._ '
.
, ' ~, .

6~S~
l~lt?mc?llta ~ua Lysi s: a~ C241135()7N5~;
. C 1I N
Calculatt?(~ ) 55-0,1 7.2~ 12.3
I?OIIJI~I (%) 5~ 3 7 .-I
5 ~r l~XAr11~1,13 (~
To a solution Or l .00 g (0.0041 nlo Le) Or 4-(L-ar~ yl)
morpholine in 50 nll Or chloroforrn ancl 0.52 g (0,0052 mole)
of triethylanline was added- 1.48 g (0 .0052 mo Le) of 6~7--
dimethoxy-2-naphthalenesulronyl chloride with s tirring at
10 room temperature.
Af~er stirrillg ror 5 llours al; roonl tenll~el-aturc, thc reacl;ior
mixture was slurrietl witll lO nll. Or water.
The atlueous layer wa~ se~aratod~ arltl -l;lle resitlual chlorororn
layer was dri.ecl over sod~ nl sll:LraL o . ~dd:i tion o r 2 nll Or
~5 acetic ac:id to the c~l.Lororornl ~ayer rol:LowQd l~y eval~or~-ti
of chlororor~ ave a viscous oily res:idue, which was re-
precipitated with Illethanol-etllyl etller Lo arrord 4-~N~-(6,7-
dimetho.Yy-2--llal~hLllalenesul:follyl)-L-a:r~ yl) nlo.rl~holille acet~te
i n a 6~% yi eld .
ZO Elernental analysis: as C2lll2~0~3N5S
C ll N
Cal culuL(~t~ ) 5 ) 07 G .;~7 12 .G5
~'ol~lcl(%) 51.~ 6.~6 1~.2
-- ~2
~ . -- . . . . __ _ . _ , .. ,, ., ... _ _ ., ., . ... ._ ____ .
.. -l~.. '^ .' , - ~ ., .
`~
.'
.~....... '' '' , ' .
r . _ _ . _, .

51
To a suspensloI-l of`:l.O g Or N -(4~6-dimellloxy-2-IlaplltIla-
ellesulrollyl)-L-alginillo in 30 m.I. of etl~ o.L was aclclcd
. little by litt:l.o 1 ml of thiollyl clllo1~ido wi.tll stirrillg.
The suspensioIl soon became a clear so.Lutioll, After the
solution was refluxed with stirrirlg for 4 hours, the
ethanol was distillcd away under reducod ~rcssure, -to give
a viscous oily resi.due, whicll was waslle(l well three t:imes
with 2~ ml of ethyl ether to afrorcl colorless alld powdery
N -(4,6-climetlloxy-2-1lRl~lltllalenesulfolly1)-L-argiIli~le ctllyl
ester llydrochloride in a 96~ yield.
elllelltal ailalysis: as ~2~1l2~0G Ll
C II N
Calculated (~) 49.l3 5-97 1.1.4G
Fourld (~lo) ll8.96 6.15 11.52
I~"Y~M.i'],J~, I.l.
,.~ A mixture of l.O g of N -(6,7-dimethoxy-2-na~llthalelle-sulfonyl)-L-argiIl:irle and l.O g Or p-toluenesulfonic acid
monohydrate in 5 m1 of butyl alcollol ~nd~ 30 m:l of ~en~ene
was refluxcd for 5 hours, while removing cllo water formed
during the reaction. 'I`lle rcactioIl mixture was collcontrated
under reduced ~ressllre, and.to thc residue was added ethyl
ether to yiel~ a crystalline sui~stance whlch was collected
~ .. .
~r ' ' . . ' '. '
~;'~ " ' ' " ` '
`1 _. , . . ~ . . . ,.. . ____. __ .. = ..

96~35:1
by f`iltratiorI~ wclsJlecl several t:imes wi-tll etllyl etller t;o
af'rord N --(6 ~7-clime tlloxy--2--napIlthalenesulrony.l )--L-arginille
butyl ester p-toluellesu1:f`olIal,e: yieLcl 92%, m.I~. 113--115C.
~3~.en~ tal L~ .y~;is: L5 C~3lllloo(~Nl~s2
C 11 N
~,rCaleulatecl(%) 53.36 . 6.1~ 8.59
~ .
~;~o~ ) 53.2 3G,.LI~~3.70
~:Al`IP1,13 1,~
To 1.2 g (0.()020 mole) of 4-etllyl-1--(NG-nitro-N -(6--
10 ehromansulfonyl)-L-c-rginyl~pipericlille was adcIe(l o.64 g
(o.ooGo mole) 0~ anisol.e an(l 3 nnI. oL llyclro~erl fluoride wllile
eooling wi tll l)ry-iee/aeetolle, aIld tllo nIixture was stirred
for 30 mitlutes i.~I an iee I)atlI. 'rlIC exeess llyclro~en L`luoricle
was evaporai;e(I at recluee(l E)ressure witll eoolillg to arf`orcl
15 arl oily produet, Wll.iCll WLS slurric~ Wi tll 100 nll of dry
etllyl etIIer. 'l`lle ol;ller layer was separatecl l~y cIeealI-tatioll,
allcl tlle ol~tai~lc(l powclel was dissolvQcl in nletllallol~ repre-
ei~itatecl witll. etllyl. etll.(3r, au(l t]lCII r:iltere(l to ~ive lj_
ethyl--l--~N --(6--ellronI LIIsulf ollyl ) -~--ar~:ilIy;l) pi.peri(lille
20 llyclrofluoricIe ill l;]IO pow(ler [orsn ill a yio.lcI ol` 63'~.
}~lemeIlta1 allalysis: as C22Il,3~,0IlN5~-IlIi`
F: ' ; . -
!
. / - -- . - . . __.--_ _ . .___. . . _ _ . . __ ,
_ ._ __. _____ _

6~51
C H N
Calculated (~) 54.41 7.47 14.42
Found (~)54.70 7.45 14.31
EXAMPLE 13
Into a suspension of 1.2 g (0.0020 mole) of 4-ethyl-1~
[NG-nitro-N2-(1,4-benzodioxane-6-sulfonyl)-L-arginyl~
piperidine and 0.1 g of palladium black in 30 ml of ethanol
and 10 ml of acetic acid was passed hydrogen gas for 30
hours at room temperature. Upon completion of the reaction,
the catalyst was filtered off, and the solvent was evapo-
rated under reduced pressure to give a viscous oily residue,which was taken up in methanol and reprecipitated with ethyl
ether to afford 4-ethyl-1- [N2-(1,4-benzoidioxane-6-sulfonyl)-
L-arginyl~ piperidine aGetate in the powder form in a yield
of 85%.
Elemental analysis: as C21H33O5N5S~CH3COOH
C H N
Calculated (%) 52.35 7.07 13.27
Found (~) 52.65 7.01 13.12
EX~MPLB 14
Into a suspension of 2.0 g (0.0026 mole) of 4-ethyl-1-
- 45 -
- - ~ ' . -

51
(N ,NG-dibel1Gy:lo~cycarl)ollyl-~12-(211-3,4-cli1lydro-l,5--
benzocdioxepin-7-sulfonyl )-L-argillylJ pipericline ancl l()',~
pallad:ium-carboll in 50 m.L Or etl~allol ancl 10 ml of acotic
acid was passe(1 hy(lroge1l gas ror lO l~our~ at room tempera--
ture. ~Upon com1):1et:ioll of l;l~e reactio1l, the cala:ly~ t; wa5
filtered o1'L`, and tl1e solvellt was evaporate(l ullcler recluced
pressure to g:ive a viscous oily residue, whic1] was repre-
cipital;ed with met11allol-et1ler to give 4-etl1yl-:l-tN -(211-3,4-
dihydro--l, 5-lL)enz.o(1ioxepi1l-7-su:l l ollyl )-L-arginyl) piporidine
acetate in l;he powder form in a yield Or 8l7~o.
l~,lemental analysis: as C24113907N5S-C113C0011
C 11 N
Calculate~ 0) 5~.22 7.2~ 12.~3
Found (%) 53 .51 7 .o~ J 2 .~7
Various o tller N ~subs ti tu(;ecl-L-argi1line os l;ors iuld anLides
were syllthesized in accorclance Wi tll tlle procedures of the
above exalllples. 'I`he resu:Lts, includi1lg tlLose of the al)ove
examples, ~re sunlnlar:ized in '1`A13LF, l. In TA13],L 1, N --
substituted-L-argilline esters and amicles represe1ltecl L)y the
general formula (I) are ShOWIl by indiCatillg ~ alld }?.1 in the
formula and adcli tion moieties.
_ IIG -
~, . . . ?,
i -. ,
~ , . .. . . . . _ _ _~ _

11~!6~5~.
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47
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11~68~
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