N.SUP.2-ARYLSULFONYL-L-ARGININAMIDES AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

N.SUP.2-ARYLSULFONYL-L-ARGININAMIDES ET SELS DESDITS COMPOSES UTILISABLES EN PHARMACIE

English Abstract

ABSTRACT OF THE DISCLOSURE
N2-arylsulfonyl-L-argininamides of the formula
Image
and th pharmaceutically acceptable salts thereof have been
found to ba effective as pharmaceutical agents for the inhibition
and suppression of thrombosis.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:

1. A process for producing an N2-arylsulfonyl-L-argininamide
having the formula (I):
Image (I)

or the pharmaceutically acceptable salt thereof, wherein R is selected
from the group consisting of

(1) Image wherein R1 is selected from the group

consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10
alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C3-C10
alkylcarbonylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10
alkoxycarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15
.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10- cycloalkylalkyl, furfuryl,
tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl,
3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R2 is selected
from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl,
C7-C12 aralkyl and 5-indanyl; and n is an integer of 1, 2 or 3,

(2) Image wherein R3is selected from the group


141





consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl,
C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl.
C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15
.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl,
tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl,
3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R4 is selected
from the group consisting of C1-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl,
phenyl C7-C12 aralkyl and ring substituted benzyl wherein said substituent
is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting
of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
and m is an integer of 0, 1 or 2,

(3) Image Wherein R6 is -COOR8 wherein R8 is selected from
the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12
aralkyl and 5-indanyl; R7 is hydrogen, C1-C10 alkyl, phenyl C1-C5
alkoxy or carboxy; R6 is substituted at the 2 or 3-position; and R7
can be substituted at the 2, 3, 4, 5 or 6-position,

(4) Image wherein R9 is selected from the group con-

sisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and

142





5-indanyl; and r is an integer of 1, 2, 3 or 4,

Image wherein R10 is selected from the group consisting

of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
Z is selected from the group consisting of oxy, thio and sulfinyl; and
q is an integer of 0 or 1, and

Image wherein R11 is selected from the group

consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and
5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and Ar is selected from
the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl
substituted with at least one substituent selected from the group
consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy
and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one
substituent selected from the group consisting of halo, nitro, cyano,
hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylanlino, C7-C12
aralkyl,
Image ,

Image , Image , Image ,

143





Image , Image and


Image wherein R12 is hydrogen, C1-C10

alkyl or C1-C10 alkoxy, which comprises: reacting an
L-argininamide having the formula:
Image

wherein R is defined herein above with an arylsulfonyl halide
having the formula: ArSO2X, wherein Ar is as defined herein
above and X is halogen.
2. An N2-arylsulfonyl-L-argininamide and the pharma-
ceutically acceptable salts thereof, whenever prepared by
the process of claim 1.

3. The process of claim 1, wherein said N2-arylsulfonyl-
L-argininamide has the formula:

144



Image

wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10
alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl,
C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C2-C10
carboxylalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl,
C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10
cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl,
3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-
2-thenyl and tetrahydro-3-thenyl; R2 is selected from the group con-
sisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-
indanyl; n is an integer of 1, 2 or 3; and Ar is selected from the
group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl
substituted with at least one substituent selected from the group con-
sisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and
C2-C20 dialkylamino, phenyl, phenyl substituted with at least one
substituent selected from the group consisting of halo, nitro, cyano,
hydroxy, C1-C10 alkyl, C1-C10 alkoxy, and C2-C20 dialkylamino. C7-C12
aralkyl,

Image , Image , Image


145



Image , Image , Image and


Image wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.

4. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof, whenever produced by the process of claim 3.
5. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide
has the formula:

Image

wherein R3 is selected from the group consisting of hydrogen, C1-C10
alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10
alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C2-C10
carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl,
C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10
cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, optionally
substituted with at least one C1-C5 alkyl and/or C1-C5 alkoxy 3-furylmethyl,
tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl
and tetrahydro-3-thenyl; R4 is selected from the group consisting of
C1-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl, C7-C12 aralkyl
and ring substituted benzyl wherein said substituent is C1-C5 alkyl or


146



C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen,
C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; m is an integer
of 0, 1 or 2; and Ar is selected from the group consisting of naphthyl,
5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one
substituent selected from the group consisting of halo, nitro, cyano,
hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl,
phenyl substituted with at least one substituent selected from the group
consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy
and C2-C20 dialkylamino, C7-C12 aralkyl,

Image , Image , Image ,
, and


wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
6. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof, whenever produced by the process of claim 5.
7. The process of claim 1, wherein said N2-arylsulfonyl-L-
argininamide has the formula:

Image

147



wherein R6 is -COOR8 wherein R8 is selected from the group consisting
of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
R7 is hydrogen, C1-C10 alkyl, phenyl or carboxy; R6 is substituted
at the 2 or 3-position; R7 can be substituted at the 2, 3, 4, 5 or 6-
position; and Ar is selected from the group consisting of naphthyl,
5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one sub-
stituent selected from the group consisting of halo, nitro, cyano,
hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl,
phenyl substituted with at least one substituent selected from the
group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10
alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl,
Image , Image , Image


Image and



Image wherein R12 is hydrogen, C1-C10 alkyl
or C1-C10 alkoxy.
8. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof, whenever produced by the process of claim 7.



148



9. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide
has the formula:

Image

wherein R9 is selected from the group consisting of hydrogen, C1-C10
alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; r is an integer of
1, 2, 3 or 4, and Ar is selected from the group consisting of
naphthyl; 5, 6, 7, 8-tetrahydronaphthyl, naphthyl substituted with at
least one substituent selected from the group consisting of halo, nitro,
cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino,
phenyl, phenyl substituted with at least one substituent selected
from the group consisting of halo, nitro, cyano, hydroxy,
C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl,

Image , Image ,

Image , Image , Image ,

Image and Image


149




wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
10. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof, whenever produced by the process of claim 9.
11. The process of claim 1, wherein said N2-arylsulfonyl-L-
argininamide has the formula:

Image

wherein R10 is selected from the group consisting of hydrogen, C1-C10
alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; Z is selected from
the group consisting of oxy, thio and sulfinyl; q is an integer of 0 or
1; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-
tetrahydronaphthyl, naphthyl substituted with at least one substituent
selected from the group consisting of halo, nitro, cyano, hydroxy,
C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl
substituted with at least one substituent selected from the group
consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy
and C2-C20 dialkylamino, C7-C12 aralkyl,

Image, Image , Image ,

Image , Image . Image and


150



Image wherein R12 is hydrogen, C1-C10 alkyl or C1-C10
alkoxy.
12. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof, when prepared by the process of claim 11.
13. The process of claim 1, wherein said N2-arylsulfonyl-L-
argininamide has the formula:

Image

wherein R11 is selected from the group consisting of hydrogen, C1-C10
alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; i is an integer of
0, 1 or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an
integer of 1 or 2; and Ar is selected from the group consisting of
naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at
least one substituent selected from the group consisting of halo, nitro,
cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C10 dialkylamino,
phenyl, phenyl substituted with at least one substituent selected from
the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl,
C1-C10 alkoxy and C2-C20 dialkylamino C7-C12 aralkyl,

Image , Image ,


151




Image , Image , Image ,

Image and Image
wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
14. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof, when prepared by the process of claim 13.
15. The process of claim 1, wherein said N2-arylsulfonyl-L-
argininamide has the formula:

Image

wherein R is selected from the group consisting of

(1) Image wherein R1 is selected from the group

consisting of C2-C10 alkyl, C3-C5 alkenyl, C3-C6 alkynyl, C2-C6 alkoxy-
alkyl, C2-C6 alkylthioalkyl, C2-C6 alkoxycarbonylalkyl, C1-C6 hydroxy-
alkyl, C2-C7 carboxyalkyl, C3-C8 alkoxycarbonylalkyl, C1-C5 haloalkyl,
C7-C10 aralkyl, C8-C12 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10
cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-
3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-


152




thenyl; R2 is selected from the group consisting of hydrogen, C1-C10
alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; and n is an integer
of 1, 2 or 3,

(2) Image wherein R3 is selected from the group

consisting of hydrogen, C1-C10 alkyl, C3-C6 alkenyl, C3-C6 alkynyl,
C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl,
C1-C6 hydroxyalkyl, C2-C7 carboxyalkyl, C3-C8 alkoxycarbonylalkyl,
C1-C5 haloalkyl, C7-C10 aralkyl, C8-C12 .alpha.-carboxyaralkyl, C3-C10
cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl,
3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl,
tetrahydro-2-thenyl and tetrahydro-3-thenyl; R4 is selected from the group
consisting of C1-C5 alkyl, carboxy, C2-C5 alkoxycarbonyl, phenyl, C7-C10
aralkyl and ring substituted benzyl wherein said substituent is C1-C3
alkyl or C1-C3 alkoxy; R5 is selected from the group consisting of
hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; and
m is an integer of 0, 1 or 2,

(3) Image wherein R6 is -COOR8 wherein R8 is selected from


153




the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10
aralkyl and 5-indanyl; R7 is hydrogen, C1-C6 alkyl, phenyl or carboxy;
R6 is substituted at the 2 or 3-position; and R7 can be substituted at
the

2, 3, 4, 5 or 6-position, (4) Image wherein R9 is selected

from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl,
C7-C10 aralkyl and 5-indanyl; and r is an integer of 1, 2, 3 or 4,

(5) Image wherein R10 is selected from the group consisting
of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and
q is an integer of 0 of 1, and

(6) Image wherein R11 is selected from the group
consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10
5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and Ar is selected from
the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl
substituted with at least one substituent selected from the group consisting

154



of halo, nitro, cyano, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and C2-C10
dialkylamino, phenyl, phenyl substituted with at least one substituent
selected from the group consisting of halo, nitro, cyano, hydroxy,
C1-C5 alkyl, C1-C5 alkoxy and C2-C10 dialkylamino, C7-C10 aralkyl,


Image , Image , Image ,

Image , Image , Image and

Image wherein R12 is hydrogen, C1-C5 alkyl or C1-C5
alkoxy.
16. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof, when prepared by the process of claim 15.
17. The process of claim 15, wherein said N2-arylsulfonyl-L-
argininamide has the formula:

Image


wherein R is selected from the group consisting of:



155




(1) Image wherein R1 is selected from the group

consisting of C2-C10 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C2-C6 alkoxyalkyl,
C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, C1-C6 hydroxyalkyl,
C2-C7 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C7-C10 aralkyl, C8-C12
.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl,
tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl,
3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R2 is hydrogen,
C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl or 5-indanyl, and n is an
integer of 1, 2 or 3,

(2) Image wherein R3 is selected from the group consisting
of hydrogen, C1-C10 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C2-C6 alkoxyalkyl,
C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, C1-C6 hydroxyalkyl, C2-C7
carboxyalkyl, C3-C8 alkoxycarbonylalkyl, C7-C10 aralkyl, C8-C12
.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl,
tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl,
3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R4 is selected from
the group consisting of C1-C5 alkyl, carboxy, C2-C5 alkoxycarbonyl, C7-C10
aralkyl and ring substituted benzyl wherein said substituent is C1-C3


156




alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10
alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; and m is an integer
of 0, 1 or 2

(3) Image wherein R6 is -COOR8 wherein R8 is hydrogen,
C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl or 5-indanyl; R6 is substituted
at the 2- or 3-position; R7 is selected from the group consisting of
hydrogen, C1-C6 alkyl, phenyl and carboxy, and the position of R7 is
2, 4 or 6,

(4) 3-carboxy-4-morpholino, (5) 3-carboxy-4-thiomorpholino, (6) 1-oxo-
3-carboxy-4-thiomorpholino, (7) 4-carboxy-3-thiazolidinyl, (8) 2-carboxy-
-1,2,3,4-tetrahydro-1-quinolyl, (9) 3-carboxy-1,2,3,4-tetrahydro-2-
-isoquinolyl, (10) 1-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, (11) 2-
-carboxy-1-indolinyl and (12) 1-carboxy-2-isoindolinyl; and Ar is
selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl,
naphthyl substituted with at least one substituent selected from the
group consisting of halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and C2-C10
dialkylamino, phenyl, phenyl substituted with at least one substituent
selected from the group consisting of halo, C1-C5 alkyl and C1-C5 alkoxy,
C7-C10 aralkyl,
Image , Image and Image .


157




18. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
acceptable salts thereof whenever prepared by the process of claim 17.
19. The process of claim 1 wherein said N2-arylsulfonyl-L-
-argininamide is N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
-butylglycine.
20. N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine
and the pharmaceutically acceptable salts thereof whenever produced
by the process of claim 19.
21. The process of claim 1 wherein said N2-arylsulfonyl-L-
-argininamide is N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butyl-
glycine.
22. N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine
and the pharmaceutically acceptable salts thereof whenever produced
by the process of claim 21.
23. The process of claim 1 wherein said N2-arylsulfonyl-L-
-argininamide is N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
-(2-methoxyethyl)glycine.
24. N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)
glycine and the pharmaceutically acceptable salts whenever produced by the
process of claim 23.
25. The process of claim 1 wherein said N2-arylsulfonyl-L-argininamide
is N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)
glycine ethyl ester.


158





26. N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-
ethyl)glycine ethyl ester and the pharmaceutically acceptable salts
thereof, whenever produced by the process of claim 25.
27. The process of claim 1, wherein said N2-arylsulfonyl-L-argin-
inamide is N2-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-
ethyl)glycine.
28. N2-(4,6-dimethoxy-2-naphthysulfonyl)-L-arginyl-N-(2-methoxy-
ethyl)glycine and the pharmaceutically acceptable salts thereof, whenever
produced by the process of claim 27.
29. The process of claim 1, wherein said N2-arylsulfonyl-L-argin-
inamide is N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)
glycine.
30. N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)
glycine and the pharmaceutically acceptable salts thereof, whenever
produced by the process of claim 29.
31. The process of claim 1, wherein said N2-arylsulfonyl-L-argin-
inamide is N2-(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-
ethyl)glycine.
32. N2-(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-
-(2-methoxyethyl)glycine and the pharmaceutically acceptable salts
thereof whenever produced by the process of claim 31.
33. The process of claim 1, wherein said N2-arylsulfonyl-L-
-argininamide is N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-tetra-
hydrofurfurylglycine.



159




34. N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-
furfurylglycine and the pharmaceutically acceptable salts thereof, when-
ever produced by the process of claim 33.
35. The process of claim 1, wherein said N2-arylsulfonyl-L-
argininamide is N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetra-
hydrofurfurylglycine.
36 N2-(methyl-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofur-
furylglycine and the pharmaceutically acceptable salts thereof, whenever
produced by the process of claim 35.
37. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-
amide is N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-
38. N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-
furfurylglycine and the pharmaceutically acceptable salts thereof,
whenever produced by the process of claim 37.
39. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-
amide is 1-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-4-methyl-2-
-piperidine carboxylic acid.
40. 1-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-4-methyl-2-
-piperidinecarboxylic acid and the pharmaceutically acceptable salts thereof,
whenever produced by the process of claim 39.
41. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-
amide is 1-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-methyl-2-piper-

160


idine carboxylic acid.
42. 1-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginy]]-4-methyl-2-
piperidine carboxylic acid and the pharmaceutically acceptable salts
thereof, whenever produced by the process of claim 41.
43. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-
amide is 1-[N2-(7-methoxy-2-naphthylsulfonyl)-1-arginyl]-4-ethyl-2-piper-
idine carboxylic acid.
44. 1-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piper-
idine carboxylic acid and the pharmaceutically acceptable salts thereof,
whenever produced by the process of claim 43.


161

Description

1-1374ti9

N2-ARYLSULFONYL-L-ARGININAMIDES AND THE
PHARMACEUTICALLY ACCEPTABI,E SALTS THEREOF

This application is a division of Canadian Serial No. 266,501,
filed November 24, 1976.

BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to the discovery of certain new and
useful N2-arylsulfonyl-L-argininamides and the pharma-
ceutically acceptable salts thereof, which are of especial
value in view of their outstanding antithrombotic properties
and low toxicities.

Description of the Prior Art
In the past, there have been many attempts to obtain new
and improved agents for the treatment of thrombosis. The
N2-(p-tolylsuIfonyl)-L-arginine esters have been found to
be one type of agent which can be used and these have been
found to be effective in dissolving blood clots. (U. S.
Patent No. 3,622,615, issued November 23, 1971).
One family of compounds which have been found to be par-
ticularly useful as highly specific inhibitors of thrombin
for the control of thrombosis is the N2-dansyl-L-arginine
ester or amide. (The applicant's U.S. Patent No. 3,978,045).

However, there is a continuing need for a highly specific
inhibitor on thrombin for the control of thrombosis, which
exhibits lower toxicity.



.,., ~
~ - 2 -

1137~

SU~ IAIIY O~ T1~13 INVI~,NT:ION

It has no-~/ I)ce~l ~liscov~reci that N -arylsu] rony1
ar~inillamides exhibi~ alltithrom~otic activity and everl
lower toxicity lcvels at the same relative potencies, as
compared witll tlle N -clansyl-L-ar6ini1~e ester or amide,
The compoun~s Or thi.s invention can ~e re~resented by the
formula (I):

llN ;~,
}I N ~ I C~2C}~2CH21C~ICOR (I)
]I }INS02
Ar
wherein R is selected from the group COllSiS ting of

-10 (1) - N ~ wherein R1 is selected from the group
( C~2 )nC00~2
g 2 C10 alkyl~ C3-Clo alkenyl, C3-C alkynyl

C2-C10 alkoxya~]~yl, C2-C10 alkylthioalkyl, C2-ClO alkyl-
Sulfinylall~yl~ CL-C10 I~y(lroxyallcy]~ c2_cl0 C~lhoxyall~yl~
C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, Cl-Clo
haloalkyl, C7-C1s aralkyl, Cg-Cls ~-carboxyaralkyl, C3-Clo
cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl, tetrahydrofurfuryl,
optionally substituted with at least one Cl-Cs alkyl and/or
Cl-Cs alkoxy,3-furylmçthyl, tetrahydro-3-furylmethyl, optionally
substituted with at least one Cl-Cs alkyl and/or Cl-Cs alkoxy
tetrahydro-~2(3 or 4)-pyranylmethyl optionally substituted with
at least one Cl-Cs alkyl and/or Cl-Cs alkoxy, 1,4-dioxa-2-
cyclohexylmethyl optionally substituted with at least one
Cl-Cs alkyl and/or Cl-Cs alkoxy,~2-thenyl, 3-thenyl,
tetrahydro-2-thenyl optionally substituted with at least
one Cl-Cs alkyl and/or Cl-Cs alkoxy, and tetrahydro-3-thenyl;
R2 is selected from the

113'~9


grour) consistin~r of` l~y~lrog~ C1O al.ky~., CG-Cl~ aryl,

C7-C12 aralkyl all(i 5-indallyl; a~ n is ~n int~g~r of` ~, 2

or 3~ (2) - N\ '3 wllerei~ 3 is sel.ecte(l from
(C~12 )mC~5
R4

the group collsis tirlg of lly~lrogen, Cl -C10 a].lcyl, C3-C10

3 10 .Llcyllyl., C2-C10 alko~cyal~cyl, C2-C alkyl-
tJ~ioalkyl, C2-C10 al.kylsulfinyl.alkyl, Cl-C10 hyclroxyalkyl,
C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10
alkylcarbonylalkyl, Cl-C10 haloalkyl, C7-C15 aralkyl, C8-C15
~-carboxyaralkyl, C3-C10 cycloalkyl, C4 C10 cy y
furfuryl, tetrahydrofurfuryl, optionally substituted with at
least one Cl-C5 alkyl and/or Cl-C5 alkoxy ~3-furylmethyl,
tetrahydro-3-furylmethyl, optionally substituted with at least
one Cl-C5 alkyl and/or Cl-C5 alkoxy tetrahydro-2(3 or 4)-
pyranylmethyl optionally substituted with at least one Cl-C5
alkyl and/or Cl-C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl
optionally substituted with at least one Cl-C5 alkyl and/or
Cl-C5 alkQxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally
substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy
and tetrahydro-3-thenyl; R4 is selected from the group consisti~
of Cl-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl,
optionally substituted with at least one Cl-C5 alkyl and/or
Cl-C5 alkoxy C7-C12 aralkyl and ring substituted benzyl
wherein said substituent is C1-C5 alkyl or Cl-C5 alkoxy; R5
is selected from the group consisting of hydrogen, Cl-CI0
alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and m is an
integer of 0, 1 or 2,

R,6
(3) - ~ wherein R6 is -COOR8 wherein R8 is selected
(R7)p

--4--

1-~3 7~

from the group consisting of hydrogen, Cl-Clo alkyl, C6-C1o
aryl, C7-C12 aralkyl and 5-indanyli (R7)p is hydrogen, Cl-C10
alkyl, phenyl Cl-C5 alkoxy or carboxy; p is an integer of 1
to 5; R6 is substituted at the 2 or 3-position; and R7 can

be substituted at the 2, 3, 4, 5 or 6-position,
COOR~ ~ .
(4) -~ ~ which is optionally substituted with at


least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is
selected from the group consisting of hydrogen, Cl-C1o alkyl,
C6-Clo aryl,

C7-C12 arallcyl. ~n(l COOI~10
5-indanyl; all(:l r is arl
intc!ger of 1, 2, 3 or 1l, (5) -N ;~ erein ~10 is
\'((~1'2 )(I
selectecl fronl tlle group conSistirlg o~` llyclrogell, C~ 10 al.lcyl,

C6-ClO aryl, C7-C~2 arallcyl and 5--indanyl; Z is sel.ected from
the group consi.s ting of oxy, tlLio an(l slll (`i.nyl; alld q :is
COOIll 1


an integer oi' O or 1., a~ld (6) -N\ ~ ~ ?irl ~11


is se,lected f`rom tlle g,roup consis ting of lly(irogell, Cl-ClO

6 ClO ~ryl ~ C7-C12 arallcyl ancl 5-in(lally 1; i i s


illteger ol' O, 1. or 2; j i.s an integer of` O, 1. or 2; alld thc
Sun) of i+j is all integer of 1 or 2; an(l Ar is selectecl from

t}le group collS.iSting Or naplltllyl~ 5,6,7,8-tctrally(lrorlapiltllyl,

optionally substituted with at least one Cl-C5 alkyl and/or
Cl-C5 alkoxy

- 1~37~f~{t


n~ tl~yl slJbsti.tuto(l witll at least one sut>~tituetlt selecte
from the groll~ consisting of halo~ nitro, cyano, hydroxy,
Cl-C10 alkyl, Cl-C1O alkoxy an(l C2-C20 ~iallcylamino, phenyl,
phenyl su~stitutecl Wit~l at least one substitllent selectetl
from the group con~isting of halo, nitro, cy~lo, hydroxy,
C1-Clo alkyl, C]-C10 alkoxy and C2-C20 ~ialky~-~mirlo, C7-C12

yl,and~


and


~ } 1~12 which are optionally substituted with at least
LO one Cl-Cs alkyl and/or Cl-C5 alkoxy, wherein R12 is hydrogen,
Cl-C10 alkyl or Cl-C10 alkoxy.
Also encompass~(l witllin tllis invelltioJI aro l~harnlaceutically
accepta~le scllts thcreof.
This invention also relates to a nlet]lo(l f`or inhil)i.ting
activity an~l sl~ppre~slJl~ activation or tllr(~ml)i.n in vi.vo,
'. WhiCIl Comr~ri~e~ i~lt;rO~Cin~ illtO a livi~lg l)~)(ly a })harma-
ce~ltica~y Orrcc~ivc amo~lnt ol` all N2-ur~lxlllrol~y:l-1-
arginiJIan~ le or thc ~ armaccutically acccp~ )lo salt thcrcol`.
This invention is also a process for producing an N -arylsulfonyl-
~O L-argininamide having the formuIa (I):
HN
/C - Nl -CH2CH2CH2cHcoR (I)
H2N H HNS02
Ar
B

li;~'7~




or the pharmaceutically acceptable salt thereof "~ erelrl R lS SeleCTSea
from the group consisting of
/ Rl
(1) -N wherein Rl is selected frorl the group
(CH2)nCR2
9 f C2 C10 alkyl, C3-C10 alkenyl, C3-Clo alkynyl, C -C
alkoxyalkyl., C2-C1O alkylthioalkyl, C2-C1O alkylsulfinylalkyl, C3-Clo
alkylcarbonylalkyl, Cl-C1O hydroxyalkyl, C2-C1O carboxyalkyl, C3-Clo
alkoxycarbonylalkyl, Cl-ClO haloalkyl, C7-C15 aralkyl, C~-C15
~-carboxyaralkyl, C3-Clo cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl,
tetrahydrofurfuryl, 3-furylmethyl~ tetrahydro-3-furylllletllyl, 2-thenyl,
3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R2 iS selected
from the group consisting of hydrogen, Cl-ClO alkyl, C6-C1O aryl,
C7-C12 aralkyl and 5-indanyl; and n is an integer of 1, 2 or 3,
/ 3
(2) -N wnerein R3 is selected fronl the group
CH-(c~2),ncOo!~s ::
R4




- 6a -
B

1137~




sistill~J of hy(b-oge~ Cl() alkyl~ C3-Cln alk~r~ C3 C10 y y
C2-C10 alkoxyalkyl, C~-Cl(~ alkylLhioalkyl, C2-Cl() alkylsulrinylalkyl,
Cl-C10 hyclroxv,31kyl, Cl~-C10 carl)ox~alhyl, C~-Cl(~ ali:t)xycarbonylalkyl.
C3-C10 alkylcarbonvlalkyl, Cl-ClO haloaliyl, (:7-C15 .nr.llkyl, C~-Cl~,
cl-carboxyaralkyl, C3-(:1r) cy(loalkyl, (~-Cl() cyclo.lliylalkyl, rurFuryl,
tetrahydrofurfuryl, 3-fu)ylllletllyl, tetrallydr()-3-furyllllethyl~ 2-thenyl.
3-thellyl, tetrahydlo-2-tllellyl, and tetrdhydro-3-lhellyl; R4 is selected
from the group consistillg of Cl-C10 ali;yl, carl)oxy, C2-C1O alkoxycarbonyl,
phenyl C7-C12 aralkyl and rillg substituted berlzyl wllerein said substituent
is Cl-C5 alkyl or Cl-C5 alkoxy; R5 is selecteci frnm the grou;) Collsistillg
of llydrogen, Cl-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indallyl;
and m is an inteyer of 0, 1 or 2,
~ .
~ (3) -N ~ ~1heleill R6 is -COOR8 wllereili R~ is selected from
t




R7


the group consisting of hydrogen~ Cl-C10 alkyl, C6-C10 aryl, C7-C12
aralkyl and 5-indanyl; R7 is hydrogen, Cl-ClO alkyl, l~henyl Cl-C5
alkoxy or carboxy; R6 is substitutecl at the 2 or 3-position; and R7
can be substituted at the 2, 3, 4, 5 or 6-position,
C~
~ (CIi2)~ wherein Rg is selected from the group con-
sisting of hydrogen, Cl-C10 a!kyl, C6-(10 aryl, C7-C12 a~-alkyl and




- 6b -
B





5-indanyl; an~l r i~ arl inte~er o~ 1, 2, 3 or ~.
COORln
>-~
(5) -N 7 whereill Rl() is selectrcl fronl the group consisting
~( C112 ) (1
of hydrogen, Cl-C1O a1kyl, C6-C1O aryl, C7-C12 aralkyl and 5-inddnyl;
Z is selectecl frolll the group consisting of oxy, thio and sulfinyl; and
q is an integer of O or 1, and
COOKl 1
~(C1~2);~
(CH2)J ~ wherein ~11 iS selected from the group

consisting of hydrogell, Cl-ClO alkyl, C6-C10 aryl, C7-C12 a~^alkyl and
5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i ~ j is an integer of 1 or 2; and Ar is selected fronl
the group consistincl of.naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl
substituted with at least one substituent selectecl from the group
conslsting of llalo, nitro, cyano, hydroxy, Cl-CIO alkyl, Cl-C10 alkoxy
and C~-C20 dialkylamino, phenyl, phenyl substituted with at least one
substituent selected froln the group consisting of halo, nitro, cyano,
hydroxy, Cl-C10 alkyl, Cl-ClO alkoxy and C2-C20 dialkylalnino, C7-Clc
aralkyl,



-1 ~ ' ~~ X o ~



B - 6c -





and



~ } R12 wherein R12 is hydrogen, Cl-C10

alkyl or Cl-C10 alkoxy, which comprises: reacting an
L-argininamide having the formula:

HN ~
,_,,C - N - CH2CH2CH2CHCOR
NH~
wherein R is defined herein above with an arylsulfonyl halide
having the for~ula: ArS02X, wherein Ar is as defined herein
above and X is halogen.




- 6d -

ti9

DETAILED DESC~IPTION OF T~IE PREFERRED EMBODI~ENTS

This invention relates to a group of N -arylsulfonyl-L-
argininamides of the formula (I):

HN ~
H N~ 1 2cH2cH2lcHcoR (I)
H HNSO2
Ar

wherein R is selected from the group consi~ting of

(1) - N \ 1 wherein Rl is selected from the group
( CH2 )nCR2
consi9ting of C2-C10 alkyl~ such as ethyl, propyl, butyl,
isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl
of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-
butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of
3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-
butynyl, 3-butynyl or the like~ alkoxyalkyl of 2-10
(preferably 2-6) carbon atoms, such as methoxymethyl, ~ ~ :
ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl,
2-propoxyethyl~ 2-methoxypropyl~ 3-methoxypropyl, 3-
ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl,
4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl
of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl,
ethylthiomethyl, propylthiomethyl, 2-methylthioethyl,

1-1374~9

2-ethylthi.oetllyl, 2-1)roi)ylthioet~lyl, 3-metllylthiopropyl,
2-methylthioprol)yl, 3-ethylthiopropyl, 3-propyltlliopropyl~
~-metlly]tll:iol~lltyl~ /I-etllylthioI~utyl, Il--btltyltlliobutyl~
5-butyltllio~entyl or the like, allcy:lsulf`inylall~yl of 2-10
(pre~erably 2-6) carbon atoms, such as methylsulfinylmethyl,
ethylsulfinylmethy.l, propylsulfinylmet}lyl, 2-methylsulfinyl-
ethyl, 2-etllylsul~inylethyl~ 2-propylslllfinylethyl, 3-
methylslllriJIy]l)ropyl~ 3-ethy]sulfi.nylprolyl or the lil~e,
hy(1roxyalkyl Or I -l.O (preferal)ly 1-6) carboll atoms, such
as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-
hydroxypropyl, 4-hydroxybutyl~ 3-hydroxybutyl, 5-hydroxy-
pentyl or the llke, carboxyalkyl of 2-10 (preferably 2-7)
carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-
carboxypropyl, 3-carboxypropyl, l-carboxybutyl~ 2-carboxy-
buty:L, 4-carboxybuty:L or the like, alkoxycarbonylalkyl of
3-10 (preferahly 3-8) carbon atoms, sllch as methoxycarbonyl-
metllyl, 2-ethoxycarl~ollyletllyl, 2-etl~oxycarborlylpropyl,
3-metlloxycarl)oJIyll)rol)yl~ l-metlloxycarbolly.ll)lltyl, 2-etlloxy-
c~r1~onylb-ltyl., /I-nletlloxycarl)ollylblltyl or tlle lilce,
alkylcarbonylalkyl of 3-10 carbon atoms, such as methylcarbony-
lethyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon
atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-
chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or th~
like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such
as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-
phenylhexyl, l-phenylethyl, 2 phenylpropyl or the like,
-carboxyaralkyl of 8-15

-- 8 --

li~'7~C~

(preferably 8-12) carbon atoms, such as ~ -carboxybenzyl,
~ -carboxyphenethyl or the like, C3-C10 cycloalkyl, such
as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohept~
cyclooctyl, cyclononyl or cyclodecyl, C4-C10 cycloalkylalkyl,
S such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl
2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl,
tetrahydrofurfuryl, optiorally substituted with at least one
Cl-C5 alkyl and/or Cl-C5 alkoxy 3-furylmethyl, tetrahydro-3-
furylmethyl, optionally substituted with at least one Cl-C5
alkyl and/or Cl-C5 alkoxy tetrahydro-2(3 or 4)-pyranylmethyl
optionally substituted with at least one Cl-C5 alkyl and/or
Cl-C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally
substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy,
2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted
with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, and
tetrahydro-3-thenyl; R2 is selected from the group consisting
of hydrogen, Cl-C10 alkyl, such as methyl, ethyl, propyl,
butyl, tert-butyl, hexyl, octyl, decyl or the like, C6-C10
aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl
of 7-12 (preferably 7-10) carbon atoms, such as benzyl,
; phenethyl or the like, and 5-indanyl; and n is an interger
of 1, 2 or 3,
~R3
(2) - N wherein R3 is selected from the
ICH (CH2)mcOoR5
R4

group consisting of hydrogen, Cl-C10 alkyl, such as methyl,
ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl
or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms,
such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like,
alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-
propynyl, 2-butynyl, 3-butynyl or the like, alkoxyalkyl of
2-10 (preferably 2-6) carbon atoms, such as

~137~


methoxymcthyl1el,lloxymcthyl, I)ropoxymetllyl., 2-methoxyethyl,
2-et;lloxyetlly] ~ 2-1)rol)oxyetl~yl~ 2-methoxypropyl, 3-methoxy-
proL)yl~ 3-etlloxyl)lollyl., 3-propoxypropy~ -methoxyl)lltyl~
4-etlloxyblltyl, ~-hlltoxybutyl, 5-butoxypel-1tyl or the like,
alkylthioalliyl oL` 2-:1~ (preferably 2-6) carboll atoms, such
~s methyltllio~ ly:l~ e~hylthiomethyl~ prol)ylthionletllyl, 2-
methylt~ioetllyl, 2-ethyltllioethyl, 2-propylthioethyl, 3-
metllyltlLioprol)yl, 2-methylthiopropyl, 3-etllylthiopropyl,
3-proF)ylthiopl-opyl, Il-mctllyltlliob~lty], I~-ethy]thiob-ltyl,
4-butylthiobutyl, 5-butylthiopentyl or the like, alkyl-
sulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such
as methylsulfirlylnnethyl, ethylsulfinylmethyl, propyl-
sulfinylmethyl$,2-methylsulfinylethyl, 2-etllylsulfinylethyl,
2-propylsulfinyletllyl, 3-methylsulfinylpropyl, 3-ethyl-
sulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably
1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropy], 2-1ly~roxypropyl, 4-hy(lroxyl)lltyl, 3-
lly(lroxyl-lll;yl, r~-llydroxypclltyl or tllC l~ c, carl)oxyalliyl of
2-1~ (I)rel`cr;ll)ly .>-7) c.lrl)oll atom~, s~lcll 1~ C;l.l'bOXylll('t1l
2-c1rboxyctllyl~ 2-(:1rl)oxyl)rol)y]~ 3-c1rl)oxyp]~ol)y1~ 1-
carl~oxyl)lltyl~ '-carl)oxyl)utyl~ 11-carboxyl)lltyl or tllc like,
a.ll;oxycarl)o~lylalky,l ol` '3-:1() (})rcf`cral)ly '3-~3) C1r-)011 atoms,
such as mett~oxycarl)olly.lmetlly.l, 2-metlloxyc1rl~ollyletllyl~ 2-
ethoxycarbollylprol~yl, 3-mettloxycarbol~yll)rol)yl~ l-metlloxy-
Cl ~`I)OIl y I l)ll l.y 1, >--(` tIIOXYC1I`I)OIIY J 1)ll l, y l, 11--lll(` tll() XyC1 r~l)olly.l1)1ltyI



I ~) _

li;~t~ 9

or the like, alkylcarbonylalkyl of 3-10 carbon atoms, such as
methylcarbonylethyl or the like, haloalkyl of 1-10 (preferably
1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethy
2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or
the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such
as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexy~
l-phenylethyl, 2-phenylpropyl or the like, G~ -carboxyaralkyl of
8-15 ~preferably 8-12) carbon atoms, such as G~ -carboxybenzyl,
~ -carboxyphenethyl or the like, C3-C10 cycloalkyl, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl or cyclodecyl, C4-C10 cycloalkylalkyl,
such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,
2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl,
tetrahydrofurfuryl, optionally substituted with at least one
Cl-C5 alkyl and/or Cl-C5 alkoxy 3-furylmethyl, tetrahydro-3-
furylmethyl, optionally substituted with at least one Cl-C5
alkyl and/or Cl-C5 alkoxy tetrahydro-2(3 or 4)-pyranylmethyl
optionally substituted with at least one Cl-C5 alkyl and/or
Cl-C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted
with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, 2-thenyl,
3-thenyl, tetrahydro-2-thenyl optionally substituted with at least
one Cl-C5 alkyl and/or Cl-C5 alkoxy, and tetrahydro-3-thenyl;
R4 is selected from the group consisting of alkyl of 1-10
(preferably l-S) carbon atoms, such as methyl,ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, carboxy
alkoxycarbonyl of 2-10 (preferably 2-5) carbon atoms, such as
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or the like,
phenyl, optionally substituted with at least one Cl-C5 alkyl
and/or Cl-C5 alkoxy aralkyl of 7-12 (preferably 7-10) carbon atom~
such as benzyl phenethyl or the like, and ring substituted benzyl
wherein said substituent is alkyl of 1-5 (preferably 1-3) carbon
atoms, such as methyl, ethyl, propyl or isopropyl, or


--11--

1:~3'7~ 3
alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy,
ethoxy, propoxy or isopropoxy; R5 is selected from the group
consisting of hydrogen, Cl-C10 alkyl, such as methyl, ethyl,
propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like,
C6-C10 aryl, such as phenyl, m-tolyl, naphthyl or the like,
aralkyl of 7-12 (preferably 7-10) carbon atoms, such as
benzyl, phenethyl or the like, and 5-indanyl; and m is an
~t~6
integer of 0, 1 or 2, (3) -N ~ wherein R6 is -COOR8
(R7)p
wherein R8 is selected from the group consisting of hydrogen,
Cl-C10 alkyl, such as methyl,ethyl, propyl, butyl, tert-
butyl, hexyl, octyl, decyl or the like, C6-C10 aryl, such as
phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12
(preferably 7-10) carbon atoms, such as benzyl, phenethyl
or the like, and 5-indanyl; (R7) is hydrogen, alkyl of 1-10
(preferably 1-6) carbon atoms, such as methyl, ethyl, propyl,
isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl
Cl-C5 alkoxy or carboxy; p is an integer of 1 to 5; R6
is substituted at the 2 or 3-position; and R7 can be substitutecl
at the 2, 3, 4, 5 or 6-position,
COOR ~
(4) - ~ ¦ which is optionally substituted with at
~ CH2 rr
least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is
selected from the group




-12-

11~'74~i,9


collsisting of lly(lrogcll~ C~-C10 alkyl, sucl~ as methyl, ethyl,
propyl, bllt;yl~ ~ert~ ttyl~ hexyl~ octyl, decyl or the lilce,
C~~C10 uryl, SIICII as phellyl ~ m-tolyl, naplltllyl. or the like,

arulky:L of` 7-L2 (prcf`crab:l.y 7-10) carboll UtomS~ sllch as bellzyl,
phenetllyl or the like, and 5-indanyl; ~n(i r is all integer of
1, 2, 3 or ll,
coor~ O
~ .
(5) -N ~ wllcre:irl Rlo is selected from Ihe group
~C112)(1

consisting of hydrogell, Cl-C10 alkyl, such as methyl, ethyl,
propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like,

C6-C10 aryl, such as phenyl~m-tolyl~ naphthyl or the like,
aralkyl of 7-12 (preferably 7-10) carbon atoms, such as
benzyl, phenethyl or the like, and 5-indarlyl; Z is selected

from the group consisting of oxy (-O-), thio (-S-) and
sulfinyl (-SO-); q is an integer of O or 1, and


C~
~(CII2) ~ whereill ~ll is selectcd ~rom the grollp

COllsi.Stil)g Or lly(lro~cll, cl-clO al];yl, sucll us metllyl, ethyl,
I)rol)yl, blltyl, telt-l?~ltyl, llcxyl., octyl, decyl ~r tlle like,
C6-C10 aryl, SllCh aS phellyl, m-tolyl, naplltllyl or the like,
aralkyl of 7-12 (preferably 7-10) carbon atoms, such as
berlzyl, ~tlelle~tlyl or the like, arl(l 5-irld.lllyl.; i is an




~ 13 -



integer of 0, l or 2; j is an integer of 0, 1 or 2; and the
sum of i-tj is an integer of 1 or 2; an~ Ar is seleeted from
the group eonsisting o~ naphthyl, sueh as l-naphth~l and 2-
naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally su~stituted
with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy ~uch as
5,6,7,8-tetrahyclro-l-naphthyl and 5,6,7,8-tetrahydro-2-
llaphthy1, naplltllyl substituted Wittl at least one substituent
selectetl fronl the grollp eonsisting of ha:lo, such as fluoro,
chloro, ~)romo arl(l iodo, ni-tro, cyano, hydroxy, allcyl of
1-10 (preferabl.y 1.-5) carbon atoms, SUCIl as methyl, ethyl,
propyl, isopropyl, butyl, isobu-tyl or the lilce, alkoxy of
l-lO (preferably 1-5) earbon atoms, such as methoxy, ethoxy,
propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy,
pentyloxy or the lilce~ and dialkylamino of 2-20 (preferably
2-lO) carbc)ll atoms, such as dimethylamillo, dietllylamino,
N-methyl-N-ethylamino or the ].i]ce, phenyl, phenyl substituted
~ith at least one substituent seleeted from the group eon-
SiSting Or halo, sueh as fluoro, ehloro, bromo and iodo,
nitro, eyano, hyclroxy, alkyl o.f l-10 (preferably 1-5) carbon
atoms, such as methy:l., ethyl, propyl, isopropy]., butyl,
isol)llty.L or th(3 lilcc3, allcoxy of 1-1.0 (preferal)ly 1-5) carbon
atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy,
see-butoxy, tert-butoxy, pentyloxy or the lilce, and
dialkylamino of 2-20 (preferably 2-10) earbon atoms, sueh
as dimethylamino, cliethylamino, N-methyl-N-ethylamino or
the like, aralkyl of 7-12 (preferably 7-lO) earbon atoms,




-- I 11 --

1`~3~J~g


such as bcnzyl, phenethyl or the like, and ~ ) ,

~ ' ~0~


~ ~ ~ and ~ } R12


which are optionally substitllted with at least one Cl-C5 alkyl
and/o~ Cl-C5 alkoxy, wherein R12 is h~dToqen, alkyl of 1-10


(preferably 1-5) carbon atoms, such as methyl, ethyl, propyl
or the like, or alkoxy of 1-10 (preferably 1-5) carbon atoms,
such as methoxy, ethoxy, propoxy or the like.
Suitable illustrations of Rl in the above formula (I) are
C2-C10 alkyl, such as propyl, butyl, isobutyl, pentyl,
hexyl and octyl, C3-C6 alkenyl such as allyl, C3-C6 alkynyl,

such as 2-propynyl, C2-C6 alkoxyalkyl, such as 2-methoxyethyl,

2-methoxypropylJ 2-ethoxyethyl and 3-methoxypropyl, C2-C6

alkylthioalkyl, such as 2-ethylthioethyl and 2-methylthioethyl,

C2-C6 alkylsulfinylalkyl, such a9 2-methylsulfinylethyl~

Cl-C6 hydroxyalkyl, such as 2-hydroxyethyl and 3-hydroxyb.utyl,
C2-C7 carboxyalkyl, such as l-carboxybutyl, C3-C8 alkoxycarbonyl-

alkyl, such as 2-ethoxycarbonylethyl~ C7-C10 aralkyl, such a9



-- 15 --




betlzyl al(J pher~etllyl~ C8-C12 .~1 -ca:rboxyaralkyl, such as ~ -
carboxyphenetllyl, C3-Cl~ cycloalky:L, SllCh as cyclopropyl,
cyclohexyl and cycloheptyl, Cl-C10 cycl.oalky~allcyl, such as
cyclohexylmetlly:l, t`lm ruryl, tetrallydrorurrllryl~ 3-furylmethyl,
tetrahydro-3-fulylmetllyl~ 2--thenyl, 3-thenyl, tetrahydro-2-
tllollyl all(l tetrallyclro-3-thenyl.
~uitabl.e i.Llustrlt;iorls of R3 in the above I`ormula (I) are
hy(lrogerl, Cl-CI() allyl.~ sucll as methyl, propyl, butyl,
isobutyl, pentyl, iloxyl and oc-tyl., C3-C6 al]cenyl, such as
allyl~ C3-C6 allcynyl, sueh as 2-propynyl, C2-C6 allcoxyalkyl,
such as 2-methoxyetllyl~ 2-methoxypropyl, 2-ethoxyethyl dlld
3-methoxypropyl, C2-C6 alkylthioalkyl, sucll as 2-ethylthio-
ethyl and 2-metllylthioethyl, C2-C6 allcylsulfinylalkyl, such
as 2-methylsulfinylethyl~ Cl-C6 hydroxyal]{yl, sucll as 2-
hydroxyethyl and 3-hydroxybutyl, C2-C7 carboxyalkyl, such
as l-earboxyblltyl, C3-C8 alkoxycarbonylallcyl, such as 2-
ethoxycarL)onylctllyl, C7-C10 arallcyl, sucll as l)ellzyl alld
l)llell~tllyl~ C8-C12 ~ -carboxy~ra]ky~, sllcll as ~ -carl)oxy-
pholletllyl, C3-CI~ cyc:loa~l;yl, sucll as cyc]o~ o~yl, cyclohexyl
all(l cycloll(!l~lyl, (Il-Cl~ cye.loa.LI;ylallcy:l, sllcll as cyclolloxyl-
metllyl, f`urf`uryl, tetrahy(lrofurt'uryl, 3-l'urylmetllyl,
tetrahy(lro-3--rllrylm(3tllyl, 2--thetlyl, 3-thc!llyl, tetrahydro-2--
thellyl an(l tetrully(lro-3-thenyl.
~ui-table il:LIlstratiolls Or ~1l in the above fornlula (I) are
C1-C5 allyl, sllch as metllyl and propyl, e.lrl)oxy, C2-C5

ti9


alkoxycarbonyl, such as ethoxycarbonyl~ C7-C10 aralkyl,
such as benzyl, and ring substituted benzyl wherein said
substituent is Cl-C3 alkoxy, ~uch a~ 4-methoxybenzyl.
Suitable illu~trations of R7 are hydrogen, Cl-C6 alkyl,
such as methyl, ethyl, propyl and isopropyl, phenyl and
carboxy, and the suitable position of R7 is ~J 4 or 6.

COOH
)~ ,
Suitable -N Z groups are 3-carboxy-4-morpholino,
\-(CH2)/
3-carboxy-4-thiomorpholino~ 1-oxo-3-carboxy-4-thiomorpholino
and 4-earboxy-3-thiazolidinyl.

COOH
Suitable -N ~ ~ groups are 2-carboxy-1~2~3~4-

tetrahydro-l-quinolyl, 3-earboxy-1,2,3,4-tetrallydro-2-
isoquinolyl, l-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl,
2~earboxy-1-indolinyl and 1-earboxy-2-isoindolinyl.
Suitable illustrations of R2, R5, R8, Rg, Rlo and Rll are
hydrogen, Cl-C10 alkyl, sueh as methyl~ ethyl, tert-butyl
and oetyl, C6-C10 aryl, such as phenyl and m-tolyl, C7-ClO
aralkyl, such as benzyl, and 5-indanyl.




- 17 -


Sui~able illustrations o~ Ar in th~ above formula (I) are
naphthyl, such as l-naph-thyl and 2-naphthyl~ 5,6,7,8-
tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-1-naphthyl
and s,6,7,8-tetrahydro-2-naphthyl, naphthyl substituted
with at least one substituent selected from the group
consisting of halo, such as chloro and bromo, hydroxy,
Cl-C5 alkyl, such as methyl, ethyl and isopropyl, Cl-C5
alkoxy, such as methoxy and ethoxy, and C2-C10 dialkylamino,
such as dimethylamino and diethylamino, phenyl, phenyl
substituted with at least one substituent selected from the
~roup consisting of halo, such as chloro, Cl-C5 alkyl, such
as methyl, ethyl and isopropyl and Cl-C5 alkoxy, such as
methoxy, C7-C10 aralkyl, such as phenethyl, ~ )

such as ~ ~ , such as


and . ~ , such as ~ .

The preferred Ar groups are l-naphthyl, 2-naphthyl~ 5,6,7,8-
tetrahydro-l-naphthyl~ 5,6,7,8-tetrahydro-2-naphthyl, 5-
chloro-l-naphthyl, 6-chloro-2-naphthyl, 6-bromo-1-naphthyl,
5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-
naphthyl, 6-methyl-1-naphthyl, 7-methyl-1-naphthyl, 7-methyl-
2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl,



~ 18 -

1~3~ i9


f"7-dimetllyl-2-l-al)lltllyl, 6-isopropy:L--2-llaphtllyl, 5--methoxy-
.I-naphthyl ~ fi-mc tlloxy-2-napllthy.l, 7-methoxy-2-rlclplltltyl ~ '
,6-dimetlloxy-2-1laE~ hyJ, 6,7-dimetlloxy-2--1aplltllyl, G,7-
(lictlloxy-2-rlclplltl~yl, 5-di.mctlly~anurlo-1-llal)lltllyl~ 5-
dimethylamillo-2-rlapllthyl~ 5-diethylamino-1-naptlthyl, 6-
dimettlyla~ illo-L-Ilal~ tllyl, 6-climethylami.llo-Z-naptlt}ly.L ~
chlorol)hcllyl., 2,1~,5-trichlorophenyl~p-to1y], anisyl, 3,4-
dimettloxyllhelly~, 3,/~,5-trimetl-loxypllerlyl, ~


~ ) and (~3

Illustrative of suitable N -arylsulforlyl-L-argininamides of
sufficient activity are the fol.lowing:

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

N -(fi,7-~limctllo~y-2-1laplltlly1sll]follyl)-~,-argi~lyl-N-
propylglycille t;crt-blltyl cster

N --(fi,7-~ tllo~y--,"--ll<ll>lltlly:L~ rolly~ rillyl--N--
hllty:lg1ycille

N -(6,7-dinletlloxy-2-lla~ LIlylsulronyl)-L-argillyl-N~
bllty:lg]ycillc tert-l~lltyl ester




_ 19 _

~3'7~69


N -(6,7-(linletl~c)xy~ aplltllyls-l:Lrorlyl)-l,-<ltgillyl.-N-
i obutyl~,lycillc

N -(6,7-(limcttloxy-2-tlap}lthy:Lsulfollyl)-L-artri.nyl-N-
pentylglycine

N -(6,7-~1i.mcthoxy-2-llaplltllylsulfollyl)-L-argirlyl-N-
hexy]gly CillC

N -(6,7-dimetlloxy-2-llaphthy:Lsulfonyl)-L-argirlyl-N-
o c ~:yl~lycill c

N -(4,6-~imetlloxy-2-naphthylsulfonyl)-I,-arginyl-N-
butylg]ycinc

N -(6,7-~lietlloxy-2-rlaphtllylsulfonyl)-L-argillyl-N-
buty]glycille

N -(6-methoxy-2-llapllthylsulfonyl)-L-arginyl-N-butylglycine

N2-(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-butylglycine

N -(7-methoxy-2-naph-thylsulfonyl)-L-argillyl-N-propylglycine

N -(7-methoxy-2-naphtllylsulfollyl)-L-argirlyl-N-butylglycine

N -(7-methoxy-2-llaplltllylSulfollyl)-L-argillyl-N-pentylglycine

N -(2-naphthylsulfollyl)-L-arginyl-N-butylglycine

N -(Z-nal)lltllyl~ ronyl)-l,-argillyl-N-b~ltylglycine ethyl cster



~() _

1~3'~9

N -(2-naphthylsulfony].)-L-arginyl-N-butylglycine ben~yl
ester


N -(2-naphthylsulfonyl)-L-arginyl-N-butyl-~ ~alanine


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


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


N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-
butyl-~ -alanine


N -t6-bromo-1-naphthylsulfonyl)-L-arginyl-N-butylglycine


N -(6-methyl-2-naphthylsulfonyl)-L-arginyl-N-pentylglycine


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


N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl-N-
butylglycine



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


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


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


1~37~69


N --( (), 7--( l i ~ ( ) Y y ~ y l ~ O J ~ f, i l l y ~--N--
IIIC l,llO~y(~t:llyl )~, I )'(`.i 11'~! (?tllyl C~ l,C:I`

N ((-,7--~ ncl.lloxy-.'-lla7)lllllyl~ill1 fo]lyl )--1,--a~gil-ly~--N-
(2-mctlloxyetllyl )~1 yc.irle o ctyl es ter

N -(6,7-(1inlcl llox:y-2-1lal)lltllylsulron~ -arginyl-N-
(2-mel;lloxyetlly:L)glycirle t)cn~yl ester

N -(6,7-d:i mel;llo,Yy-;'-ll~lL)ILl;hylsu:l rOIly~ )-I,-a~gillyl.-N-
(2-mctl~oxycl;llyl)gLyc:ille '3-methy:lpllellyl e.ster

N -(6, 7-(lime thoxy-2-l1aplltllylsul ronyl ) -I,-arginyl-N--
(2-methoxyetllyl)glyc~ e 5-indanyl ester

N --(G ,7-dimethoxy-2-1laphtl-lylsulfonyl )-L,-arginyl-N-
(2-methoxyetllyl)-~,--alanine ~:

N -(6~7-dimetho:;y-2-naplltllylsul ronyl )-L-arginyl-N-
(2-metlloxyel,l~yl)- ~, -alulli.ne etllyl estel

N --(G,7--d.illlcl,llo.Y~ tllyls~ `olly.l )--N-(2--nlctlloxyctlly:l )--
N--('~--c~rl~oxyl~rol~yl )--l,--arg:i7l:ill.lm.i.(lc

N --(G,7--(limclLIoxy--;'--n~ l;llylsllll`olly1.)--N--( '-metlloxyc?tllyl)--
N -( '3-terl~ tOXyc;ll l~ony:l pro~yl ) -L-arp;.i ll:i llanli(le

N -(6,7-dimctlloxy-,-rla~ tllylslllrollyl)-N-(3-nlel:lloxy-
2() prol~yl )g,l yc:i ue




-- 22 --

1~37~

N -(6,7-~lirnethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(2-ethoxyethyl)-~ -alanine


N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-
(2-methoxypropyl)glycine


N2-(6~7-diethoxy-2-naphthylsul~onyl)-L-arginyl-N-
(2-methoxyethyl)glycine


N2-(4,6-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-
(2-methoxyethyl)glycine


N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-argillyl-N-
(2-methoxyethyl)glycine ethyl e~ter


N -(6-methoxy-2-naphthyl9ul~onyl)-L-arginyl-N-(2-
methoxyethyl)glycine


N -(5-methoxy-1-naphthylsul~onyl)-L-arginyl-N-(2-
methoxyethyl)glycine


N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-
methoxyethyl)glycine



N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-
methoxyethyl)glycine ethyl ester


N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-
methoxyethyl)-~ -alanine




- 23 -

tii9

N ~ naphthylslllfonyl)-L-arginyl-N-(2-methoxyethyl)glycine


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


N -(5-chloro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-
ethyl)glycine


N -(6-chloro-2-naphthyl~ulfonyl)-L-arginyl-N-(2-methoxy-
ethy~)glycine


N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-
ethyl)glycine


N -(7-methyl-1-naphthylsulfonyl)-L-arginyl-~-methoxy-
ethyl)glycine


N -(6,7-dimethyl-1-naphthylsulfonyl)-L-arginyl-N- (2-
methoxyethyl)glycine


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



N -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-
ethyl)glycine
N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-
ethylthioethyl)glycine

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




-- 24 _

{j9


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


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


N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(3-hydroxybutyl)glycine


N -(6,7-dimethoxy-2-naphthyl~ulfonyl)-L-arginyl-N-
(l-carboxybutyl)glycine


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


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


N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
benzylglycine tert-butyl ester


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



N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
benzyl-~ -alanine


N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
benzyl- ~ -alanine tert-butyl ester




- 2~ -

113~ 9


N -(f~7~ metlloxy-2-lla~lt~lyls~ `orlyl)-L-~r~i.nyl-N-
pllCll~tlly~ lllillC

N _(11 ,f)-~lin~ctlloyy-2-~ ltlly~ o~ly~ r~i.llyl-N
benzylg],ycine

N -(7-methoxy-2-J-Ia~ tl-lylsulronyl)-L-argirlyl-N-
phenetlly:l glycinc

N -(7-metl~oYy-2-llar)ll~llylsu].forlyl)-L-arginyl-N-l~ellzy].-~ -
alani.ne

N -(6-mctl-loxy-2-naplltllylsulronyl.)-N-ben~yl-N-(3-
c rboxypropy].)-l,-argininamicle

N -(6-methoxy-2-rlapllthylsulfonyl)-N-benzyl-N-(3-tert-
butoxycarbonylpropy].)-l,-argininamide

N -(5-methoxy-1-naplltllylsulforlyl)-L-argillyl.-N-
benzylglycine

N -(2-naphtllylslllronyl)-L-arginyl-N-benzyl-~ -a]anine

N -(2-nap~ y.ls~l.lt`oJIy.l.)-L-arc,illy].-N-l)cll~ylglycillc

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

N -(5,6,7,8-tetrahyclro-2-naphthylsulfollyl)-L-argillyl.-N-
benzylglyci.rlc



- Z6 -

li;~'7'~9

N -(5~GJ7~-tCtraIIY(IrO-2-rIaP}It1IY19U1~OIIY1)-L-arginY1-N
b (~Jl ~ Y~ Lrl i rl

N -(7--mCtl~Y1--2~ PI~tIlY15I11fOnY1)--L-arg:ilIYI.-N-PIIenetlIY1
g I y Cill e

N -( 6 ~7-di.methOXY-2-llal)I1thY1 SU1 fnIIY1 ) _L-LIrgj.rIY1-N-(~ -
carhoxyphellethyl. )glycine

N -(6 ,7-(1ime tl~oxy-2-naphthylsulfonyl )-I,-arginyl-N-
cyclohexylmet}lylglycine

N --(6,7--dimethoxy-2--napllthylsulfonyl)--L--argi.nyl--N-
cyclohexylmetllylglycille tert-butyl es ter

N -(6~7-dimethOXY-2-naPhthY15U1fOnY1)-L-arginY1-N-
cycloheptylglycille

N -( 4, G-di methoxy-2-napht}lylslll fonyl ) -L-arginyl -N-
cyc ] o hoxyl ~.1 y C:i ll e

N -(7-met}IOXY-2-11aPIItIIY15U1rOrIY1 )-L-argirIY] -N-CYC1OheXY1-
f~ yc~

N --((;--mel.lloxy--~-nu~ l,lly~ .LJ`ollyl )--L--urt,illyl--N--cyclollexyL--
motllylglycillo

N --( r~--nlelNIOI;Y--I--II;~ .IIYI .`;111 I`OIIY I )--I,--;.11~g.j.11Y I--N--CYC.I OlleXYI.




27

~ ~374f~9


N -(5-metlloxy-l-nclplltllylsulf`ollyl)-I,-arginy:L-N-
cyclohexyllllell~yL-¦~ -a.~allirle tert-L~utyl ester

N -(fi~7-d.i.nl(?tlloxy-.~ al)lltllylsul.l`ollyl)-l,-.lr~illy:l-N-
cyclo}l~xylgl.ycil-
~

N -(6,7-(1illletl~oxy~2-1lapllthyl.sulfonyl)-l,-argi.llyl-N-
cyclo}lexy.L-~ -a.lall:i.rle

N -(6,7-dimetllo~y-2--lap]lthylslllfonyl)-L-argillyl-N-
cyclohexyl-~ -ala~ e tert-butyl ester

N-cyclopropyl-N-(3-carboxypropyl)-N -(6,7-cl;.methoxy-2-
naphthyl.sulf`onyl)-L-argininamide

N -(l-naphthylslllfollyl)-L-arginyl-N-cyclohexylglycine

N -(5,6,7,8-tetrahydro-1-naphthylsulronyl)-L-arginyl-N-
cyclohexylg:Lycine

N -(5,6,7~8-tctrallydro-2-naplltllylsulfonyl)-1,-arginyl-N-
; 15 cyclohexyLmethylglycine

N -(7-meLIIyl-'-~ llyl.Sulf`onyl)-L-argilly:l-N-cyc~ollexyl-
mc t llyl gly c:irl c

N -(7-methyl-2-1laphthylsulfonyl)-L-arginyl-N-furfurylglycine

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



- 28 -

1:~374f~9


N -(7-1ncl;]loxy-~ tltllylstllfollyl)-L-arginy].-N--

furf`llrylglyc~




N -(7-metlloxy-'-na~ tl~ylsulfolly:l)-L-argilly:L-N-
f rfurylglycille tert-l~utyl ester


N -(7-metlloxy-2-llaplltllylsulfonyl)-L-argi]lyl-N-
totrahydro~ rrllrylglycirlc


N -(5-(~inl(3tl1ylal1l:il1o-l-llapllt~lylsulfonyl)-L-~r~i~lyl-N
tetrahydro ru r fll rylglycille


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

tetrahydrofurfllrylglycine

N -(l-naplltllylsul rOI-yl ) -L-arginyl-N-tetrally(lrofurfur
g]ycine


N -(6,7-dimethyl-1-naphthylsulforlyl)-L-arginyl-N-
tetrallyclrofurfurylglycine


N -(5,G,7,8-tetrally(lro-1-naplltllylsulfollyl.)-L-argillyl-
N-tetrally(irorllrf`lll yl.gl ycitle

N --(G ,7-d.i nlc~ ~11oxy-2-llu~ tlly~ su:ll`ollyl )--L--argillyl -N--
tctr~ y(lrol`llr.l`-lrylg,I.yci.llc

N -(6,7-dinlctllo~y-,'-1lal)lltlly]sull`o~lyl.)-L-al~ginyl.-N-
l~ yl~ -llli 11(3




- 2~ -



N -(G~7-(1:ime~lloxy-2-1laa~lltilylslllf`ol-lyl)~L,-arg~ yl--N--
L~utylala~ e I ert;-hlltyl ester

N --(6~7--~1imcl;lloxy-2--1lal)lltllylsu1.rolly].)~ ar~ yl--N--
pelltyla].arline

N --(6,7-~limethoxy-"-llaphtalylsul.fonyl)--L-argirlyl-N-
bcrl~.yl alanine ,,

N ~-( 6 ~7-di metlloxy-2-]nlr)llthylslllfonyl ) -L-arginy.l.-N-
phene thyla.lallille

N -( 6, 7-dimethoxy-2-1lapllthylsulf:`onyl ) -L-arginyl -N--
cyclohexyla].alli]le

N -(4 ,6-dimethoxy-2-naphthylsulfonyl )-L-arginyl-N-
cycl ohexyl metllylal anine

N -( 7-methoxy-2-naphthylsulfonyl )-L-arginyl-N-propylalanine

N --(6,7--~limothoxy-2-1lclpllt}lylg-llrollyl)--1~--arginyl-~(2-metllo~y-
ethyl )aLallinc

N --(fi,7--(I~ lel.llo~y--.!-u;ll)lll llylsu~ ~`ony.l )--l,--al~gillyl.llorvalillc

N -(6,7-~1i.motl~oxy-2-1laphthylsulfonyl.)-L-arginyl-N-
butylaspartic acid

N -(6,7-(limeLlloYy-2-llal)lltlly:LsulLfollyl)-L-nrgillyl-N-
l~utylasp<lrtic uci.(l (liethyl ec~ ter



- 3~ --

g

N -(6,7-dimethoxy-2-~lap}lthylsulfollyl)-l,-argillyl-N-
b nzylaspart::ic acid


N -(6,7-dimetlloxy-2-rlaptltllyl.slllf`ollyl)-L-arg.illyl-N-
benzylaspartic acid dlethyl ester


N -(6,7-di.methoxy-2-lla~lltllyls-ll.follyl)-L-argilly].-N-metlly:l-
~ -plleny~ alanl]l (~


N -(6,7-dimetl-1oxy-2-napllthylsulfollyl)-L-arg:inyl-N-methyl-
-(4-metlloxyphenyl)alanine


l-[N2-(6,7-dimethoxy-2-1laphthylsulfonyl)-L-arginyl~-2-
piperidirlecarboxyli c acid

Ethyl l-~N -(6,7-di.methoxy-2-rlapllthylSIllforlyl)-L-argirlyl~-
2-pi~eridineearboxylate


l-[N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-
piperidineearboxylie aeid


l-[N -(6,7-dimethoxy-2-napllthylsulforlyl)-L-arginyl~
methyl-2-piperidineearboxylic aeid

1--tN --(7--mctlloxy--2--naplltllylslllfonyl )--I,-arginyl~--4--methyl-2--
piperidineearboxylie aeid



l-tN -(5-methoxy-1-naphthylsulfonyl)-L-argillyl~-4-methyl-2-
pi~eri(lillec.lrl~oxy.lie aeid : .




- 31 -

1:~3';'~


Ethyl l-~N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl~
methyl-2-piperidinecarboxylate


l-~N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-
methyl-2-piperidinecarboxylic acid


l-~N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl~-4-
methyl-2-piperidinecarboxylic acid


l-tN2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~ -4-
ethyl-2-piperidinecarboxylic acid


l-~N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-
piperidinecarboxylic acid


l-rN -( 6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-
propyl-2-piperidinecarboxylic acid


l-~N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-
isopropyl-2-piperidinecarboxylic acid


l-tN -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-6-
methyl-2-piperidinecarboxylic acid



l-tN -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-methyl-2-
piperidinecarboxylic acid


l-[N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-3-
piperidinecarboxylic acid




- 32 -



Methyl l-~N -(6,7-dimethoxy-2-napllthylsulfonyl)-L-arginyl~ -
3-piperidinecar~oxylate

l-tN -(7-methoxy-2-naphthylsulfony:L)-L-arginyl~-3-
piperidinecarboxylic acid

l-[N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-2, 6-
piperidinedlcarboxylic acid

l-tN2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-
phenyl-2-piperidinecarboxylic acid

l-~N2-(1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-
piperidinecarboxylic acid

Ethyl l-~N -(l-naphthylsulfonyl)-L-arginyl~ -4-methyl-2-
piperidinecarboxylate

l-[N -(2-naphthylsul~onyl)-L-arginyl~-4-isopropyl-2-
piperidinecarboxylic acid

Ethyl l-[N2-(2-naphthylsulfonyl)-L-arginyl~-4-isOPropyl-
2-piperidinecarboxylate

l-[N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl3-
- 4-methyl-2-piperidinecarboxylic acid

Ethyl l-[N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-
arginyl~-4-methyl-2-piperidinecarboxylate




~ 33 -

~:~37~t~9


l-[N -(6-chloro-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-
2-piperidinecarboxylic acid


l-[N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~-
2-piperidinecarboxylic acid


l-[N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-
piperidinecarboxylic acid


l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-
2-piperidinecarboxylic acid


l-rN -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-
2-piperidinecarboxylic acid


Ethyl l-[N -(7-methyl-2-naphthyl~ulfonyl)-L-arginyl~-4-
isopropyl-2-piperidinecarboxylate


l-[N2-(6-methyl-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-
2-piperidinecarboxylic acid

1 - [N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-2-
hexamethyleneiminecarboxylic acid



4~ CN - ( 7-methoxy-2-naphthylsulfonyl)-L-arginyl~-3-
thiomorpholinecarboxylic acid


4-~N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~ -3-
carboxythiomorpholine l-oxide




- 34 -

1-13~9


4-~N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl~-3-
morpholinecarboxylic aci~

4-[N -(7~methoxy-2-naphthylsulfonyl)-L-arginyl~-3-
morpholinecarboxylic acid

3 - [N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-4-
thia olidinecarboxylic acid

2-rN -(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-
1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid

2-~N2-(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~
i oindoline-l-carboxylic acid

N -(4-chlorophenylsulfonyl)-L-arginyl-N-butylglycine

N -(2~4,5-trichlorophenylsulfonyl)-L-arginyl-N-butylglycine

N2-tosyl-L-arginyl-N-butylglycine

N -(4-methoxyphenylsulfonyl)-L-arginyl-N-benzylglycine

N -( 3,4-dimethoxyphenylsulfonyl)-L-arginyl-N-(2-methoxyethyl)
glycine

N -(3,4,5-trimethoxyphenylSulfonyl)-L-arginyl-N-(2-
methoxyethyl)glycine

N -phenethylsulfonyl-L-arginyl-N-furfurylglycine

<~


N ~ -t)en~o-li oxall -G-sulfonyl)-L-argirlyl-N-(2-methoxyethyl)
g] ycine

N~--(f ,7--c~ y l e~e(li oxy--2--naplltlly:l sul rOlly:l )--I,--argi llyl -N--
(2-mctlLoxyetllyl )gl ycine

l-~N -(2-cl:ibell~c)r~lrarlyl)-L--arginyl~ -2-piperi c~inecarbo~Yylic
ac:i(l

Of ttle compoullcls c~r this invention, it ~ill be l~lclerstood
that the fo.Llowirlg compounds are most preferred clue to their
high level Or antittlrombotic activity ancl lo~ level of
toxicity.

N -(6,7-climethoxy-2-naphthylsulfonyl)-L-arginyl-N-
butyLglycine

N2-(7-methoxy-2-napllthylsulrorlyl)-L-arginyl-N-butylglycine

N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(2-methoYyetlly~)f,rlycirle

N -(6,7-<limet}loYy-2-rlapllthylsulronyl)-L-argi,nyl-N-
(2-methoxyethyl)glyci,rle ethyl ester

N -(l~,G-~li,motlloxy-2-lllplltllylsu]follyl)-L-~rf~ yl-N
(2-metlloxyetllyl)f,rlycille

N -(7-methoxy-2-napllthylsulfonyl)-L-arginy~-N-(2-
methoxyetllyl )glycine



-- 36 --

1:~37~9

N -(5tfi~7~-tc~r~lly(lro~ aph~llylsulrorly~ -arginy~-N
( 2-me t~loxye tllyl )e~ yci.le

N -(7-metlloxy-2-]lcll)lltlly1.sll1rollyl)-l,-argirlyl-N-tetrallydro-
furrurylglycillo
N -(7-metIIY:L-2-~ )1It~Y1SII1rOIIY1)-L-argiIIY~-N-tetra}IYdrO-
L`ur.rurylgl ycillc
N -(6~7-(IinIetIIOXY-2-IIIPIIt}IY1SU1fOnY1)-L-argiIIY1-N-
totra11y(1roI`Ilrr~lry.lgLycille

1-~N -(6,7-dimethoxy-2-naphthyls-llfoslyl)-L-arginyl~-4-
methyl-2-piperidinecarboxylie acid

1- CN -( 7-metlloxy-2-llaphtllylsulrollyl)-L-argin
methyl-2-piperidinecarboxylie acid

l.-tN -(7-methoxy-2-naphthyl.sulfonyl)-L-arginyl~ -ethyl-
2-piperidinecarl)oxyl.ic aeid

'I`he pllarm~collt:ica1:ly acceptal.)l.e sa.l.ts o:f the above compounds
are of cours-? a:lso inelll(l(?d within t11e seope of this
illV('lltiOII,
As one skilled in the art ean readily appreeiate, tlle
carbon atom of the N -arylsulfonyl-L-argininamides, to
whicll the carl)oxyl. gro~ or tlle ester tl~oreo~` is attaehed
call 1)e an asymmo1;ric carhosl atom allowi.llg ror the exi.stence

i;~3~ i9


ol` t~ro o~ticnlly active isomers, the n- alld l,-diastereoisomers,
as wcl 1. as l:he raccnlat(?, I)l,-mixture .
In accordallce ~i tll f'i.n(lings conccrnir-g tl~(! alltitllrombotic
act;iv.i ty o r s.,cl, compoun(ls possessillg un asymltletl lc carborl
atom, the compoullds of the present inventioll having the
D-conrigllra t ioll ar c more active than thoS(! of the L--
conl`ig~lral;ioll ull(l arc tho prer(!rrc(l compollll(ls, a]tllough the
1,- an(l I)l,-l'ornl.s of ~lle :instant compollll(ls ar(! also considerecl
wi thill tll(? purview Or the present inverltiorl .
Thc above compourl(1s are intende(l only to illustrate the
variety of structures which can be used in the process of
this invention, an(l tlle above listing is not to be construed
as limiting the :3cope of tlle invcntion.
}?or the preparatiorl of the compowlds Or thls invention,
various methods can be employed depending UpOII the particu-
lar starting materials and/or intermediates involved.
Successful preparal ion of theSe compounds is possible by
way of` severa1 syllthetic routc!s which are outlilled below.
(a) Con(lensatiorl of' an L-ar~inirlami(lc witll an ary].su]follyl
~ 11-1 1 .i.ll(!
TlLiS pI'OCCSS mily bc! i,llus trated as fol~ ows:

C -- N -- Cll2C112C112 jcllcOOll (11 )
Il NH2




~ 38 --




IIN ~
~C --N -- C112C112C112Cl~COOll ( t;)
R" IIN
~' I
R "'
+ RTI (IV) >

IIN
~C - N - Cll2c~l2cll2cllcoR (V) >
R" IIN
1~' 1


IIN ~
C -- N -- CH2cE~2cll2cHcoR ( VI )
N 1 12
+ ArS02X ( VII )

~N ~ :
~C -- N -- C}12C112Cll2cllcOR ( I )

I~NS2
Ar

~n Lllc abovc l`ornllllas ~ 1~ arl~l Ar are as ~lerino(l llcrein
above; X is lla~ogen; R"~ is a protective group for :-
the ~ -am:ino group, such as benzyloxycarbonyl or tert- ;
l~utoxycarbollyl; R~ and R" are selccted from tlle group
con~istillfr Or llydrofren an(l protoctivo grollps ror thc
gllatli(lill() grollp~ ~ucll as nitro, tosyl, trityl,



-- 39 --

1~37~9


oxycarbollyi all(l the like; ancl at lcast one Or R~ and
~" is a protc-ctive group for the guanidlno group.
rhc N~-arylsulrotlyl-L-argillinamicle (I) is prepared by
tllc con(lellsatiotl of an L-ar~inillami(le (VI) with a
sul~stalltially eqllimo1ar amount of an ary1sulfony1
hali(lc (V:II), prcferably a ch10ride.
Tllc con(lcllsatioll reaction is genera]ly efrected in a
suita~)l.e react:ioll-iJIert soLvent in the presence of an
excess Or a ~ase, s~lch as an orgallic l~ase (triethyl-
amine, pyridine) or a solution of an inorganic base
(sodillm hydroxi(le, potassium carbonate), at a tempera-
ture of` ~C to the boiling temperature of the solvent
for a period of 10 minutes to 15 hours.
The preferred solvents for tlle condellsation include
benzene-clietllyl ether, diethyl ether-water and dioxane-
water.
~fter the reaction is complete, tlle rorme(l salt is
extracted with water, and the so1vent is removed by
such stanclard mealls as evaporation under redllcecl
2~ ~rossnro Io ~,ivc lllo N2-arylsu1L`ollyl-l-argillinamide
(~.), wllicll call bo ~uriricll ~y trituratioll or recrystalli-
ZtltiOII rrom a sllital~le solvellt~ sllcll as ~ie-thyl ether-
tctr~llydrol`llrall~ di.otllyl ethor-mctllt~lol ancl water-

lllCtllallO.l ~ OI' Illtly bo CllrOmtlLOgraplle(l Oll silica gcl.
I`l~o l-arci~illanu(los (Vl.) startirl~ nul~olia:Ls rcquirctl

1:~3~ 9

for the condensation reaction can be prepared by
protecting the guanidino and ~ -amino group9 of L-
arginine (II) via nitration, acetylation, formylation,
phthaloylation, trifluoroacetylation, p-methoxy-
benzyloxycarbonylation, benzoylation, benzyloxy-
carbonylation, tert-butoxycarbonylation or tritylation
and then condensing the formed NG-substituted-~2-
substituted-L-arginine (m) with a corresponding
amino acid derivative (IV) by such a conventional
proceqs as the acid chloride method, azide method,
mixed anhydride method, activated ester method or
carbodiimide method, and thereafter selectively
removing the protective groups from the formed NG-
substituted-N -substituted-L-argininamide (V).
The amino acid derivatives (IV) which are the starting
materialq for the preparation of the NG-substituted-
N2-9ubstituted-L-argininamide9 (V) are represented by
the following formulas:

H-N~ 1 ( vm ) H-N~ 3 (IX)
(CH2)nCR2 1 ('CH2)mCR5
R6 R4
I COORg

R7 (X) ~ (XI)



- 41 -

~3~i9

COORlo COORll

CH~ (XII) \ (CH2)~ ~ ( xm )

In the above ~ormulas, Rl, R2, R3, R4, R5, R6, R7, Rg,
Rlo, Rll, Z, n, m, r, q, i, and ~ are as defined herein
above.
The amino acid derivatlves of the above formula (vm)
or (IX) can be prepared by the condensation of a
haloacetate, 3-halopropionate or 4-halobutyrate with
an appropriate amine having the formula RlNH2 or
R3NH2. (See, J. Org. Chem., 2~ 728-732 (1960)).
The condensation reaction is generally carried out
without a solvent or in a Solvent, such a~ benzene or
ether, in the presence of an organic base, such as
triethylamine or pyridine, at a temperature of O C to
80C for a period of 10 minutes to 20 hours. A~ter the
reaction iB complete, the formed amino acid derivative
is separated by such conventional mean~ as extraction
with a suitable solvent or evaporation of the reaction
solvent and thereafter purified by distillation under
reduced pressure.
Among the amino acid derivative~ amino acid tert-butyl
ester derivatives are preferred, because they are easily
converted to other ester derivatives by acidolysis in



- 42 -

1:~374~


the presence of` a corresponding alcohol employing an
inorganic acid (HCl, H2S04, etc.) or an organi~ acid
(toluenesulfonic acid, trifluoroacetic acid, etc.).
In accordance with the proce9s employed for preparing
~ 2-piperidinecarboxylic acid derivatives (X), the
following scheme is illustrative:

NaOCl ~ R KOH~ ~ R7 _HCN>

H Cl
(XIV) (XV) (XVI)

R7 H20 > ~ R7
N CN (H~) N C02H
H
(XVII) (xvm)

In the firat reaction of the aforementioned scheme, an
appropriately substituted piperidine (XIV) is contacted
with an aqueous sodium hypochlorite solution at a
temperature of -5C to 0C. The reRultant product (XV)
is isolated by extraction with a solvent, e g., diethyl
ether~ and then treated with pota9sium hydroxide in a
lower alkanol solvent to give the 1,2-dehydropiperidine
(XVI). The action of cyanogenating agents, e.g.,
hydrogen cyanide or sodium cyanide converts the 1,2-
dehydropiperidines (XVI) to the corresponding 2-cyano



~ 43 -

~3~4~9'


analogs (XVII). Hydrolysis of the 2-cyanopiperidines
(XVII) to yield the 2-piperidinecarboxylic acids
xvm) is effected by treatment of the 2-cyanopiperidineS
(XVII) with an inorganic acid, such as hydrochloric
acid or sulfuric acid.
The arylsulfonyl halides (VII) which are the starting
materials for the preparation of the N2-arylsulfonyl-
L-arglninamides (I) can be prepared by halogenating
the requisite arylsulfonic acids or their salt~ e.g.,
sodium salt~, by conventional methods well known to
those skilled in the art.
In practice, halogenation is carried out without a
solvent or in a quitable qolvent e.g., halogenated
hydrocarbons or DMF in the presence of a halogenating
agent, e.g., phosphorous oxychloride, thionyl chloride,
phosphorous trichloride, pho9phorous tribromide or
phosphorous pentachloride, at a temperature of -10C
to 200C for a period of 5 minutes to 5 hours. After
the reaction is complete, the reaction product is
poured into ice water and then extracted with a solvent
such as ether, benzene, ethyl acetate, chloroform or
the like.
The arylsulfonyl halide can be purified by recrystalli-
zation from a suitable solvent such as hexane, benzene
or the llke.



- 44 -

~i37~9

(b) Removal of the NG-su'Dstituent from an NG-substituted--
N -arylsulfonyl-L-argininamide
This process may be illustratecl as follows:

HN
H2cH2cH2cHcoR (V) ,~
R " HN
R~ I
R"~

HN ~C-I -cH2cH2cH2cHcoR (XIX) ArSO2X (VII)

R ~ 2

HN ~,
C--N--CH2 CH2 CH2 CHC OR ( XX )
R~ HNSO2
R~ I
Ar


C-N-CH2CH2CH2CHCOR ( I )
H HNS02
Ar




45 . s




' '

~ ~374~9


ln the above ~ormulas~ 1~, Ar, X, R', R" and ~"~ are
as clefi.nccl hereirl above
Tlle N -ary1slll.l`ollyl-L-argininami(le (1) i.s prepared by
renlov~ g tl~e N(~-substituent f`rom an N(-substituted-
N -arylsulfonyl-I-argininamide (XX) by means of
aciclol.ysis or ~Iyclrogellolysis.
I`he aciciol.ysi s is generally effecl;ed by contacting
tlle N~-substituted-N -arylsulfonyl-L-argininamide
(XX) and an excess of an aeid 9UCI~ as llydrogen
fluoride~ ~Iyclrogen chloride, hydrogell l)romide or
tri.fl.uoroacetic acid, without a solvent or in a solvent,
SUCII QS an etller ( tetrahydrofurall, dioxane), an alcohol
(metllat~ol, etllanol) or acetic acid at a temperature of
-10C to 100C, and preferably at room temperature for
a period of 30 minutes to 24 hours.
The products are isolated by evaporation of the solvent
and the excess acid, or by trituration with a suitable
so.lv(?llt rol.l.owed l)y filtration ancl dryi.ll~.
IICCaUSC 0~` tllC IlSe 0.~ C! CXCOSY ;IC~ tllc PIO(IIICI:S
are g(`ll(`lUI IY l,lIC aCi~l a(~ OII ~:al.l,S 0~` tllc N--
arylsulrollyl-L-argininami(les (I), whicll can be easily
convcrt(!(l lo a E`ree amicle by ne~ltr;l:l.izal;ioll.
The removal Or the nitro group aud tlle oxycarbonyl
group, e.g., benzyloxycarbonyl, p-nitrobellzyloxy-
carbollyl, i.s rea~lily accompl.i41le(l l~y tlle llydrogenolysis.



~ ~6 --

li3746i9

At the same time, the benzyl e~ter moiety which can
be included in the R group is converted to the carboxyl
group by the hydrogenolysis.
~he hydrogenolysis i8 effected in a reaction-inert
solvent~ e.g., methanol, ethanol, tetrahydrofuran or
dioxane, in the presence of a hydrogen-activating
catalyst, e.g., Raney nickel, palladium, or platinum,
in a hydrogen atmosphere at a temperature of 0C to
the boiling temperature of the solvent for a period
of 2 hours to 120 hours.
The hydrogen pressure is not critical, and atmospheric
pressure is sufficient
The N -arylsulfonyl-L-argininamides (I) are isolated
by filtration of the catalyst followed by evaporation
of the solvent
The N -arylsulfonyl-L-argininamides can be purified in
the same mànner as described above.
The NG-substituted-N2-arylsulfonyl-L-argininamides (XX)
starting materials can be prepared by condensing an
NG-substituted-N2-substituted L-arginine (m) (generally
the NG-sub9tituent is nitro or acyl, and the N2-
substituent is a protective group for the amino group,
such as benzyloxycarbonyl, tert-butoxycarbonyl, or the
like) and a corresponding amino acid derivative (IV)~
selectively removing only the N -substituent of an



-- 47 --

li3~469


-snbstit~1te(l-N -substituted 1,-arginiJ1amide (V) by means
of cata1ytic hydrogenolysis or ac.i.dolysis, and tllen
co11(1c11si11~ thc th1ls obtai11ed N -stll)slitl1t~d-l,-
al~ lli(lc (~ ) witll all arylstllt`o1lyl lla.l.ido (Vll),
preferably a chloride in the presence of a base in a
so~verlt. T11cse reaction conditions are as c1escribed
abovc i11 tlle con(lc1lsation Or an l,-argilli11amide with an
aryls11~`o1ly] l~a~ide, and the removal oI` the NG-
substitllont f`rom an NG-subst.ituted-N --arylsulronyl--L--
argin:inamide.
(c) Condensati.o1l of an N -arylsulfonyl-I,-arginyl halide
with an amino acid derivative
This process may be illustratecl as follows:

11
1~ ~
~C-N-C~12CH2CH2CHCOO~I (II)
N}12
+ Ar~02X (VII)

Il
IIN ~
1I N ~C N Cl"C112C~121CIIC0011 (XXI) >
IINS02
l~r




-- 48 --

li37~9


IIN ~
,c-N-clt2c~t2cH2c~lcox (XX~I)
~NS02
~r
-~ Rll(IV) ->

ll
IIN ~
Il N ~ 2 2 2ll~COR(I)
IINI:;02
Ar

In the above formulas, R, Ar and X are as defined
herein above.
The N -arylsu]fonyl-L-arginirlamide (I) is prepared by
- the condensation of an N -arylsulfonyl-L-arginyl
halide (XXII), preferably a chloride witll at least an
equimolar amount of an amino acid derivative (IV).
The condellsation reaction can be carried out without
an added solvent in the presence of a base. However,
satisfactory results will be obtainect with the use of
a ~olvollt SllCIl ~14 I)asic solve~lts (~limi~tllylformamide~
dimethylacetamide, etc.) or halogenated solvents
(chloroform, dichloromethane, etc.).
The amolult of the solvent to be used is not critical
and may vary from abollt 5 -to 100 times l;l~e weigllt of
t;~lo N -arylslllrollyl-l-ar~irlyl hali(te (XXI])



49
.

1~3~4~9


I'reftrretl con(lellsatioTI rcactiol~ tem~eratures are in
the range of rrom -10C to room temperature. The
reaction time is not critical, but varies with the
amino acid dcrivative (IV) employed. In general, a
period Or from 5 minutes to 10 hours is operable.
The obtaiJIed N -arylsulfonyl-L-argininamicle can be
isolated a~ld lurifit~d in the same manller as described
abovo.
The N -arylsull`ollyl-L-ar6rinyl halide (XXII) starting
matcrials re(luired for the con(lensation reaction can
be prepared by reacting an N -arylsulronyl-L-arginine
(XXI) with at least an equimolar amount of a halo-
genating agent such as thionyl chloride, phosphorous
oxycllloride, phosphorus trichloride, phosphorous
pentacllloride or phosphorus tribromidc. The halogena-
tion can be carried out with or withollt an added solvent.
The preferred solvents are chlorillate(l hydrocarbons such
as chloroform ~Id dichloron)ethalle, an~l etllcrs such as
tetrahydrol`llran and diox~ule.
: 2~ t~llo~ . t>l` t.ll~ lvt~llt lo l)~ t~ lot clitic~l
nll~ nlay vary l`rom a~out 5 to 1()0 times tlle weight of
tllc N -aryl~ult`ollyl-L-argilline (XX~).
l'roferrc(l rcactioll temperature arc in tllc ratlge Or
-10 C to room teml~erature. The reaction time is not
critical, l~ut varies with the ha1Ogellatillg agent and



-- 50 --

1~37~i9


reaction temperature. In general, a period of 15
minutes to 5 hours is operable,
The N -arylsulfonyl-L-arginine~ (XXI) which are the
starting materials for the preparation of the N -
arylsulfonyl-L-arginyl halides (XXII) can be prepared
by the condensation of L-arginine (II) with a sub-
stantially equimolar amount of arylsulfonyl halides
(VII), by a method similar to that described in the
condensation of an L-argininamide with an arylsulfonyl
halide.
(d) Guanidylation of an N -arylsulfonyl-L-ornithinamide or
an acid addition salt thereof
This process may be illustrated as follows:

H2N--c~2cH2cH2cHcoR (~cm) --->
HN I o2
Ar

HN ~
H N ~ CH2cH2cH2lcHcoR (I)
HNS02
Ar

In the above formulas~ R and Ar are as defined herein
above.
The N -arylsulfonyl-L-argininamide (I) is prepared by



-- 51 --

li374~9

guanidylating an N -arylsulfonyl-L-ornithinanude
(XXlI) with ~1 ordinary guanidylating agent such as
an 0-alkylisourea, S-alkylisothiourea, l-guanyl-3,5-
dimethylpyrazole or carbodiimide. The preferred
guanidylating agents are the 0-alkylisourea and the
S-alkylisothiourea.
The guanidylation of the N -arylsulfonyl-L-ornithinamide
(xxm) with the 0-alkylisourea or S-alkylisothiourea is
generally effected in a solvent in the presence of a
base at a temperature of from 0C to the boiling
temperature of the solvent for a period of from 30
minutes to 50 hou~s.
Examples of the preferred bases are triethylamine,
pyridine, sodium hydroxide and sodium methoxide.
The base is used in an amount of 0.01 to 0.1 equivalent
to the N -arylsulfonyl-L-ornithinamide.
Examples of the preferred solvents are water, water-
ethanol and water-dioxane,
After the reaction is complete, the N -arylsulfonyl-L-
argininamide (I) is isolated by evaporation of the
solvent followed by removal of the excess base and the
formed salt by a water wash.
It i9 well recognized in the art that an ester deriva-
tive of the N -arylsulfonyl-L-argininamide (I) wherein
R2, R5~ R8, Rg, Rlo or Rll i9 alkyl, aralkyl, aryl or



- 52 -

li374~;9

5-indanyl, can be prepared from a carboxylic acid
derivative of the N -arylsulfonyl-L-argininamide
2~ R5~ R8, Rg, Rlo or Rll is hydrogen by
the conventional esterification methods well known to
those skilled in the art. It is also well recognized
in the art that the carboxylic acid derivative can be
prepared from the ester derivative by the conventional
hydrolysis or acidoly~is methods. The conditions under
which e~terification, hydrolysis or acidolysis would
be carried out will be each apparent to those skilled
in the art.
The N -arylsulfonyl-L-argininamide (I) of this invention
forms acid addition salts with any of a variety of inorganic
and organic acids. Some of the N -arylsulfonyl-L-argininamides
containing a free carboxyl group, wherein R2, R5, R8, Rg,
Rlo or Rll is hydrogen, forms salts with any of a variety
of inorganic and organic bases.
The product of the reactions described above can be isolated
in the free form or in the form of salts. In addition, the
product can be obtained as pharmaceutically acceptablc acid
addition salt4 by reacting one of the free bases with an
acid, such as hydrochloric, hydrobromic, hydroiodic, nitric,
sulfuric~ phosphoric, acetic~ citric, maleic, succinic,
lactic, tartaric, gluconic, benzoic, methanesulfonic,




~ 53 -

1~37469

o ~ l i c, ~ o l ~ I ( l l (? .~ U I [ () l l i. C ~I C i. ( l o r
;llC .1 i 1~(?~ 1 11 <I Y:i IlI.i I ~I r III-IIIIIC? 1`~ 1~ll(? ~) 1'()(1ll (` 1, Cllll l)C OL) t LillCC
LS ~ 11'111ilC(~II I i (`11 1 I y ~1(`(`(?1) t:~LL) I (? YCI I L.Y 1)~ IIC l.:i ll~r OIIC! 0 r tlle

I)ot.lsY.il.llll ll)~ o~ l(?, i~rllrllo~ llll lly~ o~ ly~.clnli.llc,
roca~ le, (I:il)~ Ianl.il)(?, .I.-e~ c]l Lm.il~ N,N '-(I:il)c?n:~,y:l.etlly1el1e-
clial~ le, N-ctllyll)il)c~t~:i.(l:inc 01~ tllc .lil;e.
elriY C? ~ t r(?~ 111(?11 1; O r L 11(~ s.ll. L s ~i t ll ~- 1.) LY (? O r aci(l resul ts
ill ~1 r('g(?llel'al..i()ll ol' L:IIC? rt'(!(` allli.(l(`.
1 0 l~ s s t a t -? ( l . I L ) -) V (?, ~ N --.~ y l. Y I I .I r O l l y ~ r ~ a llLi ( l c? y ~
the sall;s- tll(?l~eof c)l` thi~; illVO]ltiOII are cllar-lctc?ri~e(l l~y
their ~ ,llly ~l~cc:i.ri.c i.n~ i.tory act:i.v~ y a~.linsl; throml)ir
as well as ~ lC.i. L' Slll)S t.lll tial. lacli o L` L o~;:i ci. ty~ all(l
Lllcr(?~`ol~e t~ ;(? collll~o~ e lls(~ lL :ill ~ (I(?ternlirlatioll .
Or t11roml~:ill :il~ l).lood as clia~,]lostic re.~ e]lts, an(l/or ror the
mediccLl COII trol o L` prC?Vell tion Or tllrOllll)OSis,
Tlle com~)o~lllclY o r` tl~:i.Y i.nvclltloll are al.Yo USC?rll1 as arl
illllil):i tO1~ ol' l)l.atel et ~lg~rc?~atioll ~
Tlle a]l ti throml~o L i c ac l;i.vi ty O r L hc N -arylsulfonyl-L-
~o arg:i.llillanli.(l(~ ` Llli~; .i.llV(?lll,i.OII \~/aY COIIII)al'('(l w.i.tll tllat ol~
a kllowll allt:il:lllollll)c)L,:i.c aC~ellt, N -(p-l;o.lylsll:l I`olly].)-L--
argiJli.]le mCI:II~'I c~ite:l~ del.c.rlllilli]~,~,r tl~c ~ :i]lo~,e]l coa~u-
latioll time. Tlle mecl~jllremellt Or tlle l`.il)rino~ell coa~,,rulatio
tinle waY colldllcte(l aY l`ollows:
~rl ~.8 nll ali(l~loL ol` a l`.il)r.i.no~;c]l solllL.i.oll, wlli(llll.l-l L)ee



- 5~ -

~:~3~

prcpared by disso1ving 150 mg of bovine fibrinogen (Cohn
fraction I) sllpplied hy Armour Inc. in 40 ml of a borate
saline buffer (pH 7.~), was mixed with 0.1 ml of a borate
saline buffer, pH 7.4, (control) or a sample solution in
the same buffer, and 0.1 ml of a -thrombin solution (5 units/
ml) supplied by Mochida Pharmaceutical Co., Ltd. was added
to the solutions in an ice bath.
Immediately after mixing9 the reaction mixture was trans-
ferred from the ice bat-h to a bath maintained at 25 C.
Coagulation times were taken as the period between the time
of transference 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 are 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
50-55 seconds to 100-110 seconds,
The concentration required to prolong the coagulation time
by a factor of two for the known antithrombotic agent,
N -(p-tolylsulfonyl)-L-arginine methyl ester, was l,lOO~m.
The inhibitors are shown in Table 1 by indicating R and Ar
in the formula (I) and the addition moiety.
When a solution con-taining an N -arylsulfonyl-L-
argininamide of this invention was administered intravenously



~ 55 ~

~i3';'4~9


into LlnirllaL l)odie:;, I;llc lligll alltitllronll)otic activi.ty in tlle
C:irCll lati.ll~ oO(I was mai.l~t.liJIo(l f`or from ol)e t;o tllree IlOUrS .
'I`]~ a1r.~ r~-r ~leeaY ol` 1,1l0 ~Irlti-tllrOnll~OI;~;C COm~)O~II1(l$ Or
tll;S j~V(`IILj.()ll jll (~;~C~I.Iat~ 100(1 W;1S :;IIOWII 1,0 1~0 a~pro--
ximately 60 minutos; the physiologi cal condi. tions of the
host allima:ls trat, ral)l)it~ (log allcl cllimpan~ee) were well
maintaille(l. ~rhe exl~erime~ltal decrease Or r:ibrinogeJl in
aninla.l.s causo(l l)y illl`l.lsiorl of tllrombirl was satisfactori.ly
controllecl l~y s:imultalleolls inf`usion of tlle compounds of
thi s inven ti on .
Tlle acute to~cici ty values (I,D50) determined by intraperito--
neal. admini.stlatioll of substa~lces of formula (I) in mice
(male, 20 g) rallge rrom about l,000 to l0,000 milligrams per
kilogram of body weight.
Represelltative LD50 values for tl~e compolm~ls of this inven-
tiOlI are sllown :in the roll.owing Tabl e .
..._.

(~ ) o l ~ I, D ~ o ( nlg/l; g )
N --( 7--mO t lly I -2~ )Jl l,lly I ~;ul l'ollyl )--1,-- >
arg:irlyl-N-lllll.yltrlyo:illo 1,500
2 ~ . ...... ..
N -(6,7-(1imotlloxy-2-1laplltllylsulI'ollyl )-L-
arginyl-N-(2-metllo~:yethyl)glycirle 1,~00-2,400
2 '' ------ . .... _
N --(6 ,7-(limethoxy-2-rlapllthylsulf'onyl )--L--
arginyl--N--(2--ethoxyethyl )--~--alanine 660-1, 000
.. .. _ ........... ...... _ .. _.




- 56 -

469


~ . .
C o mpo ull d ~D50 ( mg/kg )
2 __
N --(/1 ,6-diltl~tl~oYy--,?--n~plltllylsu] ronyL )--1,--
. l l '~ N--(, '--111 ( ! 1, ~ l l y ~ c .i 1 l ~ 6 6 0--1, 0 0 0
_
N ~-(7-me tlloxy-2 naplltllylsulforlyl )-L- 2, 000
arginyl--N-( 2 -me thoxye tllyl )glyci.ne
. . . ,.
N~-(5~6~7~ ;etr~llly~iro-l-naplltllylsulfolly:l )- ~ r
I,-argillyl -N-(, -metlloxyetlly:L )g] yc:i ne 1, ~00
2 ~ __
N --( 6, 7 -di me l:llyl -:1--nzlphl;l-lylsul ronyl )--L-- >
iar6:irlyl -N-( 2-me tlloxycthy]. )glyc:ine 1, 500
. ._
N -( 6, 7--d :i mc! tho xy-2 -napllthyl suL fonyl ) -1,-
arg:inyl-N-(2-etllyl thioethyl )glyc.ine >1~ ()00
.
N -(6,7-dimethoxy-2-naE)httlylsulfonyl)~L- >1 000
arginyl-N-bell~yl.glycille ~
~ . _
N2-(4,6--limettloxy-2-rlapllthylstllronyl )-L,-
argilly:L-N-l)ell~yl~;lyc~ e 1,000
_ _ . __ . ___
N -(5-methoxy-1-1lill)lltllylsulrollyl )-L-- ~1 000
arginyl-N-t)erl~ylglycine ~
. . _ . ._ ._ . . .
.~ N -(6,7-climetlloxy-2-tlapllthylsulfonyl)-L-
arginyl-N-phenethy:l glycine ~1, 500
~- 2 --~- ~ - --- _ _
N --(6 ,7--dimet;lloxy-2--llaphthylsulfonyl )-L-
arg:i.tlyl-N-cyc lollexyl gl ycine ~1, 500
. _ . __ _ .__ .~
N -( 6, 7 -di me thoxy-2 -naphthylsul fonyl ) -L-
arginyl-N--cycl ollexy~metllylgl.ycine ~1, 500
_ . .
N -(7-nletllyl -2-rlal)lltlly.l sll].rorly:L )-L- 600
argi.rly:l.--N-tet:rally(ll orllrrltryLglyci-lle . _




~ 57 ~

li3~ 9


..
~ompollrlcl ~ 50 (mg/lcg)
. .. _._ ___
N -(~),7-dimctlloxy-,'-l1a~ tllyls~ `ony])-l,- ~2
~llf,i~ l-- N--~(`t l~ `of~ rllryl ~r~ ~Cill(~
._ ._ ._
N -(G~7-(1imetlloxy-2-naptlttlylsulf`onyl)-L- > 1 roo
arginyl-N-butyla]<llline "
_ . .
N -(4,~ imetlloxy-2-1lclpllthy:Lsulfonyl)-l,- > ~,5~0
argilly1-N-cyclollrxy.lmetlly]cllallin(?
l-~N~-(f)~7-~limetlloxy-2-rlapllttlylsu]fc)llyl)-l~- 1 500
arginyl~-2-pil)cri(lillecarbo.Yylic acicl ,
... .. .
Ethyl l.l- N -(7-metlloxy-2-rlaphttlylsulforlyl)- 670-1 000
L-arginyl~ -nletl~yl-2-piperidirlecarboxy~ate
l-[N2-(4~6-climetlloxy-2-naphthylsulfonyl)-
L-arginyl~-4-nlethy]-2-piperidinecarboxyli.c 670-1,000
acid
~ __ .
]-[N -(l-napllthy:lslllt`onyl)-L-arginyl)-4- 700-1,000
metl~y.l-2-~)ipol-idillecarboxylic acid
. . . _ ... . __
]-- CN -( 5-dimetllylamillo-1-naptltllylsulfo~lyl)-
L-arginyl~-2-pil)e]iAirlecarboxy.]ic acid 700-1,000
_
11- [N - ( 7-motlloxy-~ aplll:hylsuL ronyl ) -L- ~ 1,~00
alginy.l~-'3-nlolpllolillocarl)oxy.lic aci(l
.. _ _ I
2-¦N--(~ nI(~I;IIO~;Y-2-~ )IItIIY~ Y-I-)-I~-
arg:illyl~-1,2,~ ol.lally(lloiso(~ inolillc-~- ~ 1,000
C ;l 1 ~ " (~ j ( 1
, _ .
2- LN -( ~j ~ 7--(IinI~ t~ Y-2-IIa})IItIIY1SII11 OI~Y I- )-IJ- ~ ::
ar~rillyl~ isoin(lt,lillccurl~o.~ylic acid ~ 1,00()

On the other hall(l, 1,D5~ values ror N -dallsyl-N-b~ltyl-L-
arginil~amide and N -d~lsyl-N-methyl-N-buty:l-L-argirlinamide
aI'e 75 and 7~ mill.i~,ram~ per ki.logranl~ rcspective]y.




- 58 -

1~374~9


Tlle therapelltic agellts Or tllis inventioll muy be admilliYtered
alolle or in conll)illaLioll wi LII pllarmcleeutlcul Iy uecc!ptclble
carriers, tlle l)ro~)or~ion Or whieh is determine(l by tlle
so lul~i ] i ty arl(l el~elll:i ca I n.ltllrc! Or the eompollllcl~ ellosen routeof administration and standard pharmaeeuti eal praetiee .
F`or exampl e, the compounds may be in jeeted parenterally,
that is, intramllsclllurly, intravenously or sul~eutaneously.
F`or parenteral ac1nlinistration, the eompourl(ls may be used in
the form Or sterile solutions eontailling other solutes, for
exampl(?, suff`icierlt saline or g]ueose t;o malce the solution
isotonic. L`he eoml)ollllds may be administerecl oral]y in the
form of` tablets, capsules, or granules eontaillirlg suitable
eXCipi.elltS SUCIl as starch~ laetose, white sugar and the like.
Tlle compoun(ls mly be aclmillistereci sub~itlgllu11y in the form
f troehes or lozetlges in whieh eaeh aetive ingreclient is
mixed wi th sugar or eorn syrups, f`lavoring agents and dyes ~
and tllell delly<irate(i su~`riei ently to make the mixture suitable
ror pressillg into so]i d form. The eompoullcis may be aci-
ministered ora] ly ill the form Or solutions W}liCh may eontain
eolorin~ un(l rlavorillg agetlts. l'hysiciulls will cletermine
the dosage of the present therapeutie agents whieh will be
most suitab:Le, and dosages vary with tlle mocie of administra-- -
tion and the particular compourld chosen. In acldition, the
dosage will vary wi tll the particular patient under treatment .
When the composition is administered oral]y, a larger quantity



~ 59 -

1137~9


of` l l~e clCt.iVe a~''CIIt will be re~ ired to pro~ ce tlle same
er`recl; as canse(l wi.tll a small(?r llualltity gi.verl parenterally.
lle tller~r)ellt:ic dosage :is genera.11y 10-50 mg/lcg of acti.ve
ingrc(licllt pal ellter.l l Iy, 10-5()0 mg/l<g ora.l..l.y per day .
Having generally described the invent;ion, a more complete
unders tanding can bC! obtai.ned by reii`erence to certain specific
exampleS, wlli cll are :inc1~l(led fot~ purposes of i.lltls tration
on~y ~n(l are not inten(le~i to be l.imi.ti.ngr l.llll.e::;S ot]~erwise
sp e ci. ~'i ed .




~ ~0 _

1~37~9

EXA~IPLE

(A) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine:
To a well stirred solution of 83.6 g of L-arginine in
800 ml of 10~ potassium carbonate solution was added
114.7 g of 6,7-dimethoxy-2-naphthalenesulfonyl cnloride in
800 ml of benzene. The reaction mixture was stirred at
60 C for 5 hours, during which time the product precipi-
tated. After one hour at room temperature, the precipi-
tate was filtered and washed ~uccessively with benzene
and water to give 129 g (76 percent) of N2-(6,7-dimethoxy-
2-naphthylsu~fonyl)-L-arginine, M.P. 252-5 C.

(B) N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride;

A suspension of 2.00 g of N -(6,7-dimethoxy-2-naphthyl-
sulfonyl)-L-arginine in 20 ml of thionyl chloride was
stirred for 2 hours at room temperature. 4ddition of
cold dry diethyl ether resulted in a precipitate which
was collected by filtration and washed several times
with dry diethyl ether to give N2-(6,7-dimethoxy-2-
n phthylsulfonyl)-L-arginyl chloride.

(C) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyliN-
butylglycine tert-butyl ester:




- 61 -


To a stirre~ solution of 2.6/~ g of N-butylglycine
tert-butyl ester in 20 ml of c~oroform was carefully
added N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl
chloride obtained above. The reaction
mixture was allowed to stand at room temperature for
one hour. At the end of this period, the reaction
mixture was washed twice with 20 ml of saturated sodium
chloride solutlon and evaporated to drynes~.
The residue was triturated with a small amount of water
to give a crystalline material. This was collected by
filtration and recrystallized from ethanol-ethyl ether
to give 2.28 g (82 percent) of N -(6,7-dimethoxy-2-
naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl
ester, M.P. 164-166C, I.R. (KBr): 3,390, 3,165, 1,735,
1,370 cm 1.
Analysi9 - Calcd. for C28H4307N5S-~H2S3 (perc
C, 52.98; H, 7.00; N, 11.04 Found (percent): C, 52.69;
H~ 6.98; N, 10.86

(D) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
butylglycine:
To a solution of 2.00 g of N -(6,7-dimethoxy-2-
naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl
ester in 20 ml of chloroform was added 50 ml of 15%
HCl-ethyl acetate. The reaction mixture was stirred



- 62 -

37~tjg

for 5 llours at room temperature. At tlle end of this
peri.od, tlle relcti.on mixture wclS evaporate(i to dryness.
The residllc was w.lslled several times wi. th dry diethyl
ctller an(l cllromatographed on 80 ml. ot` I)aiaion (~) SK 102
ion exchallfre resin (200-300 mesh, ~I form, manufactured
hy Mi tsllbi.slli. Cllcmical Industries Limited) paclced in
water, wa.;lle(l ~/i th ~/ater an(:l e.lu ted wi th 3% ammonium
hy(lro~c:i d e so] u tion.
Thc f`rlctior~ ted from 3% ammoni~lm hy(lroxi(le solution
was evaporate-l to dryness to give 1.l~3 g (79 percent)
o f N -( 6, 7-dime thoxy-2 -naph thylsul fonyl ) -L-arginyl-N-
butylglyci.ne as an amorphous solid, I .R . (KE3r): 3, 360,
3,140, I.,622 cm 1
Ana.LysiS - Calcd. for C2~ l35N507S (percent)
C, 53.62, H, 6.56; N, 13.03 F`oulld (percent):
C, 53.48; H, 6.43; N, 12.98
The following compounds are prepared in a sirnilar
manll( r:
N -(7-m~ thyl -2-n1phtllylsulronyl ) -L -ar~,inyl--N-butyl--g -
alal~ c

N2--(7--mctlly.l--2-napllthyl.Sul~onYl)-N-(2~ el.llo~;yctllyl)-N-(3-
carboxypropyl )-L-argininamide

N -( 5-methoxy-1-naphthylsulfonyl. )-I -arginyl-N-(2-
methyl thioethyl )glyclne



-- 63 --

1~ 37~9

N -(5-methoxy-1-naphthylsulfonyl)~L-arginyl-N-(2-
methylthioethyl)glycine tert-butyl ester


N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-
methylthioethyl)-~ -alanine


N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-
( -methylthioethyl)glycine


N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-
methylthioethyl)glycine


N -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-
methylthioethyl)-N-(3-carboxypropyl)-L-argininamide


N -(6,7-dimethoxy-2-naphthylSulfonyl)-N-(3-
methylthiopropyl)glycine


N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-
ethylthioethyl)-~ -alanine


N -(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N
benzylglycine benzyl ester



N -(6,7-dimethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-
tert-butoxycarbonylpropyl)-L-argininamide


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




- 64 -

~i3~ i9

Il-N{ N -(f)~7-(1imcllloxy-2-rla~ thylSulrollyl)-L-arginyl) -
N-cyclolloxy~an)inobutyric acid

N -(/I,6-llimctlloxy-2-rlaplltllylslllPolly~ ,-ar~ yl-N-
phelle tllyl~ lanille

N -(6-methoxy-2-rlaphthylsulfonyl)-L-argiJIyl-N-(3-
pllcllylpropy:l)glycine

N -(5-mot;l~oxy-~-napllthylslllrolly.l.)-l,-argi.lly~.-N-~crl~yl-
~ -alalline

N2-(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydro-
furfurylglyci.lle

N -(7-11ydroxy-2-naphthylsulfonyl)-L-arginyl-N-
tetrally(~rorurrllry]glycille

N -(5-cyano-1-naph1;hylsulfonyl)-L-arginyl-N-tetrahydro-
. furfllrylgl.ycille

N -(6,7-dinletlloxy-2-naphtllylsulfonyl.)-1,-arginyl-N-
tetrahydrorurfuryl-~ -alanine

N2-(7-methyl.-2-rlaphtllylsulfonyl)-L-argillyl-N-
tetrahydrof-lrfuryl-t -alanine

N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl-N-
t~trahy(lrorllrrllrylalanine



- ~5 -

1~37~69


N -(7-metl-1oxy-2-slapllthylsulforlyl)-N-(3-carboxypropyl)-
N-tetrally~lrorllrfuryl~ arginillami(le

N -(7-methoxy-2-naphtllylsulfonyl)~ arginyl-N-butylalanille

N -(7-methoxy-2-napllthylsulfonyl)-L-argi.nyl-N-pentylalanin~

N2-(5-methoxy-1-1lapllthylsulfonyl)-L-argirlyl-N-butylalanine

N -(6,7-(1:inletlloxy-2-nal)hthylslllfollyl)-L-argirlyl~N-
isoblltylalallille

N -(7-methoxy-2-rlaphthylsulfonyl)-L-arginyl-N-benzylalanin

N -(6,7-dimethoxy-2-naphthylsulfollyl)-L-arginyl-N-(3-
phenylpropyl)alanine

N -(5-methoxy-1-naphthylsul~onyl)-L-arginyl-N-benzylalanin-

N -(7-methoxy-2-naphthylsulfonyl)-L-argirlyl-N-cyclo-
hexylalanille

N?-((j~7-~ llel;lloxy-2-~ tlly~ lrolly~ -argillyl-N-
cyclohc.~y:llllctllylalanillc

N -(6,7-climetlloxy-2-rlaplltllylslllt`ony.])-l,-.lrgillyl-N-
bu tylbu tyrinc

N -(6,7-climetlloxy-2-rla~hthyJslllfoJlyl)-l,-ar~ yl-N- :
( ~--r" l yl m~ yl )~rl yc i 11C`


N ~ 7-(1imc~lloxy-2-naphthylSulror-y]. )-L-arginyl-N--
( tel,r;llly(llo-3-1`1~rylmetllyi )g:lycine

N -(6,7~ in)etlloxy-2-~ p~lthylslllrolly~ arginy]-N--
( 2--t ~ l y l ) ~r .l y c ~

N -(7-methoxy-2-napllthylslllrollyl )-I,-arginyl-N-
( 3-t~lellyl )glycille

N -( 6 ,7-dime thoxy-2-rlapllthylsulforlyl )-L-arginyl-N--
( tetrahy(lIo-2-thenyl )glycine

N -(7-methoxy-2-naphthylsu.l fonyl )-L-argirlyl-N-
( tetrahydro-3-thenyl )glycine
--N2-(6,7-dimethoxy-2-naphthaylsulfonyl)-L-arginyl-N-(2-acetylethyl)glyc
N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(4-methoxyfurfuryl)glyci
N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methylfurfuryl)glycine
N2-(6,7,-dinlethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(l,4-dioxacyclohexylmethyl)glycine
l-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L- arginyl]-4-methoxypiperidin
2-carboxylic acid
l-[N2-(6,7,-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-5-
methylhexamethyleneinline-2-carboxylic acid
l-[N2-(3,7-dimethyl-2-dibenzofuranyl)-L-arginyl]-4,4-dimethyl-2-
piperidinecarboxylic acid
N2-(3-methoxy-5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-
(tetrahvdro-2-pyranylmethyl)glycine--
EXAM~' LE 2
.

(A) N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride .

A suspension of` 2 .5 g of N -(6-methoxy-2-napllthylsulfonyl )-
1,--arginine i n 20 m~ of tllionyl chl.oride was s tirred for
2 hollrs at room temperature . Add1 tion of cold dry ethyl
et~er reslllted i.n a precipitate whicll was collected by
fil-tratioll and washed several times wi th dry ethyl ether
to gi ve N -( 6-me thoxy-2 -naphthylsul follyl ) -L-arginyl
chlo ri d e,


--67--

~3~i9


(~) Ethy]. 1-[~ -(6-nlethoxy-2-1lat~hthylsulfollyl)-L-argirlyl~-
2-piper.i.dillecclrboxylate
~o a stirred solutioll of 2.2 g of otllyl 2-piperidine-
carl)oxylate an~ .l ml of trietllylamille in 50 ml of
chloroform~ which was cooled in an ice-salt bath, was
actded .in port:iolls N2-(6-methoxy-2-naplltllylslllf`ollyl)-L-
arginyl chlor:i-le ot~taine(l above. Th(
rcacl:.i.ol-l mixture was stirred overlli~rll~ at room tempera-
ture. At the en(l o~ this perioct, 500 ml of chlorororm
was ad(le(l and ttle chloroform solution was ~ashed twice
with 50 ml of saturated sodium chloride solution, dried
over anhy~trous sodium sulfate and evaporated in vacuo.
Tlle oily residue ~as washed with ethyl ether to give
2.9 g of powdery ethyl l-~N -(6-methoxy-2-rlaphthyl-
sulfonyl)-L-arginylJ-2-piperidinecarboxylate.
For analysis of the product, a portion of the product
was converted to the flavianate, M.P. 192-3C.
I.R. (K~r): 3,210, l~747, 1,638 cm l
Allalysis - C~lc~l. for C25H356N5S Cl~ll6 8 2
C, 49.58; 1[, l1.87; N, 11.56 Foul-l(l (percent): C, 49.24;
Il, 4.7~; N, 1.1.85

(C) l-tN -(6-methoxy-2-napllthylsulfonyl)-L-arginyl~-2-
r~ r~ rl)o xyl i c ~ ci ~l
A solllt:ioJI ol` 2.~ ~ Or otl~yJ. l-~N -(~)-motllo~y-2- ~:
~laplltlly.Lsll.LL`olly:l)-L-argillyl~-2-piperidi.llecarl)oxylate in


- 68 -

1~3~9

15 ml Or rnethanol and 10 ml of 2N-NaOH solution was
warmed to 60 C and held at that temperature for 10
hours. At the end of -this period, the reaction mixture
was concentrated and chromatographed on 200 ml of
Daiaion ~ SK 102 ion exchange resin (200 - 300 mesll,
H form, manufactured by Mitsubishi Chemical Industries
Limited) packed in water, washed with ethanol-water
(1:4) and eluted with ethanol-water-NH40H (10:9:1).
The main fraction was evaporated to dryness and washed
with ethyl ether to give 2.0 g of l-~N -(6-methoxy-2-
naphthylsulfonyl)-L-arginyl~-2-piperidinecarboxylic
acid as an amorphous solid.
I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm
Analysis - Calcd. for C23H3106NsS (percent)
C, 54.64; H, 6.18; N, 13.85 Found (percent):
C, 56.88; H, 6.31; N, 13.83

The following compounds are prepared in a similar manner:
N -(6-chloro-2-naphthylsulfonyl)-L-arginyl-N-butylglycine

N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-
ethoxyethyl)glyclne

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




- 69 -

li3~ 9


N ~ 6-(linle~ll<)xy-2-naplltllylsulfollyl)-l,-argillyl-N-
(2-rllctlly:l, tllio(.~ yl )~].ycil-o

N'---( ~1, (i -(I i Illl` ~hox y--,'--n;~ lly 1~ 1 1 ouy 1 )--1,--a I'C~ y I--N--
phene-tllyl - ~ -a I anine

N -(6,7-dimetl-1oxy-2-rlap}lthylsulrollyl)-N-benzyl-N-(3-
carl)oxypropyl. )-I,-argininamide

N2-(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-
cyclohoxylllorleucirle

N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-
butylisolellcille

N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-
pentylbutyrine

N2-(6,7-diethoxy-2-l1aphthylsulronyl)-L-arginyl-N-
butylalanille

N - ( 6,7-dimethoxy-2-naphthylsulfonyl)-L-arginy].-N-
cycloheptyl alanille

N -(7-metboxy-2-naphthylsulronyl)-L-arginyl-N-(2-
methoxyetllyl )alanine

N -(6,7-dimethoxy-2-naph-thylsulfonyl)-L-arginyl-N-
(2-ct:hoxyetllyl)alanine



- 70 -




N -(7-methoxy-2-rlaphthylsulf`onyl)-L-arginyl-N-
cyc]ohexyl-~ -a~anine


N ~ y--"--~ 1 hy I .';11 1 l`o t l y l. )--1,--~ g i l l y l--N--(2--
methoxyethyl)norvaline


N ~(6,7-dimetlloxy-2-1laphthyls~ orlyl)-l,-arginyl-N-
ben~ylleucille


l-~NZ-(5-metlloxy-l-naphtllylsulfonyl)-L-arginyl~-4-
ethyl-2-pipericlinecarboxylic acid


; l-[N2-(6-methoxy-2-naphthylsulfonyl)-1,-arginyl~-4-
ethyl-2-piperi(iinecarboxylic acid


l-CN -(ll,6-cli.methoxy-2-naphthylsulfonyl)-L-arglnyl~
- ethyl-2-piperidinecarboxylic acid

l-[N2-(5-ethoxy-1-naphthylsulfonyl)-1,-arginyl~-4-ethyl-
2-piperidinecarboxylic acid

:L-[N -(7-ethoxy-2-naphthylsulfollyl)-l,-argillyl~
ethyl-2-pi.peri(linecarboxylic acid


l-CN2-(6,7-diethoxy-2-llaphthylsulfollyl)-L-arginyl~-4-
ethyl-2-piperidi.llecarboxylic acid

l-~N2-(7-metlloxy-2-naplltllylsulfonyl )-I,-argi.tlyl~-ll-
I;ert~ ltyl-2-l)iperi.~1:inecarhoxylic aci(l

~:~37~69


l'helly]. l-~N -(7-methoxy-2-naphthylsul.forlyl)-L-arginyl~ -
4-ethyl-2-E)il)eridinecarl)oxylate

13e~ .y.] 1-[N~-(7-motlloxy-2-1lapl~tllyl.~ rollyl)-L-z~rgil-yl~ -
4-ethyl -2-pi.peridirlecarboxylate

Ben~y] l.-[N -(fi,7-(li.methoxy-2-naplltllylsulfonyl)-L-
argilly.l~ -methyl-2-piperidillecarboxylate

l-[N -(5-nitro-1-l1ar~ht}lylsul rorlyl ) -L-arginyl~
mcthy.l.-2-pipori.(lirlocarboxylic acid

l-~N -(7-llyclroxy-2-naphthylsulfolly].)-L-arginyl~-4-
ethyl-2-piperiAinecarboxylic acid

l-[N -(5-cyano-1-rlaphthylsulfonyl)-L-arginyl~ -methyl-
2-piperidinecarboxylic acid

l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl) -4-
ethyl-2-piperidinecarboxylic acid

1-~N~-(5-dinlotllylalllillo-1-l1aphthylsulrollyl)-L-arginy]~-
1y l -~ )i r) (~ c cL~ )o xy l :i c ~ Ci (l ';

l-~N -(2-nupll~llylsull`ollyl)-L-argilly]J -ll-etllyl-2-
pil)eri(lillocari)oxyl:ic aci~

l-~N -(5,fi~7,~ tl~lly(lro-2-l-lar)~ yl~ `c)~lyl)-r,-
ar~i]ly.l~-ll-etllyl-2-1)ipcridirlccarl,oxylic acid

1~7~9

l-[N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~-
4-methyl-2-piperidinecarboxylie acid


l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-6-
methyl-2-piperidineearboxylic aeid


l-tN -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-tert-
butyl-2-piperidineearboxylie aeid


l-~N2-(5-nitro-1-naphthylsulfonyl)-L-arginyl~indoline-
2-earboxylie acid


2- ~N -( 5-eyano-1-naphthylsulfonyl)-L-arginyl~isoindoline-
l-carboxylic acid


4-[N -(7-methyl-2-naphthylsulfonyl)-L-arginyl]thio-
morpholine-3-earboxylie aeid


4-[N -(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl~
morpholine-3-earboxylic aeid


4-~N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-
arginyl~-3-earboxythiomorpholine l-oxide



4-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~morpholine-
3-carboxylie aeid


4-~N -(7-ehloro-2-naphthylsulfonyl)-L-arglnyl~morpholine-
3-earboxylic aeid




~ 73 -

1~L3~9

4-~N2-(7-hydroxy-2-naphthylsul~onyl)-L-arginyl~
morpholine-3-carboxylic acid


4-~N ~(5-nitro-1-naphthylsulfonyl)-L-arginyl~thio-
morpholine-3-carboxylic acid


4-tN -(5-cyano-1-naphthylsulfonyl)-L-arginyl~thio-
morpholine-3-carboxylic acid


4-~N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl~
morpholine-3-carboxylic acid


Ethyl 4-rN -(4,6-dimethoxy-2-naphthyl~ulfonyl)-L-
arginyl~ morpholine-3-carboxylate


4- ~N2-(5-ethoxy-1-naphthylsul~onyl)-L-arginyl~
morpholine-3-carboxylic acid


4-rN2-( 5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~ ~
thiomorpholine-3-carboxylic acid :


3-tN -(l-naphthylsulfonyl)-L-arginyl~thiazolidine-4-
carboxylia acid

2-~N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyll-

1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

2-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl~
isoindoline-l-carboxylic acid




- 74 -

1~3~4~9


2-~N2-(~1~G-(limel,~loxy-2-1lal)hthylSulrollyl )-L-arginyl~-
1,2,3,~1-tetrally(lto:iso(~ lolirle-3-carhoxylic acid

'--~N --( r~--n~ y--l ~ > 1~ y l ~ l rO I ~ y l )--1 --1 1 ~ri ~ I y.l.
isoin(loli.lle-l-carboxylic acid

2-[N2-(5-ethoxy-.1-naphtllylsulronyl)-1 -arginyl~-l ,2, 3,4-
tetrahydroisoquinoline-3-carboxylic acid

EXA~PLE 3

(A) NG-nitro-N -( tert-butoxycarbonyl)-L-arginyl-N-(2-
methoxyethyl)glycine ethyl ester:
To a stirrecl solu-tion of 28.3 g of NG-nitro-N -(tert-
butoxycarbollyl. )-I-arginine in 450 ml Or dry tetrahydrofuran
were addo(l i.n turl-l 12 ,ll ml of triethylamine and 12 .4 ml
Or isobutyl. chlorof ormate while keeping the temperature
1t -5 C. After 15 minutes, to this was added 111.2 g of
N-(2-mct;hoxy(?tllyl)glycine ethyl oster, alld the mixture
wa~ s tirro(l 1`0r 15 minutes at -5 C . ~\t the end of this
el.i.o(l, tll(? r olct:iOII mixtur(? was WUI m(?(! to r oom tempera-
llllc. I`h( :;olvellt wa~ cvll)0rut(3(l alld tllo resi(ll~e talce
ul) in /10() ml ol` ethyl acetate, and wuslle(l succesSively
with 200 m.]. of water, 100 ml of 5% sodillm bicarl-onatc
~;ollll;ioll, 1()() ml ol` .1()% c:i l;rlc uci(l :;olllt:i.nll ulld 200 ml
of wul or. Tl~o otllyl acctatc soluti.ol~ wus dr:i.o(l ovor




~ 75 --

-
~37~6~

anhydrolJs sodj.llm sulfate. Upon evar)oration of the
.solveIlt~ tlIc I~e.si(Iue was disso:I.ve(l i.I~ 20 ml of ch.l.oro-
fo ~t, and thc XO]UtiOII was applied to a colu~ (80 cm
x 6 cm) Or 500 g Or silica gel packe(I in chloroform.
The procIuct was e].uted first with chloro~`orm, ~Id then
3~ nletha~IoJ.-chlorororm. The fraction eluted from 3%
methaIlol-c}llolororm was evaporate(I to dryness to give
25.8 g (63 ~ercent) o:f NG-nitro-N -(tert-butoxycarbonyl)-
L-arginyJ.-N-(2-nIetIloxyethyl.)glycine ethyl ester in the
.form Or a sy~
]:.R. (IC~r): 3,300, 1,740, 1,690 cm

(B) N -nitro-L-arginyl-N-(2-methoxyetIIy.l)glycine ethyl ester
hydrocIIloride:
To a stirred solution of 29.8 g of NG-nitro-N2-(tert-
butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine
ethyl ester in 50 ml of ethyl acetate was added 80 ml
of 10~ dry }ICl-ethyl acetate at 0C. After 3 hourS,
to this solutioI-l was added 200 ml of dry ethyl ether to
precipitate a viscous oily product.
This was fi.ltercd and washed with dry ethyl ether to
give 24.1 g of N -nitro-L-arginyl-N-(2-methoxyethyl)
glycine ethyl ester hydrochloride as an amorphous solid.

(C) N -llitro-N -(6,7-dimethoxy-2-naplIthylsuJronyl)-L-arginyl-
: N-(2-methoxyethyl)glycine ethyl ester:



_ ~fi _

~37~

To a stirred solution of 4.0 g of NG-nitro-L-arginyl-
N-(2-methoxyethyl)glycine ethyl ester hydrochloride in
20 ml of water and 20 ml of dioxane were added in turn
2.5 g of sodium bicarbonate, and 3.5 g of 6,7-dimethoxy-
; 2-naphthalenesulfonyl chloride in 30 ml of dioxane at
5C, and stirring wa~ continued for 3 hours at room
temperature. At the end of this period, the solvent
wa~ evaporated and the residue dissolved in 40 ml of
chloroform, and washed with 10 ml of lN hydrochloric
acid solution and 20 ml of water.
The chloroform solution was dried over anhydrouA sodium
sulfate. Upon evaporation of the solvent, the residue
was chromatographed on 50 g of silica gel packed in
chloroform, washed with chloroform and eluted with 3%
methanol-chloroform. The fraction eluted from 3%
methanol-chloroform was evaporated to give 5.3 g (87
percent) of N -nitro-N -(6,7-dimethoxy-2-naphthyl-
sulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in tl
form of an amorphous solid.
3 I.R. (K~r): 3,240, 1,740, 1,630 cm 1

(D) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(2-methoxyethyl)glycine ethyl ester:
To a ~olution of 3.00 g of N -nitro-N -(6,7-dimethoxy-
2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine




~ 77 ~

1~374f~i9

olllyl (~ r~o nll o~ o~ 1ll(l ().5 ml Or acotic
.i.~l W~ .5 F of`~ n~ ucl~ atl~l t~l~rl t}le
mixtllrc ~as ~llal;en ill a hy(lrogen atmospllere for .1.00
llolll~ .It loo~ tll~. A~ (l Or-tlli~ ~eriocl,
the ethanol so.Lution was filtered to remove the catalyst
and evaporated to give an oily product. Ilepreci.pitation
with ethano.l.-ethy1 ether gave 2.53 g (91~o) of N -(6,7-
dimetlloxy-2-1laplltllylsulfonyl )-L-arginyl-N-(2-methoxyethyl)
g1ycine ethy.l. ester.
~or ana1ysi.s o.f the product, a portion Or the product
was converted to the flavianate; M.P. 185 C, I.R. (KBr):
3,375, 3,200, 1,740 cm 1.
A~la1ysis - Calcd. for C25~l37N58S C10l6 2 8
C, 47.67; ~l, 4.92; N, 11.12 Found (percent):
C, 47.6ll; ll, 4.81; N, 11.12

(E) N2-(6,7-dimethoxy-2-naphthy1Su1fony1)-L-argilly1-N-(2-
methoxyethyl )~rl ycine:
A solutioll of 2.5 g of N -(6,7-dimethoxy-2-l1aphthy1-
Slll l`ollyl )-l,-a]~giny.l -N-(2-mel;hoxyotllyl. )~l.ycillc ethyl
esl:er in ~ ml. of eth~lo1 alld 7 ml. ol`.lN ~odium hydroxide
SO lutiOll was stirrcd for 30 hours at room temperature.
At ~he en(l of` tllis period, the so1utioll was concentrated
to 5 ml, chroma~ogra~lled on ~0 nll o~` ~aiaion ~ ~K 102
ion exchull~e re~ill (200 - 300 mesh~ ll i`orm manufacturo~

1~37~S~


by Mi~su~)islli Cl~emical Il~d-lstries Limited) packed in
water, wasl~e(l with water, and elute(l with 3% ammonium
hydroxi(le SOlUtioll, Tlle rraction elllte(l from 3%
allllllollillm llydro~;:i(le solllt,ioll was evapor-ll,ed '~,o (Iryness,
ancl the rcsid~le ~as puriried by reprecipitation with
ethanol-etl)yl ctller to give 1 32 g (72 percent) of
N -(6,7-(1imetlloxy-2-naphthylsulfollyl)-L-argillyl-N-(2-
methoYyetllyl)glycille as an amorphous solid.
I.ll. (KL3r): 3,380, 3,180, 1,630 cm 1
~na]ysis - Calcd. for C23lI33N508S (percent): C, 51.20;
Il, 6.17; N, IZ.98 Found (percent): C, 50.93;
~, 6.02; N, 12.63
The following compounds are prepared in a similar marner:
N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-
N-(2-ethoxyethyl)glycine

N -(5,6,7,8-tetrahydro-2-naphthylsul~ollyl)-L-arginyl-
N-(2-methoxyetllyl)glycille

N -(7-ethyl-2-naphthylsulfonyl)-L-argillyl-N-(2-
methoxyethyl)glycine

N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-
cyclollexylglycine




~ 79 -

1~37469


N -(7-metlloxy-2-1lapllthylsulronyl)-L-argiJIyl-N- ~ :
(3-cyclol~exyl)~ opyIglycine

2-~N -(7-nletllyl-2-naplltllylslllfollyl)-1,-arginyl~-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic ac.id

2-tN2-(7-nlethyl-2-naphthylsulrollyl)-L-arginyl~
isoincloline-l-carboxylic acid

2-tN2-(6~7-dinlcthyl-2-napllthylsulforlyl)-L-argillyl~
isoi.nclol,ille-]-carboxylic acid

2-~N -(2-naphthylsulfonyl)-L-arginyl~i,soindoline-l-
carboxylic acid

2-~N -(5,6,7,8-tetrahydro-2-napllthylsulfollyl)-L-
arginyl~-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid

2-~N2-(5,6,7,8-tetrahydro-1-naphtllylsulfonyl)-L-
urgillyl~i,soilldo.lillc-l-carl)oxy]ic uci-l
~ CN -(5-(IIIOrO-I-~ IYI~IILrOIIYI)-I-;Irf~;IIY1~-
3,~ ;llly(tloiso~ llolillc--3--c~t~l~oxylic ~ci(l

l-CN ~-( 5-1~y~lJoxy-,l-nal~lltlly.lsu:lrollyl)-l,-urginy.l3 -
1~2~3,11-tctrallydroc]llirlo:linc-2-carl)o~y:lic aci(l




- 80 -

li3~4ti,9

2-~rN -(5-dimotllylaniino~ aplltllylstl~follyl)-L-ar~inyl~
iso~ (101.ine-.l-carl)oxylic aci(l

2-~N2-(l-l~ tllylslll rOny~ -arginy~ 2~3
tetrahydroisoquinoline-3-carboxylic acid

EXAMplL 1l

(A) L-arginyl-N-(2-methoxyethyl)glycine ethyl ester
hydrochloricle:
To a solutiorl of l~ o g of NG-nitro-l-arginyl-N-(2-
me-tlloxyethyl)glycine ethyl ester hydrochloride in 50 ml
of ethanol was added 0.5 g of palladium-black and then
the mixture was shaken in a llydrogen atmosphere for
150 hours at room temperature. At the end of this
period, tlle ethanol solution was filtered to remove
the catalyst and evaporated to give an oily product.
Reprecipitatioll witll ethanol-etllyl ether gave 3.0 g
(81%) of L-argirlyl-N-(2-metlloxyetllyl)~lycille ethyl
o~t~r llydrochlor~itle in tlle form Or a ~owder.

(~) N -(4,6-(iin1otlloxy-2-nclplltllylSulforlyl)-~-arginyl-N-(2-
methoxyethyl)glycine ethyl ester:
To a well stirred solution of 2.00 g o r L-arginyl-N-
(2-metlloxyetllyl)glycirle etllyl estor hy(lrocll]oride and
1.95 ~ of K2C03 in 20 ml. of water and ]0 ml of dioxane




- 8l -

1~3~ 9


was adlie~l drnl)~/ise a solutioll of 2.17 g of 4,6-
climetlloxy-2-JIa~ thalerlesll~forlyl chloricle iJI 30 ml Or
dioxalle over a period Or 30 m:i~lutes wlli]e mair~taining
tlle te~ )e~ rc llt 0C. Thc reuctioll nuxture ~/as
stirred for an ad(,litiOnal 5 hours at room temperature.
At the ell(l of` tllis period, tlle solvent was evaporated
alld the reYi,(llle talcer~ ) in 50 ml of chloroform.
'rhe chlorororm sollltion was filtere(l to remove the
insollll~le material alld clried over anhydro-ls soclium
sul~`atc. A(ldil;ioll of 150 ml of etllyl ether to the
chloroform solution resulted in a precipitate which was
separated by decantation and purified by reprecipitation
with ethanol--ethyl ether to give 2.31 g (72 percent) of
N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(2-methoxyethy])glycine ethyl ester.
For analysis of the product, a portion of the product
was converted to the flavianate; M.['. 225-227 C,
1.1~. (KJlr): '3,375, 3,200, 1,742 cm 1. -.
,~ Analys;,s -- Calcd. for C25ll37N 08S-C ll~
N208S (percent): C, 47.67; H, 4.92; N, 11.12
Found (percent): C, 47.62; Il, 4.84; N, ll.i8

(B) N -(4,6-(lillletlloxy-2-rlaplltllylsulfo~ly1)-l,-argillyl-N-(2-
nl(~tllox~cl,lly~ r~ ycil~




- 82 -

~ ~3~7~9~

N - (4 ,6-dime~IIo~y-2-naphtIlylslllrorlyl)-L-arginyl-N-(2-
methoxyetIlyl)g.IyciIle was ol~tai~led in the form of an
amorp}Ious sol:id in a m.~lner similar to that described
~an~ 3 (r,)
I.R. (ICIJr): 3, 360, 3,180, 1J610 cm 1,

EXAMI'L~ 5

(A) N2-(6,7-dimethoxy-2-naphthylsùlfonyl)-L-arginyl-N-
phenetIIylglyci.lle:
N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-
arginyl-N-phenethylglycine b.enzyl ester was prepared
by the procedure described ln Lxample 3, and has a
melting point of 133-5 C.
To a SOlUtiOII of 3.00 g of NG-nitro-N -(6,7-dimethoxy-
2-naphthylsl.llfonyl)-L-arginyl-N-pherIethylglycine benzyl
ester in 50 ml of ethanol and 0.5 ml. Or aCetiC acid was
added 0.5 g of` palladium-black and thcn the mixture was
shakerI in ~ ~Iydrogen atmosphere for 100 hours at room
tompetal~ o~ At tlIc on(I of this l)or:io~I, I;IIc ethanol ~.
50 Lll tion w.~s l`i.LI;orc(I to rcmove thc cata:Iyst and
evaporate(i to dryness. The residue was washed several
times with dry ctlIyl other and chromatograplled on 80 ml.
of ~aiai.on ~ ~K 102 ion exchange resi.n (200 - 300 mesh,
H form, manufactured by M.i.tsu~)ishi Chemica]. Industrios



- 83 -

1~37~69


Limi. ted) pac1cc(l in water, waslled wi. th water, and elutecl
wi th ~% ammoni um hyclrclxi(le solnltioll . rhe fraction
clutcd l`rom 1~ nmnlonillm hy(lloxi(lc SO.llltiOII was evapo-
rute(l I;o dryllcs:; to give 1..7l g (7()"~0) Or N -(6,7-

dime thoxy-2 -naphthylsul fonyl ) -L-arginyl-N-phenethyl -
glycille as all amorpllolls solicl
I .R. (K}3r): 3, ~360, 3,200, 1, 590 cm 1
Alla:Lysj.s - Cal.cd. for C28ll35N507S (percellt) C, 57.42;

H, 6.02; N, 11.97 Fowld (percent): C, 57.09;
Il, 6.06; N, 11.7ll



EXAMP I E 6


(A) N -( 6 ,7-dimetlloxy-2-naplltllylslll. follyl ) -L-1rgirlyl-N-(2-
methoxyetllyl)glycyl chloride hydrochloride:
A suspensiorl of 2 .00 g of N -(6,7-dimethoxy-2-naphthyl-
sulfonyl )-L-arginyl-N-(2-methoxyethyl )glycine in 20 ml
of thionyl chloride was stirred for 2 hours at room
temperature. A(iAition of co].d dry ethyl ether resulted
in a precil)itnt;e which was collectecl ~)y fi.ltration and
wasllc<l sevl?ru.L ti.mcs with clry ethyl cther to give N -
( 6, 7 -dimethoxy-2-naphthylsulfoslyl )-L-argi n yl -N -( 2 -
methoxyetllyl )glycyl clllori(lc hydroch:lo ride .




_ ~ _

1~3'74~j9

n) N -(6,7-d:inIot,lloxy-2-~lal)IltllyIsul~oIlyI.)-L,-arginyl-N-(2-
met}IoxyelI~y.L)g:I.yciJle m-tolyl ester IIycIrochlori(Ie:
A mixtIlre oL` 2.00 g of m-cresol and N -(6,7-dimettloxy-
2-1la~ tllyls~l1f`ollyl)-L--arginyl-N-(2-nlotlloxyetllyl)glycyl
chloride hydrochl.oride obtainecl above was heated at
90 C ror 50 min~Ites. ~t the en~t of this period, the
reacl;ion n~i~tnrc was cool.ed, WaSlleCI several times with
dry 0t;IIYl Cttlel', arId t:heIl clissolve-I i.n 1.0 ml o~ dry
e l: lly~. 1 1 CO 110 1. Addi.tioll of` cold dry etIIy:I etIIcr
resultcd in a precipitate which was washed several
times with (lry ethyl ether to give 2.12 g (86 percent)
of N -(6,7-dimetIloxy-2-naphttlylsulfonyl)-L-arginyl-N-
(2~metIIoxyethyl)glyciTle m-tolyl ester hydrochloride in
the form of a powcier.
I.R. (KBr): 3,250, 3,100, 1,740, 1,640 cm
The f`ol.Lowi.ng compoI.mds are prepared in a similar manner:
N -(6,7-dimethoxy-2-naphthy1sulfonyl)-L-arginyl-N-(2-
etllyltII.ioetlly~)g.Lycille phenyl ester

N -(f~7-(l.imotIIoxy-2-l~ lltIly:Islllf`onyI)-~ rg,:iTlyI-N-(2-
oI:IIy.II;Il:iootIlyI)~,lyc:ille benzyl est,or

N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
ben~yl.g.lycine pIIenyl. ester




- 85 ~

li3~4~9

N ~-( G, 7-(l i nle tllc)xy-2-na~)ll I; llyl~;ul t`olly~ I.,-arginyl-N-
r,l ~ r~ I yci ]I ~ zy l o~

,
N -( ( J 7 -/I ~ Y-- --I 1~ Y ~ I OII Y I ) -I--;I L ~ Y I--N--
totrally(llol`-lrl:`ury.l.~rl.yc.ille pllellyl. oYter
,,
l~lenyl l- (N -(7-metlly:L-2-llapl~LIIylsulrorlyl )-L-arginylJ--
-otllyl-2-pi.l)e~ illecarhoxylal:e

13ellzyl 1- [N -(7-metllyl-2-rlaphtllyls;lllronyl)-L-arginyl~--
Il-e thyl-2-pi~eri(liillecarboxylate
Benæyl 1- ¦N -(~-CII1OrO-2--l1aPI1thYLSU1rOrIY1 )-L--argiIIY1~--
Il--nnethyl-2-piperi(linec~rboxyl.~Ltc

1~ thyl ~ N - ( 7 -mo t llyl -2 -llaph t llyl slll L`ollyl ) -L-arbrinyl
mo rpllo lille -3 -c arl~o ~cyla t e

Varioll~ otller N -arylYul f`otlyl-I,-arg:irlillllnli~les or
s.ll Is tlloreol` wero sylltllcsi.æe-l in accorclallce
witll tlle proco~lllre oL` tlle al)ovo exanlpl.es, all(l tlle l;est
re~lllts are ~ulllnlari~e(l in Tal).lo .L.




~ 86 --

1:~3'~i9


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-- 88 --

1~374~i9



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- 9D -

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-- 91 --



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-- 92 --

1 ~ 3'7469


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-- 93 --

1~3'7~i9



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-- 96 --


1~3746'9



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-- 98 --

1~3'7469



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Tablets suitable for oral administration
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Ingredient Amount per tablet
. -- . . . . .. _
: N -(7-methoxy-2-naphthylsulfonyl)- 250
L-arginyl-N-(2-methoxyethyl)glycine

Lactose 140

Corn starch 35

Talcum 20

Magnesium stearate 5
.
. Total 450 mg
. ._

EXAMPLE 8


Capsules for oral administration
Capsules of the below were made up by thoroughly mixing
together batches of the ingredients and filling hard
gelatin capsules with the mixture.


_. . . __ .._ _ .... _
Ingredient Amount per capsule


N -(7-methoxy-2-naphthylsul~onyl)- 250
L-arginyl-N-(2-methoxyethyl)glycine

Lactose 250
. ..... _.. _ . .
Total 500 mg
._ . _ _ .. . .


- 121 -

li374ti9

EXA~tl'_E 9

Sterilc solution ror inrllsion
Tlle ~`ollowing ingl~o(l:iollts arc dissolvcd :in wator for
intravellous perfusloll an~l the resul ting solution i9 then
s terili zed .

. .. .. _.
lngredi ents Amoun t ( ~)
~, ------ __. _
N ~ -( 7 -mc 1,11oxy-2-llapll thylsul rOtly~ ) _ 2 5
L-argi nyl -N~ me tlloxyctllyl )~] ycinc
Buffer sys-tem As desired
Glucose 25
Distille<l water 500 ~:




- I "'! --

1:~3~469

PREPARATION A

Arylsulfonyl chloricles

(A) ~odium 6,7-dimetl~oxy-2-rlaphthaleneSUlfona-te
To a well stirred solution o~ 70.8 g of sodium 6,7-
clihydroxy-2-naplltll11enesulfonate anti 77.2 ~ of sodium
hydro~ide in 450 ml of water was added dropwise 230 ml
Or dimethyl sulfate at 60C over a period of one hour,
durillg whicll timo the product precipitated. To this
reaction mixture was added in portions 38.8 g of sodiùm
hydroxide, and stirring was continued for one hour.
After one hour at room temperature, the precipitate was
filtered, washetl with ethanol and dried to give 50 g of
sodlum 6,7-dimethoxy-2-naphthalenesulfonate.

(B) 6,7-dimethoxy-2-naphthalenesulfonyl chloride
To a stirred suspension of 50 g of finely divided sodium
6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethyl-
forn~lmi~le was adt~ed dropwisc 62.2 m] of thionyl chloride
at room l;cnls)oratllre. After 30 minutos, Lhe reaction
mixture was pourc(l illtO 1 ~ of ice water~ and the precipi-
tate ri~ torecl alld tllen dissolved into 250 ml of ben~ene.
Tlle ben~elle ~olution was repeatedly waslled with water and
drit-(l ovor antlydrous so(lillnl sllll`ate I`bc so:Lvellt wat
ovapor~Lotl l,o (Iryllo~ ill vacuo~ alld tlle rosi(luc W~IS

1:~374f~9

recrystallize(l from benzene-n-hexane (1 : l) to give
32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride~
~I.P. 127.5 - 12'~.5C
All~lysis - Calc(l. ror Cl2llll0l~SCl. (porcoll~): C, 50.26;
H, 3.87; Cl, 12.37 Found (percent): C, 50.45;
H, 4.00; Cl, 12.33
The following arylsulfonyl chlorides not previously
reportecl in the chemical literature were synthesi~ed by
thc aroremelltiolled procedure which is essentially that
as described i.n E. H. Rodd, "Chemistry Or Carbon CompoundS",
Elsevier Publistung Company, 1954, Vol m, P. 441-469.
_ _
No. Arylsulfonyl Chloride M.P. (C)
~ .. _
C10 S ~f~ ~,OC2H5
I 2 ~ C2H5118 - 119.5


2 1 2 ~ ~ OC~I~l36.S - 133.5
_ . _

~ (:lo~ ~ O) l~7 - 13

_ .




- ].2l~ -

1 ~37~

PRE}'ARATION B
Amillo acicl derivatives

(A) N-butylglycinc tert-butyl ester
To 36.5 g of butylamine was added with stirring 15.05 g
of tert-butyl clll.oroacetate over a period of 30 minutes,
while mai.lltai~ lg the temperature at 30-70C. The
reaction nLixtnre was held at 70 C for an additional one
hollr. At the en(i of this period~ the cxcess butyl amine
was evaporated in vacuo, and the residue was taken up in
40 ml of 2N NaOI~ solution and 50 ml of benzene, transferred
into a separatory funnel and well shaken. The benzene
solutioll was separated, washed with water, dried over
anllydrolls sodi.llm sulfate and filtered. After evaporation
of ben~elle, the residue was distilled under reduced
pressuro to g:i.vc 17.0 g (90.9 percent) of N-butylglycine
tcrt-~ tyl cs ter, 11.1' . 7GC/4 nmlllg .
'rhe 1'O~ lOWill~ alllillO uci(l tert-butyL cstcrs not ~reviously
rel~orLc~ tllc chcmi.cul .Litcrutllrc wcrc sy~ltllesized by
l;lIC Ul`Or-`nlOllLiO11(?(l prOCC~IlJre WlLi Cll .i:i c~selltially that
as taught by A. J. Speziale et al., J. Org. Chem. 2~ 731
(1960).




- 125 -


1~3t74~
~ .
,,
No . l~mi llo Aci(l I)crivative I~ .P .
_ _ . _ - '
1 I IN \ ~ ' 3 9 5 C / 2 0 mml I g
Cll,~CO,,-~-CIIl{~
_ -- --- -- _ ~ .
~C112CII(C113)2
2 IIN 6 5 C/ 5 mmllg
_ \C112C02-t-C41~9 . __.
3 ~(Cll2)l~cll3 89~90 C/2.5 mmHg
\C112C02-t-CI~ __

4 IIN ~ ( C112 ) 5(~ 8 3-5C /1 . 5 mn~lg
C 2C2 t C4Hg .
_ .- .~
~(CH2 )7C113 125-130 C/4 mmHg
CH2C 2 ~ t -C~ H
_ . _ . .
6 ~CI12Ctl20C113 61- 2 C/2 mmHg
\Cli2C02--t--CLIH9 ~
_ . .
7 HN~CH2CI12 0CI13 94 C/ 3 mmHg
2C112C2-t-C4~9
_
, ~ 2C 120CH3 o
8 HN 60- 3 C /3 mn~lg
\c~l2c~l2cll2co2-t-cLlli9
. . . . . _ I
9 I~N~CH2CII2CH20C~3 95~ 7C/5 mnlllg
Cll2co2-t-c4~l9
_ . . _ . __ . _
HN~ 2C1120C112C113 102 C/ 4 mmHg
\CII~(~II,,('0~-1,-CIllll~
. .




~ t26 -

1~374~

_ . _
No. Amino Aci(l l)erivative I~.l'.
-- - .
11 HN/ 2C 12 ~3) 166C/l O mmHg
(~112C02~ C1~119
__ _ _ _
/cll2cll2scll2cll3 o
12 HN \ 1 o6 - 9 C /1 . 5 mmHg
C~12C02 - t-C1~1~9
_ . _ ...... . . _ ._ .
/C112c1l2~;cll
13 I-IN\ 3 97 C/ 2 .5 mn~g
C112C02 - t--CL~1~9
_

1ll llN 101 C/ 5mn~g
~ CH2cH2cll2c02 t C4 9
_ _ _. I

15HN~0 101 C / 5 mmHg
\ Cll2C02 - t -C4~1 .
_ ._ .

16l~N--0 105 C/ 4 mm}lg
2 2C2 t CI~H9
_._

: 17 HN~0 129-130 C/8mmHg
(~lI"C02-t-C~ .
. .. . ..... _ .
I 8 / C 11~ - ~ l 4 5 C / l 5 mn il g
2-1;-( 111~)
_ . ._ _

:19 IlN\ ~ O ~ 5G C/l 0 mmHg
, ._ Cll2cll2(:o2-~-c4ll9 1 , __ _




- 127 --

1~3~ 9


N o . /~n~ o Ac- (I I)c ri v~ t i ve ~

IlJ ~ C/:~G lmlHt


2]. Cl CO -I -C~ I l U C/27 mmHg

_ _ __ _

22 ~( C112 )11CI~3 1211C/26 mmHg

C~13 _ . ____
~ 2C 20CH3
23 \CtlC02--t-CI tl9 88-- 90 C/6 mml~g


¦ \rllC; ~-t-C//H9 116- 8 C /- mmH

. - . .

2 5 l 1 2 4 ~ 167 C / I G mml~


HN ~O .
26 1CHC~)2 t C4Hg 12 ~ C/-~ mmHg




- 12B _

1~37~9

_ .
No. Am~no Acid Derivative B.P.
... _ . . ..__
~ CH2--0
27 ~ CHCO2-t-C4H 141 C/15 mmHg
CH3
_ _ ..
28 2 2CO2 t C4Hg 89 C/ 3 mmHg

_ . _ .. __ _ . -~

29 ~ CH2- ~ 111C/ 1 mmHg
CH2co2-t_c4H .
_ _ _ _ _ ~

~ CH2CO2-t-C4Hg 91- 2 C/l mmHg
.__ __ _ . _ _,
: 31 ~ CH2cH2co2c2Hs 115 C/ 2 mmHg
CH2CO2-t-C4H
- OH --- __
32 HN ~ CH2CH2CHCH3 82- 84 C/2 mmHg
2CO2 t C4Hg
. . _ ._ .. --- -- ... _ ,,_
. ~ CH2CH SOCH
33 HN 2 3 150 C/ 0.5 mmHg
_ .__ ._ _ . . - .

34 ~ CH2CH20H 95- 6 C/2 mmHg
CH2CO2-t-C4H
. . .. . _
HN ~ 2C_CH
CH2CO -t-C4H .
. _ - __ . __ _ ~_ _




- 129 _

1~37469

(1~) N-(2-metlloxyetllyl.)~,rlyci,n(? etllyl e~ster
I`o a stirred solutiorl Or ~65.2 ~ or 2-m(tlloxyethylamine
alld 202.1l t of` ~riotl~ylamillo iJl I Q Or her~zerle was a-klecl
( I 1`0 J~ W i. ::~ 0 El ::; O I I I l. i OJ I 0 1 3 3 11 . O g O ~ O 1, 1 l y 1 ~) ro n10 El C O 1, El t O i l l
200 ml of bellzelle in one hour at room temperature. At
the end Or tll:is period, the mixture was heated at reflux
for 2 hours to complete the reaction. Upon cl~lling~ -the
triethylar~ le hydrobromide was removed by filtration and
WaShe(l Wi th bell~ene. ~rter removal of the solvent, the
product was distilled in vacuo to yield 242.8 g (75.3
percent) Or N-(2-methoxyethyl)glycine ethyl ester,
B.P. 73-5 C/l~ mmHg.
The following ElmillO acid ethyl esters not previously
reportecl in the chemical literaturo were synthesized by
the aroremerltioned procedure whicll is essentially that
as taugllt by A. J. Spe~iale et al., J. Org. Chem., 2~`
7~1 (1'360)-

:o, Amillo Ao.i d J~,lhy.l I~`sl;e r ~ 1~1.1'. (( (,) o r ll.l'.
.. _ ._ _ .~

1 ~ ((II~))(II~ 57- 8C/3 mn~fg
Cll2(:()2c2ll5
. _ . _
Cll,,CI~, OCII,
2 l~ \ ~ ~ ~ 63- ll C/3 mmllg ~
Cll2cll2co2c2ll~5 - _
-




-- 13

11374~


- - - -
M.l'. ( C) or B.P.
No. ~nlillo ~ci(l l3tllyl ~tor ( (,/mmllg)
_ IlN/~ ~ . _

,H 2( ' 02 C 21-1 5 ~ ( ` /2 mn~ g

C~ L0l-2C

_
~C02C2115
~Ctl~C112(,}12CI-13 113- 6 C/3 mmHg
\ C112C02C2115
_ _
6 C12C211 ~ 116- 7C/l mmHg

\C112C02C2115 . __ .

7 /CH2CIIC}I3 78-80C/2 mm~g
\C112C02C2115 . - -
.
/(C112)~C113

8 CIIC"C2ll5 . HCl63-4 C
_ C112C02C2~15

(C) N-(2-metlloxyetllyl)glycine ben~yl ester P-tolueneSulfonate
To a solution Or 55.8 g of N-(2-methoxyethyl)glycine
tert-butyl ester in 200 ml of benzene was added 63.8 g
of benzyl alcollol and 72.9 g of p-toluellesulfonic acid
monohydrate. Tlle mixture waR lleated at rorlux for 10




- 13l- -

i~3746:~

hours with the continuous removal of water through a
Dean-Stark water trap. At the end of this period, the
sollltioll was concelltrated in vacuo, and to the residue
was ad(le(l 3~0 ml of dry ethyl etl~er. Arter 2 hours at
room temperature, the formed precipitate was filtered,
washed with (lry ethyl ether and then recrystallized from
ethyl acetate to yield 99.2 g (85 percent) of N-(2-
methoxyethyl)glycille benzyl ester p-tol~lenesulforlate,
M-l'. 95-6C.
The followillg amiJIo acid benzyl ester p-toluenesulfonate
not previously reported in the chemical literature were
syntllesize(l by the arorementioned procedure.
.
No. Amino Acid Benzyl Ester M P. ( C)
_ p-Toluenesul~onate

1~ CH2C02CH2- ~ 97 ~ 9
_ .. . _._

2 \ C 11 Z C 2 C~2--@~ 1 .? .? -- ll
_ .

¦ \~`H"COzCHz~
4 ~((~z)3 113 66 -- 8




-- I 3 ."

~37469


No Amillo l~ci(l I3c~nr~yl l~ter M 1' (C)
. 1 ) -'1`0 l ~lCII C:;ll I ~`orlc~ t e
_ . .~
r) (CH )~CH,~ I ()I -- 2


G ~ cH2--~ 14 o -- 3

. _ . _. _ . _

7 \ ~H2C~l2c2cH2~ 1 5ll -- 6
8 / C H 2 CH2--~ 13 3 _ 5


9 C112C02C~12 ~~) 13 3 -- 5

~ ~ CH2--O
lo \CH2c2c~2~ 133 -- 8
_ . _ __ ..

\ CHC 02 CH2 ~ ¦ I ( ) '3

_ _ ._ __ _ . _ __ .

~_~~




- l33 -

~37469

. . . _ _ .
No Amino Acid Benzyl Ester M P ( C
. p-Toluene~ulfonate . .
_

13 3 123 - 6 ¦

_ _ _

14 ~ CHC02CH2~ ~ 119 - 123

_ _, ...

CH2C02CH2 ~ 13 0 .




PREPARATION C

2-Piperidinecarboxylic acid~ and esters thereof



(A) 4-methyl-2-piperidinecarbonitrile
To 500 g of 10% sodium hypochlorite solution cooled in
an ice bath, there was added dropwise a solution of
33.6 g (0.21 mole) of 4-methylpiperidine acetate in
lO ml of water over a period of l hour. At the end of
this period, the reaction product was extracted twice
with 500 ml of ethyl ether and dried over anhydrous
sodium sul~ate. After evaporation of ethyl ether, the




- 134 -

7469

residue was added dropwise to a solution of 11.8 g (0.21
100 ml of
mole) of potassium hydroxide in~96~ ethanol under reflux.
Pefluxing was continued for ~n additional 10 minutes.
Ethanol was evaporated, and the residue was dissolved
into 50 ml of` 2~ sodium hydroxide solution and then
extracted with ether.
The ether layer was dried over anhydrous sodium sulfate
and then ether evaporated. The residue was added to an
ice-cooled solution of 27 g (1 mole) of hydrogen cyanide
and 25 ml of concentrated hydrochloric acid in 300 ml of
water, The solution was stirred at a temperature of 10
to 20C for 4 hours and thereafter made basic by the
addition of solid sodium hydroxide. The reaction product
was extracted with ether, dried over anhydrous sodium
sulfate and then distilled under reduced pressure to give
17 g (66%) of 4-methyl-2-piperidinecarbonitrile, B.P.
96-97C/10 mmHg.
The following 2-piperidinecarbonitriles not previously
reported in the chemical literature were synthesized by
the aforementioned procedure which is essentially that
as taught by Grundon et al., J. Chem. Soc., 1963, 3898,
Grundon et al., J. Chem. Soc., _964, 2448, R. Bonnett
et al., J. Chem. Soc., 19~9, 2092 and H. Bohme et al.,
Ber., 92 1613 (1959).




- 135 -

113~4~9


R7
N CN
H




N o 7 _ .,
l I Cl2CH3105-106C/9 mmllg.
_ . _ _ . . _
. 24-CI12CI12C1l3116 C/8 mml{g.
Cll,3
. 3 < Cll 104C/Il mmllg.
_ _ _.
ll 2-C113 _ -
. _ . .~

(B) 4-Methyl-2-piperidinecarboxylic acid hyclrochloride
A solution of 16 g of 4-methyl-2-piperidinecarbonitrile
in 250 mL Or 6N llydrocllloric acid was refluxed rOr 6
hours. Arter evaporatioll of` the solvcllt, the residue
was recrysta:Lli~ed from water to give 13 g Or 4-methyl-2-

piperid~ ecarboxylic acid Jlydrochloricle.


~C) I~`l;lly'l ~-mc~tllyl-,'-l):iJ)ori.dillecarl)oxylal;c
A so~ Lioll ol` 13 g (().072 mo.le) ol` ll-moLlly~--2~pipcricli.l-1e-
car~oxy].ic aci(i llydroclllori(le alld 50 nll ol` tlliol~yl chlo~i(le
in 300 nll of etllallol waX refluxed l`or ll llollrs. At the elld
of thi~ period, the solvent was evaporateci uncler reduced
pressllrc, ancl the re~idue was extracted Witll a solution Or
chloroform and saturated potassium car~onate solution,



- ~36 -

1~37~


The ch.lorofoln~ yer was driecl over anhyclrous sodium
sulJ`ate all(l t:llen c~l.loroform wa~ cvaporat:o(l. Di.stillation
of tlle rcsidlle glVC 7 1~ g (60~) of etllyl 1l-nletl~yl-2-
pipericl:inecarl)oxyl.lte, B.'. 7~-77 C/3 mmllg.


(D) Benzyl 4-metllyl-2-pipericlirlecarboxylate p-toluenesulfonate
A solution of` 20 g (0.1.12 mole) of 4-methyl-2-piperidine-
carboxyl.lc acid llyclrochloride~ 24 g to.224 mole) of benzyl
alcohol und 25.6 e~ (0.134 mole) Or p-toluenesulfonic acid
monohydrate i.n L00 ml. oÇ berlzene was refl.uxed for 5 hourS
with the continuous removal of water through a Dean-Stark
water trap. At the end of this period, the solvent was
distil].eA of`r, and the resi.due was was}led with ether-n-
hexane and recrystallized to give 10 g (22%) of ~enzy
4-methyl-2-piperidinecarboxylate p-toluenesulfonate,
M.P. 160-163 C.
The following 2-piperidinecarboxylates not previously
reportecl in the chemical literature were synthesized by
the aroremelltiolleA procedure.




- I~7 -

1~37469



H C02C2H5
__ .__
No. ~ Addition B.P.
._ . _._ _ .. _
1 CH2CH3 _82-4C/3.5 mmHg
_ ._ ... __ _ _ .,
2 2CH2CH3 HCl
- ~CH3 . -

3 \CH _95-6 C/2 mmHg
_. . _
4 2-CH3 l 57 C/3 mmHg



Morpholine-3-carboxylic acid hydrochloride was prepared
by the procedure described above, and has a melting point
of 200-2C.
The following starting material9 for the preparation of
the N -aryl9ulfonyl-L-argininamides were prepared by the
procedures des-cribed in the following literatures:

_
Compound Literature
_ ... .

HN ~ J. Org. Chem., 2~ 2203 (1964)
. _ _ .
C02H




HN ~ O J. Org. Chem., ~2 2203 ~1964)




- 138 -

1137469


~ ~ -
Compo~ (l Literatllre
. ._
('O~,lt
IIN ~ J. Am. Chem. Soc., 5(~ 200 (1937)
_ .. . . .. _
COz~




IIN~ ~h. Ob!ihCh. lChim., 2 2245 (1973)
_. _ . . .__._ __._
~ C021~ Ber., 44 20311 (1911)

_A _.......... . . ~

C0 H(D) or(L)¦~er-, ~ 927 (1932)




Tl~e methyl or ethyl ester of` the aforementioned compounds
were prepared by a cbnventlonal esterification procedure.
Ethyl thiomorplloline-3-carboxylate has a boiling point of
108C/4 mmllg.
Diethyl piperidine-2,6-dicarboxylate hydrochloride was
prepared by the conventional esterification of piperidine-

2,6-dicarboxylic acid and has a melting point of 184-6C.
lsoindolille-l-car~oxylic acid was prepared by a procedure
similar to that for ~he preparation of isoquinoline-3-
carboxylic acid described in Ber., 44 2034 (1911) . Ethyl
isoindoline-l-carhoxylate hydrochloride wa~ prepare~l by




-- I 1') -- ,

1~37~6i9

the convent:iollal esterification of isoindoline-l-
cnrboxylic acicl arld has a melting point of 139-140.5 C.
Ilnvillg now flll]y described the invellt;ion, it will be
npl)arcllt to OIIC of ordillnry skill in tlle nrt tllat many
changes and modifications can be made thereto without
dcpartillg from t,lle~ spirit of thc invelltion as set forth
lle rei n .