Note: Claims are shown in the official language in which they were submitted.
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