N SU2 XX-ARYLSULFONYL-L-ARGININAMIDES AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

TRADUCTION NON-DISPONIBLE

English Abstract

ABSTRACT OF THE DISCLOSURE
N2-arylsulfonyl-L-argininamides of the formula

Image

and the pharmaceutically acceptable salts thereof have been
found to be 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):

(I)
Image

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) wherein R3 is selected from the group
Image
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 alkoxyl 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 wllerein 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,

(5) 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
(6) 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 dialkylamino, 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: removing the NG-substitutent from
an NG-substituted-N2-arylsulfonyl-L-argininamide having the formula:


Image

wherein R and Ar are as defined above; R' and R" are selected from
the group consisting of hydrogen and protective groups for the guanidino
group, and at least one of R' and R" is a protective group for the
guanidino group.
2. An N2-arylsulfonyl-L-argininamide and the pharmaceutically
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 alkylsulfinylakyl, 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


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-aryininamide 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-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,

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 alkylsulfinylalkyl, 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) wherein R3 is selected from the group
Image


consisting of hydrogen, Cl-ClO alkyl, C3-C6 alkenyl, C3-C6 alkynyl,
C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl,
Cl-C6 hydroxyalkyl, C2-C7 carboxyalkyl, C3-C8 alkoxycarbonylalkyl,
Cl-C5 haloalkyl, C7-Clo aralkyl, C8-C12 ~-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 Cl-C5 alkyl, carboxy, C2-C5 alkoxycarbonyl, phenyl, C7-C10
aralkyl and ring substituted benzyl wherein said substituent is Cl-C3
alkyl or Cl-C3 alkoxy; R5 is selected from the group consisting of
hydrogen, Cl-ClO alkyl, C6-C10 aryl, C7-Clo 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-C10
aralkyl and 5-indanyl; R7 is hydrogen, Cl-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 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

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 fronl 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-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; 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
.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-l-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-
36. N2-(7-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 N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-
furfurylglycine.
38. N -(6,7-dinnethoxy-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-argirlyl]-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-arginyl]-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-[N -(7-methoxy-2-naphthylsulforlyl)-L-arginyl]-4-ethyl-2-piper-
idine carboxylic acid.
44. 1-[N -(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.
45. A process for producing an N2-arylsulfonyl-D-argininamide
having the formula (1):
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

161



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 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, 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
162




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
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-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


(6) 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

163




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 , Image and Image

wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy which comprises:
removing the NG-substituent from an NG-substituted-N2-arylsulfonyl-D-
-argininamide having the formula:


Image


wherein R and Ar are as defined above; R' and R" are selected from
the group consisting of hydrogen and protective groups for the guanidino
group, and at least one of R' and R" is a protective group for the

164




guanidino group.
46. An N2-arylsulfonyl-D-argininamide of the formula:


Image


and the pharmaceutically acceptable salts thereof, whenever produced
by the process of claim 45.

165

Description

N -AI~YLSUL.F(lNYL-L-l~ lNINAMInP,~ NI) Tll~;:
PII~RMl\CF:UTIC~LLY ACCI'PTI~BL~ S~LT~ TII~R~
I~A('~ ) Ol;~ 1`1ll~` ~ N ~ `N L`:l oN

r lt,- ~"~ "~
Tlli ~ i ll V I l l, i O I ~ i (. O t ll C (li ~ CO VC I')' O ~ ~ I l C\~
usoful N -1rylSUlrOllyl-L-11`~,rinill.1111i(lCg Illd l.llC ~)llal'
ccutically accel~t.ll)le s.llts tl~eJ coL`, wll.icll ;ll e -~' c~:ln~
value in view Or tlleir outstanclill~,r alltitl~lonll~ol;ic l~ro~)eI~tie~;
alld low toxici ties .

l~escril~t;ioll o~` lllc l'~.ior Arl;

In .the l)lSt~ there llave beel~ mally .attcllll~ts l,o ollta~ CW
and iml)rovccl al,ellt~; for tllc trcatlllcllt ol` tlllollll)o~ llc

N ~ I;oJ.ylsu1rolly1)-L-3r~inine e~ters 1l1VC l~(?CII roun(l to :
be one type Or a~,ellt wl-i cll C1~ e used cllld l,llCSC llaVC l)eCn
found to be erfective in ~issolvill~ l~lootl clol,s. (u. ~;~

Patent No . 3,622 ,615, issued Noveml)er 23, 1971 )
One ~arnily Or coml)ounds ~llicll ~lave becll roull~l to l)e l-~r-
ticularly u~;erul as lli~llly speciric inllil)itol~ Or tllroml)i
for tl~e. colltrol ol` tllrolllL)osi.s is ~ c N~-dallsy.l~ e -
ester or an~idc. (The applieant~s U.S. Patent No. 3,978/045.)



llowevcr, tllcre i.s a COllti~lUi.ll~ IICCCI Lor 1 ~ .y ~ CCi~`iC
inllibi-tor o~l tllron)l)irl for tlle control Or l:llroml~o~ ;, wllicl
exhibits lower toxicity.




-- ~ --



Sl)~ Y Ol~ lNVl~N'l`lON

It llas now ~n (liscoverecl tllat N -ary.Ls-l]~onyl-l,-
ar~irlillamid~s exhib:i~ alltitllronl~otic activi~y alld ev~n
lower toxicity l~vels at the same relative potencies, as
S compared witlL tlle N -cl~nsyl-L-argin~ sl;~r or anudc.
The compourl~s Or thi.s inverltion Call ~ r~ selltCd ~y t~lC
formula (I):

H N ~C I _ CII~C112CH2C~ICOR (I)
02
Ar

wherein R is selectecl from the group Co~l~isti~l~ of

.10 (1) - N ~ wherein Rl 1s sel~ctecl ~ro~ the group
( C~2 )nC~2
g C2 C10 all~yl, C3-Clo 21]cenyl~ C3-C a1kynyl

C2-C10 alkoxya~l~yl, C2-C10 alkyl~llioal]cy]~ C2-C10 alkyl-
sulrinyl~lkyl, CL-Cl~ lly(lroxyallcy].~ C2-CI(~ c~llhoxyallcyl,
C3-C10 alkoxycarbonylalkyl, C3-C10 alkyica.rbonylalkyl, Cl-C10
haloa1kyl, C7-Cls aralkyl, Cg-Cls ~-carboxyaralkyl, C3-C
cycloalkyl, C4-C1o cycloalkylalkyl, furfuryl, -tetrahydrofurfuryl,
optionally substituted with at least one Cl Cs alkyl and/or
Cl-Cs alkoxy 3-furylmethyl, tetrahydro-3-furylmethyl, optionally
substituted wi-th at least one Cl-Cs alkyl and/or Cl-Cs alkoxy
tetrahydro-2t3 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 a-t least one :
Cl-Cs alky~ and/or Cl-C~ 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

-3-


group consisting of ~Iyclrog~n~ C~C10 .llky~ C~-Cl~ ary].,
C7-C12 aral3~y:L cu-ld 5-:ind~lyl, ~ is c~ lt~g~r of` 1, 2

or 3, (2) - N ~ ~ leroill r~ ls ~ cte~l from
Cll-(C112 ),1lCOOR5 ~ ,

the group COII~:iS t:illg of llydrogen, C~-ClO ~llcyl, C3-C10
alke]lyl J C3-Cl~ al3cy~lyl, C2-Clo ~lko~Yyallcyl, C2-Clo alkyl-
thioalkyl, C2-ClO ~lkylsulfinyl~lkyl, Cl-ClO lly~roxyallcyl,
C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalky]., C3-C10
alkylcarbonylalkyl, Cl-C10 haloalkyl, C7-C15 aralkyl, C8-C15
~-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl,
furfuryl, tetrahydrofurfuryl, optionally substituted with at -;
least one Cl-C5 alkyl and/or Cl-C5 alkoxy 3-furylmethyl,
tetrahydro-3-Eurylmethyl, 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--th~nyl 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
o Cl-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl,
optionally substituted with at least one Cl-C5 alkyl and/or
Cl-C5 alkoxy Cl-C~ aralkyl and ring substituted benzyl
wherein said substituent is Cl-C5 alkyl or Cl-C5 alkoxy; R5 .--
i5 selected from the group consistiny of hydrogen, Cl-C10
alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and m is an
integer of 0, 1 or 2,

t3) - ~ wherein R6 is -COOR8 wherein R8 is selected
(~7)p
~, _~_


from the group consisting o~ hydrogen, Cl-C10 alkyl, C6-C1o
aryl, C7-Clz aralkyl and 5~indanyl; (R7)p is hydrogen, C~-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 s~stituted at the 2, 3, 4~ 5 or 6-position,
COOR ~

which is optionally substituted with at
~CH~ r :
least one Cl-Cs alkyl and/or Cl-C5 alkoxy, wherein Rg is
selected from the group consisting of hydrogen, Cl-C10 alkyl,

~6-C10 aryl,

C7-C~2 aralkyl an(l lO
5-indanyl; and r is an ~
integer of 1, 2, 3 or ll, (5) -N ~ wherein Rlo is
\, (C112 ) q
selected from the group consisting of hycirogen, Cl-ClO allcyl,


C6-ClO aryl, C7-Cl2 aralkyl and 5-indanyl; Z is selected from
the group consisting o~ oxy, t~lio ~ld Sulri,lyl; and q is


CR11
an integer of O or ~ d (6) -N \ ~ ~ erein R


is selected from tlle group consisting Or hydro~ell, C1-ClO

alkyl, C6-ClO aryl~ C7-C12 aralkyl and 5~ (lanyl; i is an


integer of O, l or 2; j is an integer of` O, l or 2; and the
2~0 sum of i+j is aJI i.nteger of l or 2; and Ar is selected from

the group consistill~ Or napht~lyl, 5~6~7~8-tctrally(ironaphtllyl~
optionally substituted with at least one Cl-C5 alkyl and/or
Cl-C5 alkoxy




~` 5
,h.



naphthyl ~ubstituted with at least one substituent selectecl
from the group consisting of halo, nitro, cyano, hydroxy,
10 Y Cl (~10 alkoxy al~d C2-C20 diallcylamino, phenyl
phenyl substituted with at least one subs-tituent selected
f`rom the group consisting of halo, nitro, cyano, hydroxy,
Cl-C10 alkyl, Cl-C10 alkoxy and C2-CzO dialkylamino, C7-C12

aralkylfand ~ ) ~ ~ ~ 9 ~ )


and


~ } R12 which are optionally substituted with at least
on Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein R12 is hydrogent
Cl-C10 alkyl or Cl-C10 alkox~r.
Also encompassed within this invention are pharmaceutically
acceptable salt5 thereo~.
This invention also relates to a rnethod for inhibiting
lS activity and suppressing activation o~ thromhin in vivo9
~ic~ cs:.~9~e,~ rc~ucing into a liv~ng l~ocly a ~harma~
ceuticall.y crrective amoullt Or all N -arylslllrollyl-L-
argininami-le or t~le pharmaccutically acceptalrle salt thercof.




-- 6 --



,,~

~2~


DFTAILED DESCRIPTION OF THE PREFERRED_EMBODI~ENTS

T~is invention relates to a group of N -arylsul~onyl-L-
argininamides of the ~ormula (I):

~IN
~ C - N - CH2CH~CH2CHCOR (~)
~ HNS02
Ar

wherein R iB selected from the group consisting of

(1) - N \ wherein Rl is selected from the group
( CH2 )nC OOR2

consisting o~ 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-butenyl9 2-pentenyl or the like, al~ynyl of
3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-
butynyl~ 3-hutynyl or the like~ alkoxyalkyl Or 2-10
(preferably 2-6) carbon atom~ 9 such as methoxymethyl, :
ethoxymethyl~ propoxymethyl, Z-methoxyethyl, Z-ethoxyethyl,
2-propoxyethyl, 2-methoxypropyl~ 3-methoxypropyl, 3
ethoxypropyl~ 3-propoxypropyl, 4-methoxybutyl, 4~ethoxybutyl~
4-butoxybutyl, 5-butoxypen-tyl or the like, alkyl.thioalkyl
of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl,
ethylthiomethyl, propylthiomethyl, 2-methylthioethyl,



~ 7

, _ ,, , ___ _ ,_ _,,, _. _ _ _ _., _ __ .. . .. . .. .~_ .. _ .. _ .. _ _ .. -- -- .--.. --A_ - .-- . ----'' - ' - '
. '.

}2~


2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl,
2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl,
4-r~etllylt]llObU tyl 9 4-ethylthiobutyl, 4-b-ltylthiobwtyl,
5-butylthiopentyl or -the like, alkylsu.Lfinylallcyl of 2-10
(pre-~erably 2-6) carbon atoms, such as methylsul~inylmethyl,
ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinyl-
ethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-
methylsulfirlylpropyl, 3-ethylsulfinylpropyl or the like,
hydroxyalkyl of 1-10 (preferal~ly 1-6) carbon atoms, such
as hydro~ymethyl, 2-hydroxyethyl~ 3-hydroxypropyl~ 2-
hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxy-
pentyl or the like, carboxyalkyl of 2-10 (preferably 2-7?
carbon atoms, such as carboxy~ethyl, 2-carboxyethyl~ 2~
carboxypropyl, 3-carboxypropyl, l-carboxybutyl~ 2-carboxy-
butyl, 4-carboxybutyl or -the like, alkoxycarbonylalkyl of
3-10 (preferably 3-8) carbon atoms, such as methoxycarbonyl-
~thyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl,
3-nlethoxyca~ oJ]y]propyl~ l-methoxycal~l)olly~h~ltyl~ 2-et~loxy-
carl~onylb~ltyl, Il-met~loxycarbonylb~ltyl or tl~e lik~, . `-
alkylcarbonylalkyl of 3-10 carbon atoms, such as methylcar~ony-
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 the
like, aralkyl.of 7-15 (preferably 7-10) carbon atoms, such
a~ benzyl, phenethyl, 3-phenylpropyl, 4-phenylbukyl, 6-
phenylhexyl, l~phenylethyl, 2 phenylpropyl or the like,
-carboxyaralkyl of 8-15




,~ .

~preferably 8-12) carbon a-toms, such as ~ -carboxybenzyl,
~ -carboxyphenethyl or the like, C3-ClO cycloalkyl, such
as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl~ cyclononyl or cyclodecyl, C4--C10 cycloalkylalkyl,
such as cyclopropylmethyl, cyclopentylmethy]., 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 ~ith 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, he~yl, octyl, decyl or the like, C6-ClO
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
o 1, 2 or 3,
R




(2) - N ~ wherein R3 is selected from the
CH-(cH2)mcooR5

group consisting of hydrogen, Cl-ClO alkyl, such as methyl,
~5 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 (preferab].y 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

3~


methoxyrnethyl1ethoxymethyl~ ~ropoxyrnethyl, 2-methoxyethyl~
2~ethoxyethyl~ 2-propoxyethyl~ 2-methoxypropyl~ 3-methoxy-
propyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl~
4-etlloxybutyl, ll-butoxybutyl, 5-bu-toxypentyl or the like~
alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such
as methyltlliomethyl, ethylthiomcthyl, propylthiomethyl, 2-
methylthioethyl, 2-ethylthioethyl, 2-propylthioe-thyl, 3-
methyltt~opropyl, 2-methylthiopropyl, 3~ethylthiopropyl,
3-propylthiopropyl, 4-methyltlliobutyl, 4-ethylthi.obutyl,
4-butylthiobutyl, 5-butylthiopentyl or the :Like, alkyl-
sulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such
as methylsulfinyimethyl, ethylsulfi~ylmethyl, propyl
sulfinylmethyl~2-methylsul~inylethyl, 2-ethylsulfinylethyl,
2-propylsulfinylethyl, 3-methylsulfinylpropyl~ 3-ethyl-
sulfinylpropyl or the like, hydroxy~lkyl of 1-10 (preferably
1-6) carbon atom~, such as hydroxymethyl 9 2-hydroxyethyl~
3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3
hy~lroxyl>ll-tyl, r~-lly(lroxyl)ollty:l or t~llC 1.il;c, carl)oxy~l]iyl of
2-]0 (prercr-LI)Jy 2-7) call)oll atom~J ~uc1lL~ C1rl)0~ynl0tllyl,
2-rarboxyetllyl, 2-c~rboxyprol)yl, 3-carboxypropy]., l-
car~oxyblltyJ., 2-calboxybutyJ~ ll-carboxyl)lltyl or the like,
a:Llioxycarbo~lyl.lJ.]cy.L Or ~-10 (~rc~eral~.iy ~ car~o~l atom~,
such a~ mettJoxycarbollyLnlethyl~ 2~nletl~oxycLrbollylethyl~ 2-
ethoxycLrbolly.lpropyl, ~-meLIIoxycarbo~lyi~)rol)yl, l-methoxy
~5 C~ lyll)lllyl, -~ loxy~ll)ollyJl)u~y~ ! 1. Ilo ~yc~l l'l)OIly.l 1)




''~;,

L~i
or the like, a]kylcarbonylalkyl of 3-10 carbon atoms, such as
rnethylcarbonylethyl 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
the ].ike, aral]cyl of 7-15 (prefexably 7-10) carbon atoms, such
as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl,
l-phenylethyl, 2-phenylpropyl or the like, d~ -carboxyaralkyl of
8-15 (preferably 8-12) carbon atoms, such as c~ -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 C1-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-Z-thenyl optionally substituted with at least
one Cl-C5 alkyl and/or C1-C5 alkoxy, and tetrahydro~3-thenyl;
R~ is selected from the group consisting of alkyl of 1-10
~preferably 1-5~ 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 atoms,
such a~ 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--
,''~,'

11~323~L6
alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy,
- e-thoxy, propoxy or isopropoxy; R5 is selected from the group
con~.isting 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
~6
integer of 0, 1 or 2, (3) -N ~ wherein R6 is -COORg
(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 ox 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 substituted
at the 2, 3, 4, 5 or 6-position,
COOR ~
(4) - N ¦ which is optionally substituted with at
~ CH2~r
least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is
selected from the group




..,,~

~23~



consisting of hyclrogen, Cl-C10 alkyl, such as methyl, ethyl,
propyl, butyl, tert-butyl~ hexyl, octyl, decyl or -the li]ce,
C6-C10 aryl, sllch as phenyl., m-tolyl9 naphthyl or the like,
ara:lkyl Or 7--12 (preferably 7-10) carboll atoms~ such as benzyl,
phenethyl or the like, and 5-indanyl.; and r is an integer Or
1, ~, 3 or 4,
C~l O
\
(5) -N Z wherein Rlo is selected from the group
(CH2)q

consisting of hydrogen, Cl-C10 alkyl, such as methyl, e-thyl,
propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like,
C~-C10 aryl, such as phenyl~m-tolyl, naphthyl or the like,
aralkyl of 7-12 (preferably 7-10) carbon a-toms, such as
benzyl, phenethyl or the like, and 5-indanyl; Z is selected
from the group consisting of oxy (--O-), thio (~S-) and
sulfinyl (-SO-); q is an integer of O or 1, and
:

COORl 1 ~
( c l I z ) ~ w h e l ei n n ] ] i bi ~ e ] e c t e d f ro m tlle group

COII~;iStill~ of llydrl)G'CJl, Cl--Clo ~ll~yl~ SllCIl a~ metllyl, ethyl,
~rol~yl, I)u-tyl, tcrt-l)lltyl., hexyl, octy~, dccyl clr tlle like,
C6-C10 aryl, ~uch ~S phellyl, m-tolyl, naphthyl or the like,
aralkyl of 7-12 (preferably 7-10) carbon atoms, such as
berl~yl, pllcrl~ttlyl or the like, arlcl 5-irldallyl.; i is an



'3 - ~


,, .

23~
lnteger of 0, 1 or 2; j is an integer of 0, 1 or 2; ancL the
sum of i~ ls an inte~er of 1 or 2; an~ Ar is selected f~om
the group consisting of naphthyl, such as l-naphkh~l and 2-
naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally suhstituted
with at least one Cl-C5 alkyl and/or Cl--C5 alkoxy such as
5,6,7,8-tetr~ ydro-l~naphthyl and 5,6,7,8-tetrahy(lro-2-
aphtllyl, nilphtllyl substituted witll at leasl one substituent
selectecl L~ronl tlle group eonsi.stillg o~ ha:Lo, sucll as fluoro,
chloro, brotl)o ancl iodo, nitro, eyano, hyclroxy~ allcyl of
1-10 (preferably 1-5) earbon atoms, SllCIl as met;hyl, ethyl,
propyl, isopropyl, butyl, isobutyl or -tlle li.lse, alkoxy of
1-10 (preferably 1-5) carbon a-toms, such as methoxy, ethoxy,
propoxy, isopropoxy, bu-toxy, sec-butoxy, tert-butoxy,
pentyloxy or the like~ alld diallcylamillo oL` 2-20 (prererably
2-10) carbon atoms, such as dime-thylamillo, cliethylamino,
N-methyl-N-ethylamino or the l.i.ke, phenyl, pllenyl subs-tituted
~ith at least one substituent selected rrom the group COIl-
iStillg Or halo, such as rluoro, ch1oro, bromo an~ io~lo,
ni.tro, cyarlo, hydroxy, allcyl o.f 1-~10 (p.referal)ly 1-5) carbon
atoms, SllCh clS mel!;llyl., ethy1, propyl~ isol~ropy~ lltyl,
iiobll~y.l. or l)lc Lik(, a:lkoxy ol` 1-:J() ¦~rel`eIably 1-5) carbon
atoms, 9uch .l9 metlloxy, ethoxy,propoxy, isopropoxy, bu-toxy,
sec-butoxy~ tert-b-ltoxy, pentyl.oxy or the .lil<e, arld
dial.kylamino o.f 2-20 (prererably 2-lU) earl.)oll atollls, suel
as dimethylam:ino~ ~liethylamirlo, N-metllyl.-N-etllylclllLirlo or
the like, aral]cy:l of 7-12 (preferab1y 7-10) earbon atoms,



,, -- I 11 _

~iuch aS bonzyl~ phenethyl or the like~and~


ô~ ~`0)


~ ~ _ ~ and ~ } R12


which are optionally substituted with at least one Cl-C5 alkyl
and/or Cl-CS alkoxy, wherein R12 is hvdroqen, 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 9 butyl, isobutyl, pentyl,
hexyl and octyl, C3-C6 alkenyl such as allyl, C3-C6 alkynyl9
such as 2-propynyl, C2-C6 alkoxyalkyl 7 such as 2-~ethoxyethyl,
Z~methoxypropyl, 2-ethoxyethyl and 3-metho~ypropyl, C2~C6
alkylthioa~kyl 9 such as Z-ethylthioethyl and 2-methylthioethyl,
C2-C6 alkylslllfi~ylalkyl, 9uoh as 2-methylsulfinylethyl,
Cl-C6 hydroxyalkyl~ such as 2 hydroxyethyl and 3-hyd~oxybutyl 9
Cz~C7 carboxyalkYl, such as l-carboxybutyl~ C3-C8 alkoxycarbonyl-
alkyl, such as 2-ethoxycarbonylethyl~ C7-C10 aralkyl, such as



-- 1.~ --.




~.'.'''

3:~


bell~yl and ph~nethyl, C8-C12 .~ -carboxyaralkyl, such as ~ -
carboxyphene-tllyl, C3-C10 cycloalkyl, such as cycloprop-yl,
cyclohexyl and cycloheptyl, Cl-Clo cycloalkylalkyl, such as
cyclohexylmetllyl, :fur:~uryl, te-trahydrof`urfllryl, 3~furylmethyl,
-tetrahydro-3-furylme-thyl~ 2-thenyl, 3--thenyl, te-trahyclro-2-
thenyl and tetrahydro-3-thenyl.
Suitable illustrations of R3 in the above formula (I) are
hydrogen, Cl-Clv alkyl, such as methyl9 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-methoxypropyl, 2-ethocyethyl dllcl
3-methoxypropyl, C2-C6 alkylthioalkyl, such as 2-ethylthio-
ethyl and 2-methylthioethyl, C2-C6 alkylsulfinylalkyl, such
as 2-methylsulfir.~ylethyl, Cl-C6 hyd:roxyalkyl, such as 2-
hydroxyethyl and 3-hydroxybutyl, C2--C7 carboxyalkyl, such
as l-carboxybutyl, C3-C8 alkoxycarbonylalkyl, sueh as 2-
ethoxyc~rbonyletllyl~ C7-Clo aral]cyl~ Such as ~enzyl and
l)hcllotllyl~ C~-C12 d~ -c~ o~;y~r~ y~., S~lCll US ;~( -CUl~l~OXy
phcllet~lyl, C3-Cl O cycl.oa~ yl, SllCll a.s cyc l.ol-
2~ u~ yc~ y.~ -Cl~ cyelo~:Lliyl.~.ll~y:l, sllcll ~ eyelol)~xy~.-
methyl~ furfuryl., tetrahydrofurfuryl, 3-furylmethyl,
tetrallydro-3~~urylmethyl, 2-thenyl, 3-therlyl, te-trahydro-2-
thenyl ancl tetrallydro-3-thenyl.
~uitable illustratiolls of RJ~ in the above formula (I) are
C~-c5 a.lky.l.~ sllcll us metllyl and propy~, carl)oxy, C2-C5



- l6 -



~!

23~

allcoxycarbonyl, such as ethoxycarbonyl, C7-C10 aralkyl,
such as benzyl~ and ring qubstituted benzyl wherein said
su~stituent is Cl-C3 a:Lkoxy, such as 4-methoxybenzrl.
Suitable illustrations of R7 are hydrogen, Cl-C6 alkyl,
such as methyl~ ethyl, propyl and isopropyl 9 phenyl and
carboxy, and the suitable position of R7 i9 ~s 4 or 6.

COOH
)--\ .
Suitable -N \Z group~ are 3-carboxy-4 morpholino,
\ (C~2)q
3-carboxy~4-thiomorpholino, 1-oxo-3-carboxy-4.-thio~orpholino
and 4-carboxy-3-thiazolidinyl.

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

tetrahydro-l-quinolyl, 3-carboxy-1,2,3,4-tetrallydro-2- -
isoquinolyl, l~carboxy-1~2,3,4~tetrahydro 2-isoquinolyl,
2-carboxy l-indolinyl and 1-carboxy-2-isoindolinyl.
Sui.table illu9trations of R2, R~ R87 R9- Rlo and Rll are
hydrogen, Cl-C10 alkyl, such as methyl~ ethyl, tert-butyl
and octyl, C6-C10 aryl, such as phenyl and m-tolyl, C7 C10
; aralkyl, such as benzyl, and 5-indanyl.




- 17 ~
~ .

2~


Sui-table il:lus-trations of ~r in the above formula (I) are
naphthyl, such as l-naphthyl and 2-naphthyl~ 5,6,7,8-
tetrahydsronaphthyl, such as 5,6,7,8~tetrahydro~1-naphthyl
and 5,6,7,8-te-trahydro-2-naphthyl~ naph-thyl substituted
~ith at least one substituent ~e].ected 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 methox-y and ethoxy, and C2-C10 dialkylamino,
such as di~ethylanuno and diethylamino, phenyl, phenyl
substituted wi.th at least one substituent selected from the
group consisting o:~ halo, such as chloro, Cl-C5 alkyl, such
as methyl, ethyl and isopropyl and Cl-C5 alkoxy, such as
methXYs C7~C10 arallcyl~ ~uch as phenethyl,

~uch 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-naph-thyl, 5-
chloro-l-.naphthyl, 6~chloro-2-naphthyl, 6-bromo l-naphthyl,
5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-
naphthyl, 6~methyl-l~naphthyl, 7-methyl-1-naphthyl~ 7-me-thyl-
2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl,



~ 18 -

c , , , ' , . . '

,


G,7-dimethyl-2-rlapllthyl, 6-i sopropyl-2-naphtllyl, 5-methoxy-
l-naphtllyl, 6-methoxy-2-naphthyl, 7-methoxy-2-napllthyl,
/l,6-~limt?thoxy-2-rlclpll-tllyl., 6~7-dime-thoxy-2-llapllthyl~ ~77-
ciit-~tlloxy-2~napllt~ly~, 5-dimethyla~irlo-1-rlaplltlly:L, 5-
dimethylamino-2-naptlthyl, 5-di.ethylamino-1-napllthyl~ 6-
dimettlylamillo-l-rlaphthyl, 6-dimethylamino-2-rlaphthyl, -4--
chlorophenyl, 2,4,5-trichlorophenyl~p-tolyl, anisyl, 3,4-
dimethoxyphenyl, 3,4,5-trimethoxyphenyl, ~ )


~ ~ ancl ~ ~ .

Illustrative of suitable N -arylsul~onyl-L-argininamides of
sufficient activity are the following:

N -(6,7-di~nethoxy-2-naphthylsulfonyl)-L-arginy.l-N-
propyltglyciJIe :

N -(f~,7-(limt?tlloxy-2-llapl)tlly1sl1J.fonyl)-L-ar~illyl-N-
propyJ.glycille t;ert-~utyl ester

N -(G,7-tlimetlloxy-2-~1a~ tlly:L~llJrolly.l)-L-arg:i]lyl-N-.
~utyJglycint-
~

N -(G,7-dimethoxy-2-naphtlly1sulronyl)-L-arginy1-N-
butylglycine tert-~utyl ester




_ ~9 _



~.

. ' .


N -( 6, 7 -cli.me tllo~cy-2 -llaphtllylsu:L foJIyl ) -L--a.t g.i llyl -N-
isobu tyl gl yc ine


N -( 6, 7-(1imc thoxy~2--naT)htllylsul ronyl )--L-arg:i.rly L--N-
p en tyl gl ycin e


N -(6,7-dlmethoxy-2-l1aphthylsulf`ollyl)-l,-argi~lyl--N-
hexyl gly cin e


N -(6,7-dimethoxy-2-rlaphthylsulfonyl)-L-argi2lyl-N-
o c-tylglyciJl~

N -(4 ~6-climetlloxy-2-rlaph-t~lsulfonyl ) -I,-arginyl-N-
butylglycine


N -(6,7-~1iethoxy-2-naphtllylsulfonyl )-L-argillyl-N-
butylglycine


N -( 6-methoxy-2-naphthylsul fonyl ) -I,-arginy:l.-N-butylglycine

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


N --( 7 methoxy-2--naph-tllylsul ~onyl )--L--arginyl--N-propylglycine


N -(7-methoxy-2-JIaplltllylsulfonyl )--L--arginyl.-N--butyl.glycine



N -(7-methoxy-2-naph-tllylsul :t'onyl ) -L-a:rginyl -N-pen tylglycine


N --(2-naphthylsul:f'onyl )-L-arginyl--N-butylglycine


N --(2 lla~ tlly:lslllrollyl~-l,--argillyl-N-blltyJglyciJlc ethyl cster
.



_ ;~o _
r --

i ..

L~i

N ~(2-naphthylsulfonyl)-L~arginyl~N-butylglycine benzyl
ester

N -(2-naph-thylsulfonyl)-L-arginyl-N-butyl-~ -alanine

N ~(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginy.L-N-
butylglycine

N -(5,6,7,8-tetral~ydro-2-naphthylsulfonyl)-L-arginyl~N-
pe~$ylglycine

N2-(5,6~7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl N-
: butyl-~ -alanine

~ 10 N -(6-bromo-1-~aphthylsulfonyl)-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-
prop~nyl)glyci~e

N2-(6~7-dim0thoxy-2-naphthylsulfonyl)-L-arglnyl-N-(2-
methoxyethyl)glycine




- 21 -
~:
.
,,
. ,

213~

N -(6~7-dinlc~lloxy-2-lla~ yl~ ollyl)-L-ar~illyl-N-
(2-mctllo~yetlly~){,r:lycillc etllyl ester

N (~,7-~ o~y "-ll~lltllylslllrOllyl)-l.,-<lr~ y].-N-
(2-metlloxyetllyl)glycine oc-tyl ester

N -(6,7-dimetlloxy-2-naphthyl~ulronyl)-L-arginyl-N-
(2-methoxyethyl)glycine ben~yl ester

N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-ar~inyl-N-
(2-methoxyethyl)glycine 3-methylphenyl ester

N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(2-methoxyethyl)glycine 5-indarlyl ester

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

N2-(6~7-dimethoxy-2-naphthyls~l~onyl)-L-arginyl-N-
(2-methoxyèthyl)-~ -alanine ethyl ester

N -(~,7-dillletllo~y-2-1l~lltllyl~ lrolly:l.)-N-(2~metlloxyethyl)-
N~ -carlloxyl~rnl)y~ r~rill:irlam~ e

N -(G~7-~inle-~lloxy-2-~ lylslllrollyl)-N-(2-nletlloxyet~lyl)
N-(3-terl;-l~ul;o~ carl)onylpl~opyl)-L-ilrgi.llirl.lnli(le

N -(6,7-dimethoxy-2-napllthylslllfonyl)-N~(3-metlloxy-
pro~y~)fr]ycill~


N -(6,7-dimethoxy-2-naphthylsulfonyl)-1-argillyl-N-
(2-ethoxyethyl)-~ -alanine


N -(6,7-dimethoxy-2-llaphthylsulforlyl)-L-Qrginyl-N-
(2-methoxypropyl)glycine


N -~6,7-diethoxy-2-naphthylsulronyl)-L-arginyl-N-
( -methoxyethyl)glycine


N -~4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(2-methoxyethyl~glycine


N -(4,5-dimethoxy-2-naphthyl 9 ul fonyl)-L-arginyl-N-
(2-methoxyethyl)glycine ethyl ester


N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-
methoxye-thyl)glycine


N -(5-methoxy-1-naphthylsulfonyl~-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 .


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




.. . .

~ 1- ..

~23~

N ~ na.phthylsulfonyl)-L-arginyl ~-(2-methoxyethyl)glycine

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

N -(5-chloro-1-naphthylsulfonyl)-L-arglnyl-N-(2-methoxy-
ethyl)glYcine

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

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

N (7-methyl-l-naphthylsulfonyl)-L-arginYl-~-meth
ethyl)glycine

N -(6,7-dimethyl-1-naphthylsulfonyl)-L-arginyl-N- (2-
;nethoxyeth.Yl)glycine

N -(5-dimethylamino-l-naphthylsulfonYl)-L-arginyl-N-(2
cethoxyethyl)glycine

N -(7-hydroxy-2-naphthylsulfonyl~ arglnyl-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 ~.


.
- 2L~


N -(7-methoxy 2-naphthylsulfonyl)-L-arginyl-N-~2-
methylsul~inylethyl~glycine


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


N2-(6~7-dimethoxy-2-naphthylsulfonyl)~I-arginyl-N-
(3-hydroxybutyl)glycine


N -(6,7-dimetkoxy-2-naphthyl9ulfonyl)-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-naphthylsul~onyl)-L-arginyl-N-
benzylglycine tert-butyl ester


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



N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-ar~inyl-N- ~;
benzyl-~ -alanine


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




.

3~


N -(6,7-dimethoxy-2-naphthylsulfonyl)-L~arginyl-N-
phene tllyl~ alani,ne

N _(11 ~G-dimet]lo.~cy-2-nap]lt}lylS-Il fonyl )-L-arginyl -N-
benzylglycine

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

N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-ben~yl-~ -
aLanine

N -(6-methoxy-2-naphthylsulfonyl.)-N-benzyl-N-(3-
carboxypropyl)-L-argininamide

N -~6-methoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-tert-
butoxycarbonylpropyl)-L-argininamide

N -(5-methoxy-1-naphthylsulfonyl~-L-arginyl-N-
benzylglycine

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

N -(2-1lap~ y.l~ll1 r`OJIY.I. )-L - arginY1 - N-bCn~Y1g1YCiIIC

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

N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-
benzylglyc:i.nc



- Z6 -

? 2,3 ~

N -(5,6,7,8-~tetrallydro-2-naph-thylsulfonyl)-L-arginyl~N-
benzy~ alarline

N2-~7-metllyl-2-na~hthylsulf`onyl )--L-arginyi.-N-pllellethyl--
g] ycine

N -(6,7-d:imethoxy-2-napht.hylSulfonyl)-L-argirlyl-N~
earl~oxyp}lenethyl)glycine

N -(6,7-dimetlloxy-2-naphthylSulfonyl)-L-arginyl-N-
eyclohexylmethylglyeine

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

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

N -(4~6-di.methoxy-2-naphthylsulfonyl) L~arginyl-N-
eye~.ohexylglyeille

N -(7-methoxy-2-llaphtllylsulfonyl)-L-argillyl-N-eyelohexyl-
g~yei.~lo

N -(~-nlo~ y-~ ly.lsu.LJ.`ollyl.)-L-argillyl-N-eyelollexyl-
mol;llyl~lycill(3

N -( 5--mol,lloxy-l -lulpl~ I llyl .`;1l1. I`olly.l )-I,-arg.i lly I -N-cyc l ollexy:L--
Ill~!l,lly~ o




-- ~7 --



"~

3~

N -(5-methoxy~ aphthylSUlfonyl~ L-arginyl-N-
cy~lohexylmet}lyl-~ -alanine tert-l~utyl ester

N ~ ,7-dimethoxy-2-llclplltllylsulf`onyl)-L-argi]ly:L-N-
cyclohexylglycine

N -(6,7 -di me thoxy-2-llaphthyl5ulfonyl)-L-arginyl-N-
cyclohexyl-~ -alanine

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

N-cyclopropyl~N-(3-carboxypropyl)-N -(6,7-dlmethoxy-2-
naphthyl~ul~onyl)-L-argininamide

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

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

N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-
; 15 cyclohexylmethylglycine

N2-(7-ne~ly]-2-llc~ tllylslllfollyl)-L-ar~inyl-N-cyc:lollexyl-
motllylglycirlc

N -(7-methyl-2-naphthylsulfonyl)-L-arginy~-N-furfllrylglycine

N -(7-methyl-2-naph-thylsulfonyl)-L-arginyl-N-tetrahydro-
furfurylglycine



- 28 -



~,

~2i,~

N -(7-methoxy-2-JIaphthylsulfonyl)-L-arginyl-N-
furfury~.glycille

N -(7-me-tllo~y-2-naplltllylS-Ilfonyl)-lJ-argiJlyl-N-
f`urfurylglycirle tert-bu-tyl ester


N -(7-methoxy-2-rlap}ltllylsul~onyl)-L-arginyl-N-
tetrahy(lrorur.furylglycirle

N -(5-dimetllylamino-].-rlaphthylsulf`onyl)-L-arginyl-N-
tetrahydrofurf`llrylglycine


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

tetrahydrofurfurylglycine


N -(l-naph-thylsul~onyl)-L-arginyl-N-tetrahydrof`urfuryl-
glycine


N -(6,7-dimethyl-1-naphthylsulfonyl)-L-arginyl-N-
tetrahydrofurfurylglycine


N -(5,6~7~8-tetrally~ro-1-napllthylsulf'onyl)-L-arginyl-
N--tetrahydrof`-lrt`uryJ glycine

N -(6~7-di.nl(3Llll)xy-2-llal)lltlly-.SulL`ollyl)-L-argillyl-N-
tctrallydrorurrurylglyci.lle



N -(6,7-dimQ~IIoxy-2-llul)~ltlly.l.~ulrollyl)-L-~rgi]lyl-N-
~ y~7~ o




_


.
~'

2 b3 ~

N -(6,7-~imet~loxy-2-l1aplltllylslllfonyl)-L-argiJlyl-N-
butyla~ine t~rt-butyl ester

N -(6,7-dim~t~loxy-2-1laplltllylsulronyl)-L-clIginyl-N-
pentylalarline

N -(6,7-dimethoxy-2-naphthylsul~onyl) L-arginyl-N-
b~n~ylalanine

N -(6,7-dime-thoxy~2-naphthylsulfonyl)-L-arginyl-N-
phenethylalanille

N -(6,7-dimet;hoxy-2-naphthylsulfollyl)~L-arginyl-N-
cyclohexylalanine :

N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
cyclohexylmethylalanine

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

N -(6,7-dimethoxy-2-1~apllthylsulfonyl)-L-arginyl-N-(2-metlloxy-
etJIyl.)ala~ e

N -(6~7-~ leilloxy-,-~ plll,lly:lsul~`o~ly:l)-l,-ar~r.il-y~ lorvalillo

N -(6,7 dimetlloxy-2-naphthylsulronyl)-L-arginyl-N
butylaspartic acid

N -(6,7-dinle~lloxy-2-naplltlly~sulfollyl)-l.,-arginyl-N-
~utylaspartic aci.d diotllyl ester

.

- 3~ --



.,~,........... .


N -(6,7-dimetlloxy--2-rlaplltllylsulfollyl )-L-arginy:l-N-
ben~y:laspartic aci(l

N -( 6, 7-(1:i nletlloxy-2-rlap}lthylSulrollyl )-I,-ar~ yl-N-
ben~;ylaspartlc acid diethyl ester

N --(6,7-(limo~hoxy--2-napllthyls~l:l.rollyl)-L--arg:illy:l-N--n1ethyl
~ -pllenylalani3le

N -(6 ,7-dimetl-loxy-2-l1aphthylsulrollyl )-L--argr:illyl~N-methyl-
_( l~--me t~loxyphenyl ) alanine

l-~N2-(6 ,7-dime thoxy~2-naphthylsulfonyl ) -L-arginyl~--2-
piperidillecarboxylic aci.d

Ethyl l - [N - ( 6, 7 -di me thoxy-2 -naph-i;hyl s u .l ro n y]. ) -L-argi n yl~ -
2--piperidinecarboxylate

1- [N2-( 6-methoxy-2-naph thylsulfonyl )-L-arginyl~ -2 -
piperidillecarboxylic acid

1- [N -( 6 ~ 7 -(lime l;hoxy-2-napllthy].su~ fonyl )-L-arginy Z.~ -4-
metllyl-2-pil)~?ri(li.llecarboxylic acid

1- [N -(7-mcl,llo~y-2-nap]ltllylsulronyl )-I,-argilly~ -4 -methyl-2-
piperidinecarboxylic acid

1- [N -( 5-me thoxy-l -naph-thylsul fonyl ) -L-arginyl~ -4 -methyl -2--
2 0 . ~i. r~ ~ ri. ~ l o c .~ o xy.l i c ~I c i ~




~ l _

..
I




~ .
.'

2~6

Ethyl 1~ (5-me-thoxy-1-naphthylsulfonyl)-L-arginyl~-4-
methyl-2-piperidinecarboxylate


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


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


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


l-rN -(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


1$ l-~N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-argi~yl3-6-
methyl-2-piperidinecarboxylic acid



l-~N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl~-2-me.thyl-2-
piperidinecarboxylic acid


1 [N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-3-
piperidinecarboxylic acid




, 3

~ ,................ ... .
.
l 1'-'

~ 2~:~.6

~lethyl 1- CN -( 6 7 7-di.methoxy-2-llaphthylsulfonyl)-L-arginy].~-
3-piperidin~acarboxyla-te

l-~N -(7-methoxy-2-naphthylsulfony.l)-L arginyl~-3
piperidinecarboxylic acid

l~[N -(7-methoxy-2-naphthylsulfonyl)-L-arginrl~-2, 6-
piperidinedlc~rboxylic acid

l-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4,-
phenyl-2-piperidinecarboxylic acid

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

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

N -(2-naphthylsulfonyl)-L-argirlyl~-4-isopropyl-2-
piperidinecarboxylic acid

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

l-CN (5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-
4-methyl-2-piperidinecarboxylic acid

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




- 33 -

.. .. . . . . . ..... ... . .. .. .... . . .. . . . . ... . .. .... . . . .... . . .. ... . .. . . .
..

~23~6

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


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


l-[N -(7~methyl-2-naphthyl sul fonyl)-L-arginyl~-4-me-thyl~2-
piperidinecarboxylic acid


l-~N -(7-methyl-2-~aphthylsulfonyl.)-L-arginyl~-4-ethyl-
2-piperidillecarboxylic acid


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


Ethyl l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-
isopropyl-2-piperidinecarboxylate


l-tN -(6 methyl-2-naphthylsul~onyl~-L-arginyl~-4-isopropyl-
2-piperidinecarboxylic acid


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



4-[N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl~ -3
thiomorpholinecarboxylic acid


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




- 34 -

~. _ ... , . ,.. ... ,. ,.,, . . . ., . _ .. _,__ .. ,
l .
I



4-~N ~(6~7-~ime-thoxy~2~naphthylSu].fonyl)~L-arginyl~ 3-
morpholinecarboxylic acid


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


3-[N -(7~methoxy-2-naphthylSulfonyl)-L-arginyl~-4-
thiazolidinecarboxylic acid


2 - tN2 -(6,7-dimethoxy-2-~aphthylsulfonyl)-L-arginyl~-
1 J 2,3~4-tetrahydroisoquinoline-3-carboxylic acid


2-~N2-(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl~
isoindoline-l-carboxylic acid


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


N -(294,~-trichlorophenylsulfonyl)-L-arginyl-N-butylg7ycine


N -tosyl-L-arginyl-N-butylglycine


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



N (3,4-dimethoxyphenylsul~onyl)-L-arginyl-N-(2-methoxyethyl)
glycine


N -(3r4,5-trimethoxyphenylsulfonyl)-L~arginyl-N-(2-
methoxyethyl)glycine


N -phenethylsulfonyl-L-arginyl-N-furfurylglycine




~ 35 ~
r~
~.
l l;

2~

N ~ -ben~odioxan-6-sulfonyl)-L-argirlyl-N-(2 me-thoxyethyl)
glycine

N --(fi,7--c~ll;y~ io~cy--2~ tlly~ ]rO~ly~ r~illyl--N--
(2-me-thoxyetllyl)glycLne

l-tN ~(2-dibenzorura~yl)-L-arginyl~-2-piperidillecarboxylic
acid ~'

Of the compounds of this invention, i-t will be ~Iderstood
that the following compounds are most preferred due to their
high level Or antitllrombotic activity ancl lo~ level of
toxicity.

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

N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl-N-butylglycine

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

N -~6,7-climethoxy-2-naphthylsulfonyl) L-arginyl-N-
(2-methoxyethyl)glycine ethyl ester

N -(ll,6-dinlctlloxy-2-l~apllthyls~llfonyl)-L-arginyl-N-
( 2-methoxyetllyl )glycine

N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-
me-thoxyetllyl)glycille ~;



-- ~6 --

2 :
N -(5,6,7,8~tetrahydro~ aphthylsulronyl)-l-arginyl-N-
~2-metho~yethyl)g.lycine

N -(7-methoxy-2-l1apllt}ly].slllfollyl)-L-argiJlyl-N-tetrallydro-
f` rf`urylglyci.ne

N -(7-me~hyl-2-na~ tllyl.sulfollyl)-L-arg:inyl.-N-te-trahydro-
furfurylg,lycine ''

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

1. rN -(6,7-dimethoxy-2--naphthylsul:fonyl)-L-arginyl~-4
methyl-2-piperidinecarboxylic acid

l-~N -(7-metho~y-2-naphthylsu~fonyl~-L-arginyl~-4-
methyl-2-piperidinecarboxylic acid

l-~N (7-methoxy-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-
2-piperidinecarl~oxylic acid

Tlle pllarmacelltical.ly acceptable sal.ts of the above compoundS
are of collrse a.lso incllldcd within tlle scope of this
i ll ven ti on .
As one skilled in the art can readily appreciate, the
carbon atom o r the N -arylsulfonyl-L-argininamides, to
whicll the carl~oxy.l. group or tlle ester thorco~`is attached
can l~c an a.symmctric car~on atom a:1.1Owi.n~ ~or the existence




~ 37 ~

3~;

of two optically active isomers, the D- and I-diastereoisomers,
as we~l as the racemate, DL-mixture.
In accordance with rindings concerning tl)e a11tithrombotic
activit;y Or such compollJ1ds poSSeSSi1lg an asymmetric carbon
atom, the compounds of` the pres E3nt invention having -the
D-config~1ra-tion are more active -than those Or the L-
config~lratio~ d are thc preferrec1 compounds, although the
I- and DL-forms of tlle inStal1t compounds are also considered
within the purview Or tlle present invention.
The above compounds are intended only to illustrate the
variety of structures which can be used in the process of
this invention, and the above listing is not to be construed
as limiting the scope of the invention.
~or the preparation of the compounds Or this invention,
various methods can be employed depending upon the parti cu-- -
lar starting materials and/or intertnediates involved.
Successf`ul preparation of these compounds is possible by
way of severa1 syntl~etic routes which are outlilled below.
(a) Conde11sation o~ an L-arginir1ami~lc with an ary:lsulfonyl
2 0 1~
This proccss may be illustra-ted as rOllOws

~IN
~ C -- N -- C 112 C112C l l~C}~
2 H NH2 ;~




~ 3~ --




~. ,

l~G2~L6

HN ~
~C--N--CH2CH2CH2CHCOOH (II)
I ~" E~N
R' I
R"' ~.

-~ RH (IV)



HN
~C--N--Cl-12CH2CH2CHCOR (V)

I R" E-~
R' I




HN ~
C - N - CH2CH2C~12CHCOR ~VI)
2 11 NE12




~ + ArS02X (VII)



HN
~C - N - CH2CE~2CH2CHCOR (I)
HNSo~
Ar ~'


Ill tllo above l`ormlllas~ R ~Id Ar are a~ derillc~ herein
above; X is llalogell; R"~ is a protective group for
the ~ -am.ino group~ such as benzyloxycarbonyl or tert~
buto~ycarbonyl R' and R" are seleote(l from the group
Collsistillg Or hy~rogen and protective grollps ror the
gllani~lirlo group, such as nitro, tosyl, trityl,




- 3~ - :

~2~

oxycarbonyl and the like; and at least one of R~ and
R" ls a protecti~e group for the guanidino group.
The N -arylsulfonyl-L-argininamide (I) is prepared by
thc condeJIsatioll of an L-argininanli(lo (VI) wi-th a
sulostantially equimolar amount of an arylsulfonyl
haliclc (VII), preferably a chloride.
~he condensatiorl reaction is generally e-~ected in a
suitable reaction-inert solvent in tlle presence of an
excess of a base, such as an organic base (triethyl- :
amine~ pyridine) or a solution of an inorganic base
(sodium hydroxide, potassium carbonate)-, at a tempera- ~ :
ture of 0 C to the boiling temperature of the solvent : .
for a period of 10 minutes to 15 hours. :
The preferred solvents for the condensation include
benzene diethyl ether, diethyl ether-water and dioxane-
water. ~ ~
After the reaction is complete, the formed salt is : --
extracted Wit]l water, aDd the solvent is removed by
such standard means as evaporation under re~uced
~)rc.~ rc I;o ~:ivc thc N -arylsll]rony1-J-argi~llnamide
(]:), wlli.cl~ c~l ~e puriricd ~y trituratioll or recrysta~
~atioll L`rolll a sui-tal)le solvellt, ~ucll as diethyl ether-
Lctrallytlrorllrall, dictllyl ethcr-rnetll~lol an(l watcr- ::
metll~loL, or nlay ~c cllromatograplle(l on silica gel.
l`llc L-ar~inillanu(lcs (Vl) startlrlg m.ltoria:ls require(l



~ ~0 -

;2~

for the condensation reac-tion can be prepared by
protecting -the guanidino and ~ amino groups of L-
arginine (II) vi.a nitra-tion, acetyla-tion, formylation,
phthaloylation, tri~luoroacetylation~ p-methoxy-
benzyloxycarbonylation, benzoylation9 benzyloxy~
carbonylation~ tert-butoxycarbonylation or tritylation
and then condensing the formed N -substituted-N -
substituted-L-arginine (II) with a corresponding
amino acid deriva-tive (IV) by such a conventional
process 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 N -
qubstituted-N -substituted-L-argininamide (V).
The amino acid derivatives (IV) which are the starting
materials for the preparation of the NG-substituted-
N -substituted-L-argininamides (V) are represented by
the following formulas~

H-N ~ 1 (vm) H-N~ 3 (IX)
(CH2)nCR2 ~ CH~(CH2)mCR,~ :
R4
I R6 COORg
H-N ~ (X) ~I~)r (XI)




~ 41 -

.. , . .. . . . .. ... . . . , . .. ., .. ~ .. . . .. . ..
r
.
. .
~, .

~ 23i~ ~
COO~lo COO~
CHz (XII) ~ CHz) ~ (XII)


In the above formulas, Rl, X2, R3, R4, R59 R6, R7, Rg,
RloJ Rll, Z, n, m, r, q, i, and j are as dofined 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-hal.obutyrate with
an appropriate amine having the formula RlNH2 or
R3NH2o (See, J. Org. Chem5~ 2~ 728-732 (1960)).
The condensation reaction is generally carried out
without a solvent or in a solvent, such as benzene or
ether, in the presence of an organic base, such as
triethylamine or pyridineJ at a temperature of 0C to
80 C for a period of lO minutes to 20 hour9. After the :
reaction is complete, the formed amino acid derivative
is separated by such conventional means as extraction
with a suitable solvent or evaporation of the reaction
solvent and thereafter purified by distillation under
r~duced pressure.
Among the amino acid derivatives~ amino acid tert-butyl
; ester derivatives are preferred~ because they are easily
converted to other ester derivatives by acidolysis in




, , , , , , , , . . . ; .. ... . . ... ... .. ... . . .. . .
~ ..
.,
.


: ",

~ Q2~

the presence of a corresponding alcohol employing an
inorganic acid (HCl, HzSO~, etc.) or ~n or~anic acid

~toluenesulfonic acid, trifluoroacetic acid, etc.).
In accordance w.ith the process employed for preparing
2-piperidinecarboxylic acid derivatives (X), the
following scheme i9 illustrative:


Cl> ~ R ~ ~ 7


H Cl
(~IV) (XY) (XVI)



7 2~ _~ ~ R7
N CN (H~) N C02H
H H
(XVII) (xvm)

In the first reaction of the a~orementioned schemeJ an
appropriately substituted piperidine (XIV) is contacted
with an aqueous sodium hypochlorite solution at a
temperature of -5 C to 0 C. The resultant product (XV)
is isolated by extraction with a solvent, e g., die-thyl
ether~ and then treated with potassium hydroxide in a
lower alkanol solvent to give the 1J2-dehydropiperidine
(XVI). The action of cyanogenating agents~ e.g.,
hydrogen cyanide or sodium cyanide converts the 1,2-
~0 dehydropiperidines (XVI) to the corresponding 2-cyano




~ ' - '~~



~,

analogs (XVII). HydrolysiS of the 2-cyanopiperidines
(XVII) to yield the 2-piperidinecarboxylic acids
(XVII~ 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 prepara-tion of the N2-aryls~tlfonyl-
L-ar~ininamides (I) can be prepared by halogenatin~
the requisi-te arylsulfonic acids or their salts, e.g.,
sodium salts, by conventional methods well known to
those skilled in the art.
In practice, halogenation is carried ouk without a
~olvent or in a suitable solvent e.g., halogenated ~ ~;
hydrocarbons or D~F in the presence of a halogenatin~
agent, e.g., phosphorous oxychloride, thionyl chloride,
phosphorous trichloride, phosphorous tribromide or
phosphorous pentachloride, at a temperature of -10 C
to 200C for a period 3f 5 minutes to 5 hours. After
the reaction is complete9 the reaction produc~ is
poured into ice water and then extracted with a solvent
~uch as ether, benzene, ethyl acetate, chloroform or
the like.
The arylsulfonyl halide can be purified by recrystalli-
zation from a ~uitable solvent such as hexane, benzene
or -the like.



_ 44 -
~, ''


~ . ` ,.

~ ~'~


(b) Remo~al of the N -substituent from an NG-substituted-
-N ~arylsulfonyl~L-argininamide
This process may be illustrated as follows:

HN
~IN ~C IN CH2C~IZCH21HCOR (V) -

I R" HN
F~l I
R"~


HN ~C-l-cH2cH2cH2cHcoR (XIX) _AlS02X (VII)
I R~ NH2
R'

HN ;~
fC-N-cH2cH2cH2cHcoR (XX)
I R~' HNS02
:R' I
Ar


H2cHcoR (I~
H ~SO2
Ar




- 4~ - 9

, _., . . . . .. _ _ ._ _ _._ _, _ .. _.. _ ._ . . _ .. .. ...... . _ _.. _ .. ~_. ____ . _ _ ----
f _ .
.'
,, .
"

~2~6


In the above formulas, R, Ar, X~ R'~ R" and R"~ are
as definecl llerein above.
TI1e N -arYISU1rOIIY1-L-CIrgiIIinaIt1ide 1I) j.S prepared by
removing tlle N -subs-tituent f`rom all N~-substituted-
N -arylslllronyl-L-argininamide (XX) by means of
aciclolysis or hydrogenolys:is.
Tile acidolysis is generally effected by contac-ting
the N -substituted-N -arylsulfonyl-L-argininamide
(XX) and an excess of an acid such as hydrogen
fluoride, hydrogen chloride, hydrogell bromide or
trifluoroacetic acid, without a solvent or in a solvent,
such as an ether (tetrahydrofuran, dioxane~, an alcohol
(meth~nol, ethanol) or acetic acid at a temperature of
-10 C to 100 C, ~ld pr~erably at room temperature for
a period of` 30 minutes to 24 hours.
The products are isolated by evaporation of the solvent
and the excess acidj or by trituration with a suitable
so~vellt ~ollowe(l l)y filtratioll an~ (lrying.
]lecalls(? Or tllC IlSe ol` I;l~o OXC(?:;~ ;ICi(1, tllC p.l'O~]IICtS
are ~,elleral~y tllc ~ci~ 3(l:itioll 9.-ltg oi` tllo N -
arylsul~onyl-L-argininamides (I), which can be easily
collverte(l to a ~ree an~de by ne~ttrali~ation.
The removal Or the nitro group ~Id tlle oxycarbonyl
grou~, e.g., benzyloxycarbonyl, p-nitroben~yloxy-
carl~ollyl, is rca~ily accomL~ ed by tlle hydrogellolysis.



~6 -


~ .



f

At the same time, the ben~yl ester moiety wh:Lch can
be included in the R group i9 converted to -the carboxyl
group by -the hydrogenolysis.
The hydrogenolysis is effected in a reaction-inert
solvent, e.g., methanol, ethanol, tetrahydrofuran or
dioxane, in the prasence of a hydrogen-activating
oatalyst, 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
10 of 2 hours to 120 hours.
The hydrogen pressure is not critical, and atmospheric
pressure is sufficient,
The N -arylsul~onyl-L-argininamides (I) are isolated
by filtration of the catalyst followed by evaporation
15 of the solvent
The N -arylsulfonyl-L-argininamides can be purified in
the same ~anner as described above.
The NG-substituted-N2-arylsulfonyl-L-argininamides (XX)
starting materials can be prepared by conden~ing an
20 NG-substituted-N -substituted L-arginine (DI) (generally
the NG-substituent is nitro or acyl, and the N2-
substituent is a protective group for the a~ino group 7
! such as benzyloxycarbonyl, tert-butoxycarbonyl, or the
like) and a corresponding amino acid derivative (IV)~
25 selectively removing only the N -subs-tituent of an



~ 47 -



~. l
.,




-substituted-N2-substituted L~argininamide (V) by means
of catalytic hydrogenolysis or acidolysis, and then
colldcllsill~ tlle f;llus obtained NG-sl~bstitllted-L-
Ul'~:illill.llll.idO (~lX) Willl ~1 arylsllli`ollyl lla.l.iclc (VIl),
preferably a chloride in the presence of a base in a
solvent. These reaction conditions are as described
above i.n the conde]lsation of an L-argininamide with an
arylsulfonyl ha].ide, and the remova~. of the NG-
substituent from an NG-substituted-N -arylsulfonyl-L-
argininamide,
(c) Condensation of an N -arylsulfonyl-L-arginyl halide
with an amino acid derivative
This process may be illustrated as follows: -

llN
}I N ~ N CH2CH2CH21CHCOOH (II)
NH2 ~ ,
~ ~rS02X (VII)

2V IIN
~C--N--cll2cll2c}l2cllcoo~l (XX~
~INSO
2 ~.
~r :~




~ 48 -



C-N--C112C1~2CH2C~ICOX (x~
1~2N
}LN S 2
Ar
-~ ~1 (IV)


ll
IIN ~
,C-N-cll2cH2c~l2cHcOR (I)



Ar


In the above formulas, R, Ar and X are as defined
lO herein above.
The N -arylsulfonyl-L-argininamide (I~ is prepared by
the condensation of an N -arylsulfonyl-L-arginyl
halide (XXII), pre~erably a ch]oride with at least an
equimolar amo~mt of an amino acid derivative (IV).
The condensation reaction can be carried out without
an added solvent in the presence of a baseO However,
satisfactory results will be obtained with the use of
- a solverlt sllcll as basic solven1;s (dimethyl~ormamide~
dimethylacetamide, etc.) or halogenated solvents
(chloroform, dichloromethane, etc.).
The amol~t of the solvent to be used is not critical
and may vary from abollt 5 to 100 ti mes l;lle wei~llt Or
tho N -aryls~ ol~y~ arginyl llalido (XXI])..




~ 9




.

'3~ :

Preferred condensatiorl reaction temperatures are in
the range of from -10C to room temperature. The
reaction time is not critical, but varies with the ~.
ami.no aci(l derivative (IV) employed. 131 general, a
period of from 5 minutes to 10 hours is operable.
The obtained N -arylsulfonyl-L-argininamide can be
isolated and puriried in the same manner as described
above
: The N -arylsuli`onyl-L-arginyl halide (XXII) star-ting
materials required f`or the condensa-tion reaction can
be prepared by reacting an N -arylsulfonyl.-L-arginine
(XXI) with at least an equimolar amount of a halo-
genating agent such as thionyl chloride, phosphorous
oxychloride, phosphorus trichl.oride~ phosphorous
pentachloride or phosphorus tribromide. The halogena-
tion can be carried out wi.th or without an added solvent.
The preferred solvents are chlorinatecl hydrocarbons such
as chlorororm and tlichloromethalle, and et~lers such as ~ :
tetrahydrof`uran an~l dioxane. ~.
2() 'I`l~e alllo~ , ol` tllo solvollt l;n l)o use~l is ~lol c.ritical ~ .
arl~ may vary ~`rom a~out 5 to 100 times tlle weight of ~:
the N~-arylslllrollyl-L-ar~ ine (XXI).
l'rcrerrc~ reactioll temperature are in ~lle rallge of
-10 C to room temperature. The reaction time is not
cri.tical, but -varies with the halogellating agent and

.


- 50 -




... .

a~

reaction temperature. In ~eneral, a period of 15
mlnutes to 5 hours is operable.
The N ~arylsulfonyl-L-arginines (XXI) w~.ch are the
s-tarting materials for the preparation of the N -
arylsulfonyl L-arginyl halides (X~ can be prepared
by -the condensation of L-arginine (Il) with a sub-
stantially equimolar amount of arylsulfonyl halides
(YII), by a method similar to that desc.ribed in the
condensation of an L-argininamide with an arylsul~onyl
halide.
(d) Guanidylation of an N -arylsulfonyl-L-ornithinamide or
an acid addition salt thereof
This process may be illustrated as follows:


H2N--CH2CH2CH2 ICHCOR (X~c) ~ ,
HN1~2

Ar



HN ~
~c-N-cH2cH2cH2CHCOR (I)
H2N
~INS02
Ar

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




; - 51 -

,.
,
,
',"

f ~ 3~


guanidylating an N -arylsul~onyl-L-ornithina~ide
(XXII) with an ordinary guanidyla-ting agent such as
an 0-alkylisourea, S-alkylisothiourea, l-guanyl-3,5-
dimethylpyrazole or carbodiimide~ The pre~erred
guanidylating agents are the 0-alkylisourea and the
S-alkylisothiourea.
The guanidylation o~ the N -arylsulfonyl-L-ornithinamide
(xxm~ with the 0-alkylisourea or S-alkyliso-thiourea is
generally e~ected 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 ~0 hours.
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.
E~amples of the preferred solvents are water, water~
ethanol and water-dioxane.
After the reaction is complete, the N -arylsulfonyl-L-
argininam de (I) is isolated by evaporation o~ the
solvent followed by removal of the excess base and the
~ormed salt by a water wash.
I It is well recogni~ed in the art that an cster deriva-
tive o~ the N -arylsulfonyl-L-arginina~ide (I) wherein
R2, R5~ R8, R9, Rlo or Rll is alkyl, aralkyl, aryl or
_ 52 ~




...... ,. ,. . . _ _ , _
,.
',,
,-

5-indanyl, can be prepared from a carbo~ylic acid
derivative of the N -arylsulfonyl-L-ar~ininamide
wherein R2~ R5~ Rg~ Rg~ Rlo or Rll Y
the conven-tional 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 conven-tional
hydrolysis or acidolysis methods. The conditions under
which esterification, hydrvlysis or acidolysis would
be carried out will be each apparent to those skilled
in the ar-t.
The N -arylsulfonyl-L-argininamdde (I) of tlLis invention
forms acid addition salts ~ith any of a variety of inorganic
and organic acids. Some of the N -arylsulfonyl-L-argininamides
containing a free carboxyl group9 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 o~ salts. In addition, the
product can be obtained as pharmaceutically acceptable acid
addition salts by reacting one of the free bases with an
acid, such as hydrochloric, hydrobrondc, hydroiodic, nitric,
sulfuric, phosphoric, acetic, oitric; maleic, succinic,
lactic, tartaric, gluconic, benzoic, methanesulfonic,




_

. :,


etha]leslilfollic, I)en:~ellesulfonic, p-t;oluenesulf`onic acid or
thc 1i IC(:!. In a sinli.l.ar marlller, I;he prod-lct can be obtained
as p]-larmacellticall.y accel~table salts by reacting one Or the
rree carl~oYy.l.ic acid.s Wit]l a l)ase, sucll aS sodium llydroxide,
potassium hy(lro~;:ide~ ammonium hydroxick3~ -triethylamille,
procai ne, clihe~ yl~mi.ne, l-ephenamitle, N ,N ' -diben~ylethylene-
diamine~ N-etllylpiperidirle or the like.
Likewise, treatment of` the salts with a base or a~id res~llts
in a regenerat;ioll of the free amide.
As stated above, the N arylsulfonyl-L-argi~ amides, ~nd
the salts thereof of this invention are charac-terized by
their l ighly speclfic inllibitory acti~ity against thrombin
as ~ell as by their substantial lack of t:oxicity9 and
thcrerore these compounds are usel`l.ll in the determination
of thrombin in blood as diagnostic reagents, andjor for the
medical control or prevention of thrombosis.
The compounds of thi.s invention are also useful as an
inhibitor oI` plate~.et aggregation.
The antithroml~otic ac-tivity of the N -arylsulfonyl-L-
argini.narni(le of tlli.s irlverltion was compared wi th tl~al; of
a ]cnown antithroml)otic agellt, N -(p-tolylsl.~l.rollyl)-L--
arginille rnel;llyl ester, by determining tlle fi.brinogen coagu--
lation time . The measuremen t of` the fibrinogen coagulation
time was conducted as rOllOws: :
l~n 0.8 ml al.i(LIlot ol` a ~`iL)rirlogell SO~ ,iOll, WlliC~ ad been



~ 54 ~


~ . .

~'2~

prepared by dissolving 150 mg of bovine fibrinogen (Cohn
fraction I) supplied by Armour Inc. in 40 ml of a bora-te
saline bu~fer (pH 7.4), was mixed with 0.1 ml of a borate
saline bu~fer, 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 bath to a bath maintained at 25C.
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 concerltration 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 ~actor of two for the known antithrombotic agent,
N -~p-tolylsulfonyl)-L arginine methyl ester~ was 1~100~ m.
The inhibitors are shown in Table 1 by indicating R and Ar
in the formula (I) and the addition moiety.
When a solution containing an N -arylsulfonyl-L-
argininamide of this in~ention was administered intra~enously
, .

~ 55 ~



~ .

~.~$~


illtO animal bo(lies7 the higll antithronIbotic ac~ivity in the
CirCIllati llg bloO(I W-19 nlaintaillc(l ror ~`rom one to three hours.
rl1e IIalf:lifc ror ~Iccay of tlle antl-t]lrotlIl)otic conlpoul~cls Or
~ S i.IlvollL:ioJl i.n circulatillg l~loo~i W.IS s11owl~ ~o I~e a~pro-
ximately 60 minutes; the physiological conditions of the
host aninla:Ls ~rat, rabbit, ~log an~ chimpan~ee) were well
maintained. The experimental decrease of fibrinogen in
animals caused by in-rusion of thrombin was satisfac-torily
controllecl by simultaneous inf`usion of the compounds of
this invention. ~ :
The acute toxicity values (LD50) de-termined by intraperito-
neal administration of sub5tances Or forrnula (I) in mice
(male, 20 g) range from about 17000 to lO,000 milligrams per
kilogram of body weight. ~ -
Representative LD50 values for the conpol~lds o~ this inven~
tion are shown in the rollowing Table.

. ~ .
Co~ )o~ L~ 0 (mg/Iig)
.... . . ... '; _
~-(7~ y1~ lyl~ ollyl)-]~-
~r~i nyl -N ~ I;y:l g1 yc:i n c ~ l, 500
_ ., _. _ .......... ._ .. . . _ .. ._ ___
N -(6,7-dimethoxy-2-1lapllthy~sulf`olly~)-L-
arginyl-N-(2--methoxyethyl)glycine l,900-2,400
. ,, _ . _ .
N -(6,7-dimethoxy-2-naphthylsulf`onyl)-L-
arginyl-N-(2-e-thoxyethyl)- ~-aI~lne 660-1~000
.~




- 56 - .

3 2~ 9


~ _
Compou~d 1,D50 (mg/kg)
2 _
N ~ ,6-cli-netl-oxy-2-llaplltllylsulronyl)-],-
~l~gi~ -N-(2-~llctllox~rctl~y-l)g~ ~cill~ 660-1,000
. .. ._ _ ..
N -(7-metlloxy-2-nal)hthylsulf`onyl)-L- 2 000
arginyl-N-(2-methoxyethyl)glycine t
2 - _ _
N -(5,6,7,8-tetrahy(iro-1-naphtllyl.slllfony:l)- > 1
L-arginyl-N-(2-met}loxyetllyl)glycine ~ ,500
2 ~ -- - .
N -(6,7-dimethyl-:1 naphthylsulfonyl)-L- ~1 00
arginyl-N-(2-methoY~yethyl)glycine ,5
_ . , ... ... _ . _ . _ . . . _
N -(6,7-dimethoxy-2-naphtllylsulfonyl)-L-
arginyl-N-(2-ethylthioethyl)glycille >1~000
2 ~~~~--- --- ~
N -(6,7-dimethoxy-2-naphthylsulfonyl)~L- >1 000
arginyl-N-ben~ylglycine
~ 2 ~ - -
: N -(4,Ç-dimethoxy-2-naphthylsulfonyl)-L- >1 000
argillyl.-N-Ie~zy:LglyCill(? '
_ , _. ~
N -(5-methoxy-1-naphtllylsulfonyl)--L- ~1,000
arginyl-N--ben~ylglycine ,
. ~
N -(6,7-dimethoxy-2-naph-thyls~lf~nyl)-L- .
arginyl-N-phenethylglycine ~19 500
2 -- ------_ _ .
N -(6,7-dimetlloxy-2-1laphthylsulfonyl)-L- >1 500
arginyl-N-cyclollexylglycinc J
2 - .
N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-
arginyl-N-cyc~ohexylmetllylglycine ~1,500
2 -- ~ _ .
N -(7-met~lyl-2-naplltllylslllronyl)-L- 600
arginy:l.-N-tetrallydrorllrrllrylglyci.lle :
_ ........... _ _




-- 57 --


.~ :


~ ----
C o mp ouncl _ _
~ - ----
N -( 6, 7 -di me tlloxy--2--lla~ thy~ sul fonyl )--L-- 62 0
argillyl -N-tctlallydror~lr~`ury]~]yci.lle
_ ......... .. _._ ....... __ . ...
N - ( 6 , 7 -~1 i me t llo x y--2 -nap ht hyl s u l f on yl ) -L- > 1 00
arginyl-N-bu tylalanine . 5
. _ _ ____ _
N -(/~, 6-dimethoxy-2-naphthy:lsulf`onyl ) -L- > 1 500
argilly~ -N-eyc l ohexyl me thyla~ anine ~
__ . . _ ___ ._
l-[N2-(6 ,7-dimethoxy-2-naphthylsuli`onyl )-L- 1 00
arginyl~-2-piperidineearboxylie aeid .5
. ._ _ _ . _ _ _ _ .................... . .
E-thyl [1- N -(7-methoxy-2-naphthylsulfonyl )-
L-arginyl~ -methyl-2-piperidinecarboxylate 670-1, 000
_ _ ~__ 7 ._._.___ . _._
1- [N -(4, 6-climethoxy-2-naphthylsulf`onyl ~ -
L-arginyl~-4-methy:l-2-piperidinecarboxylic 670--1,000 -:
acid ::
_. _ ~ _ . _ _ : .
l-[N -(l-napllthylsulfonyl)-L-argirlyl)-4- 700-1 000
methyJ-2-piperidinecarboxylic acid ~
.... _ ~
1- [N -( 5-dimethylamino--l-naphthylsul f`onyl ) -
L-arginyl~-2-piperidineearboxy~ie aeid 700-1,000 ~ :
__ . _ . , . ~_
4-[N -(7-methoxy-2 -naphthylsulronyl )-L- >
arginyl ~-3-mor~ o:l ineearboxylie aeid 1, OOC1
...... _ _ _ __ .
2-~N -(~7-(~1imetlloxy-Z-naphtllyl~ lrollyl)-l,-
ar~;i]lyl~-l, ','3,1~ o1;ral)y~1ro isO~ nOl itle--~-- ~ 1.,000
S~l t'l~O ~iy l ~ 1 (`.i (I
_ _ . . _ _ _
2- ~N -( 6, 7-dime thoxy-2-naphtllylsul ï ony l )--L-
ar~,rillyl~-l-isoi;~ o]itlecarboxy]ie acid ~] ,000
. ., , _

On the o tller han(l, I,D5~ vallles l~or N -dallsy~--N--butyl--L--
arginiJIamide and N -darlsyl-N-mettlyl-N-butyl-L-argininatnide
are 75 ~n~l 70 IlLi lli~rrams per kilo~ram~ respeel;ive~y.



-- 58 --



~,.,,~,


The therapeut:ic agents of this inven~ion may be admini.Ytered
alone or in coml):inati.o1l with pharmaceutically acceptable
carriers, the proportion Or which is determined by the
so11lbility an(1 chenlicul l1atllre Or -the compoll1ld, cl1osen route
of administration and standard pharmaceutical practice.
For example, the compounds may be injected parenterally,
that is, intramuscularly, intravenously or subcutaneously,
For parenteral admini.stration, the compounds may be used in
the form of sterile solutions con-taining other solutes, for
example, suff`icient saline or g~.ucose to make the solution
:iso-tonic Tlle compounds may be adminis-tered orally in the
form of tablets, capsules, or granules containing suitable
excipients such as starch, lactose, white sugar and the like.
The compounds mly be admiriistered snbli.rlglla11.y i.n tl1e form
f troches or l.ozenges in which each active ingredient is
mixed with sugar or corn syrups~ ~lavoring agents and. dyes~
and then del1ydruted s11~ficiently to ma]ce the mixture suitable
ror pressi~1g into soli.d form. The compo~ s may be ad-
ministered ora].ly in the form Or solutions which may contain
coloring al1(1 rl.uvorin~ a~ents. Physiciar1s will determine :~.
the dosage of the present therapeutic agents which will be
most suitable, and dosages vary with the mode of administra-
tion and the particular compound chosen. In additlon, the
dosage wil.l vary with the particular patient under treatment.
When the compo~i-tion is admini.stered orally, a larger quantity



~ 5~ ~




,,



of` the active agent will be required to procluce the same
effect as caused with a smaller quantity gi,ven paren-terally.
The therape-ltic dosage is generally 1,0-50 mg~/kg of active
i~lgrcclicllt palellteral.ly, 10-500 mg/kg ora].ly per (lay.
Having generally describecl the invention, a more,complete
understanding can be obtainecl by reference to certain specific
exampleS,which are included for purposes Or illustration .
only and are not intended to be limi.ting unless otherwise
speci~ied.




:




~ - 60 -



, ~, ~

EXA~LI3

(A) N --(6,7-dimethoxy-2-naph-thylsulfonyl)-L-arginine:
To a well stirred solution of 83.6 g of L-arginine in
800 ml of 10% potas,sium carbonate solution was added
114.7 g of 6,7-dimethox~r-2-naphthalenesulfonyl chloride in
800 ml of benzene~ The reaction mixture was s-tirred at
60 C for 5 hours, cluring which time the product precipi-
tated. After one hour at room temperature, -the precipi-
tate was filtered and washed successively with benzene
and water to give 129 g (76 percent) of N2-(6~7-dimethoxy-
2-naphthylsulfonyl)~ arginine, M.P. 252-5 C.

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

A suspension o~ 2.00 g of N -(6,7-dimethoxy-2-naphthyl- '-
sulfonyl)-L arginine in 20 ml o~ thionyl chloride was
stirred for 2 hours at room temperature~ Addition of
cold dry diethyl ether resulted in a precipitate which
was collected by ~iltrati.on and washed several times
with dry diethyl ether to give N2-(6,7-dimethoxy-2-
20 1 naphthylsulfonyl)-L-arginyl chloride~

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




~,~




To a s-tirred solution o~ 2.6l~ g of N-butylglycine
tert-butyl ester in 20 ml of chloroform was care~ully
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 solution and evaporated to dryness.
The residue was triturated wi-th a ~mall amount of water
to give a crystalline material. This was collected by
~iltration and recrystallized from ethanol-ethyl ether
to give 2 28 g (82 percent) of N -(6,7-dimethoxy-2-
naphthylsul~onyl)-L arginyl-N-butylglycine tert~butyl
ester, M.P. 164-166 C, I.R~ (KBr). 3,390, 3,165, 1,735,
1,370 cm
Analy5is ~ Calcd. for C28H4307N5S-2H2S03 (percen )
C, 52 98; H, 7.00; N, 11.04 ~ound (percent): C~ 52.69;
Hy 6~98, N, 10 86

(D) N -(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl N-
butyl~lycine:
To a sclution o~ 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 o~ 15~
HCl-ethyl acetate. The reaction mixture was stirred



- 62 -

~. . ,.,, ",. .. . ..... . .. . .
~a
~ ..
.,
.
, , ...
. ,,


for 5 hours at room temperature. At tlle ellcl of this
period, the reaction n~-ixt~lre was evaporated to dryrless.
The resi(llle was waslled several tlmes wi th clry diethyl
ethet an(l chrolllatographed on 80 ml of l)aiaioll ~ SK 102
ion excha1lge resin (200-300 mestl, 1-l form, mcanufactured
by Mi tsllbishi Chemical Industries Limi tecl) paclcecl in
~/ater, washed wi th water and eluted ~lith 3'10 ammo1lium
hy(lro~ e 503UtiOII.
Tho t`ractio1l ellJte~l from 3% ammo~ lm hy(lroxi(le solution
was evai~orated to dryness to give 1.1l3 g (79 percellt)
o f N -( 6, 7-dime thoxy-2 -naph thylsul fonyl ) -L-arginyl-N
butylglycine as an amorphous solid, I.R. (IC13r): 3,360,
3,140~ 1,622 cm 1,
Analysis - Calc~l. for C24~135N507S (p(~rcellt):
C, 53.62; ~1, 6.56; N, 13.03 l~ound (percent):
C, 53.48; 1-1, 6.43; N, i2.98
The followinfr compounds are prepare(l in a similar -
ma~ cr:
N -(7-motllyl-2-nal)htllylslllro1lyJ )-l,~rf~;illy1-N-~utyl--~-
2 0 a l a~ l o

Nz-(7-m(~tllyl-2-rlar~llt~lyl~u:lrorly~ )-N-(2~ ;y~l;llyl)-N-(3
carboxypropyJ )-L-argininamide

N -( 5-me-tlloxy-1-rlaphtllylsulf`ony:l ) -I -arg,inyl-N-( 2-
me thyl thioe thyl )glycine


:~:

~ .

; ~, .
~ I"'
~ I''''

3~.~

N -(5-methoxy-1-naphthylsulf~nyl)-L-arginyl-N-(2-
methylt:hioethyl)glycine tert-butyl ester


N -(5-methoxy-1-naphthylsulfonyl)-1,-arginyl-N-(2-
rnethylthioethyl)-~ -alanine


N -(6,7-diethoxy-2-naphthylsul~onyl)-L-arginyl-N-
(2-methylthioethyl)glycine


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


N -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-
methylthi.oethyl)-N-(3-carboxypropyl)-L-argininamide


N -(6,7-dimethoxy-2-naphthylSul~onyl)-N-(3-
methylthiopropyl)glycine


N -(6,7~dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-
ethylthioethyl)-~ -alanlne


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




. - 6

.. . . . .... . . . . . .. . . . . . . . . . .. .. ... . ..
r

;,~
:

~23~

I~-N{ N (6,7-di.nletl~oxy-2-naphthylsulroJly]) L,-arginyl~ -
N-cyclohexylaminobutyric acid

N ~ 6-(l.imetlloxy-2-1laplltllylsulfolly:l)-l,-argillyl-N-
pbenethyl-~ -alanine

N -(6-mettloxy-2-naphthylsulfonyl)-L-argirlyl-N-(3~
pl~etlylpropy.l.)glycine

N -(5-motlloxy-1-llaphthylsulfony~ L-ar~ yl-N-~ell~yl- ;~
~-alaniIle ' :~

N -(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydro-

furfllry:Lglycine

N -(7-hyclroxy-2-naphthylsulfonyl)-L-arginyl-N- .
teLral~y(trorurfllrylglycille

N -(5-cyano-1-naphthylsulfonyl)-L-arginyl-N-tetrahydro
. furfurylglycine

N -(6,7-dimethoxy-2-naphthylSulfonyl)-l,-argirlyl-N-
t c tratlytlrofurfuryI - ~ -alanine

N -(7-metllyl-2-1lapll-t1lylsulfollyl)-l,-argillyl-N-
tetrahycirofurfuryl-~--alanine

N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-
1;c~trahy(lrorllrfllry.1alanine



~ ~5 -
_
, ..
'; ''
,' ,




N -(7-methoxy-2~llapllthylsulfonyl)-N-(3-carboxypropyl)~
N-tetrahyclrofuri~uryl-L-argininamide

N -(7-methoxy-2-naphthylsulronyl)-1,-argirlyl~N-butyla].anine

N ~(7-methoxy-2-naphthylsul:fonyl)-L-argi.nyl-N-pentylalanine

N -(5-methoxy-1-naphtllylsulfonyl)-L-argrinyl-N~bu-tylalanine

N -(697-dimethoxy-2-naphthyls~ onyl)-L-arginyl-N-
isobuty.~alanine ~-

N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl-N-benzylalanine

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

N -~5-methoxy-l-naphthylsulfonyl)-L-arginyl-N-benzylalanine

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

N~-(G,7-(linlethoxy-2-1luplltllylsll:Lrol~yl)-L-arginyl-N-
cyclo~lc~yJmotllylalanillc

N ~(6,7-~imctlloxy-2-}1aphtllylsulfollyl)-~,-urgillyl-N-
l~utylbutyrirle

N -(6~7-~imethoxy-2-rlapllthylsll.L~oJly])-T~-arginyl-N
('~-f~ ylm~ yl )~rlycinc

,


- 66 -

N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl-N-
(tet~ahy~:ro-3-fllrylmethyl)glycin~ '

N -(6,7 di.methoxy-2-naphthylsulroTlyl)-l,-arginyl-N- , ','
(2-thenyl)glycine

N ~(7-metho~y-2-naphthylsulforlyl)-L-arginyl-N-
(3-thenyl)glycine

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

N -(7~methoxy-2-naphthylsulfonyl)-L-arginyl-N-
~tetrahydro-3-thenyl)glycine '
--N2-(6,7-dimethoxy-2-naphthaylsu1fonyl)-L-arginyl-N-(2-acetylethyl)glycine
N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(4-methoxyfurfuryl)glycine
N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methylfurfuryl)glycine
N2-(6,7,-~imethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(1,4-dioxacyclohexylmethyl)glycine
l-[N2-t6,7-dimethoxy-2-na~hthylsulfonyl)-L-arginyl]-4-methoxypiperidine-
2-carboxylic acid
l-[N2-(6,7,-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-5- "':
methylhexamethyleneimine-2-carboxylic acid
1-[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

: 25 (A) N -(6-me-thoxy-2-naphthylsulfonyl)-L-arginyl chloride,

A suspension of 2.5 g of N2-(6-methoxy-2-naphthylsulfonyl~-
L-arginine in 20 ml of thionyl chloride was stirred for
2 hours at room temperature. Addition of cold dry ethyl
ether resulted in a precipitate which was collected by
filtration and washed several times with dry ethyl ether
to give N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl
chlori,de,


~, -67-



(B) Etllyl l-[N -(6-me-thoxy-2-naphthyl9ulronyl)-L-arginyl~-
2-piperidinecarboxylate
To a stirrecl solution of 2.2 g of etlly:L 2-piperidine-
car~oxylate and ll.l ml o~ triethylami]le in 50 ml o:f
chloroform, which wa9 cooled in an ice-salt bath, was
added in portions N -(6-me-thoxy-2-naphthylsulfonyl)-L-
arginyl chloride obtained above. The
reaction mixture was stirred overnight at room tempera-
ture. At the end of this period, 500 ml of` chloroform
was actded and tlle chloroform solution was washed twice
~ith 50 ml o~ saturated sodium chloride solution~ dried
over anhydrou5 sodium sulfate and e~aporated in vacuo.
The oily residue was washed with ethyl ether to glve
2.9 g o~ powdery ethyi l-~N -(6-methoxy-2-naphthyl-
sulfonyl)-L-arginyl~-2-piperidinecarboxylate~
For analysis of the product, a portion of the product
- was converted to the flavianate~ M.P. 192-3C. :.
I3r): 3,210, 1,747, 1,638 cm 1
alysi~ - Calcd- for C25H356N5S Cl~f68 2
C~ 49.58; ll, ll.87; N, 11.56 ~`ound (percent): C~ 49.24;
}-f, 4.7~; N, 11.85

(C) l-[N -(6-methoxy-2-llaphthylsulfonyl~-l-arginyl~-2-
r~if)oridi3lecurl)0xylic aci(t
~ i.o~ ol 2.~ ~ ~r c~lly~ N~ o~y-2-
nupll~lly:LslllLollyl)-L u3~iIIyl~-2-pi~eri(li.]lecarl)oxylate in
.~ ~

6~ -


,.;~' .

2~

l5 ml of me-thanol and 10 ml of 2N-NaoLl solut.ion was
wa~led to 60C and held at tha-t temperature for lO
hours~ At the end of -thls period, -the reaction nuxture
was concentratec1 and chromatographed 011 200 ml of
Daiaion ~ SK 102 ion exchange resin (200 -- 300 mesll,
H~ f`orm, manufactured by Mitsubishi ChemiCal Industries
Limited) packed in water, washed wi-th ethanol-water
(l:4) and eluted with ethanol-water-NlIL~OH (lO:9:l).
The main fraction was evaporated to dryness and washed
with ethyl ether to gi.ve 2.0 g o~ N -(6-methoxy-2
napht:hylsulfonyl)-L-arg.inyl~-2-piperidinecarboxylic
acid as an amorphous solid.
I.R. ~K~r): 3JZ00 (broad), 1~620~ 1J150 cm
AnalySis - Calcd for C23H3106N5S (percent)
C, 54.64; H, 6ol8; N, 13.85 Found (percent):
C~ 56~88; H, 6.31; N, 13~83

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

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




- 69 -

3~


N -(4,6-(limetlloxy 2-naphtllylslllfonyl)-L-arginyl-N-
(2-methylthioethyl)glycine

N2-(~17(;-(l:lm(~ oxy-,'-~ lll.llyl~ lt`olly.'l )-I,-argillyl-N--
phene-thyl- ~ -alanine

N -(6,7-~limethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-
carboxypropyl ~--L-arginlnamide

N -~7-methoxy-2-naphthylsulfonyl~-IJ-arginyl~N- :
cyclohexylnorleucine -

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

N ~(7-me-thoxy-2-naphthylsulfonyl)-L-arginyl-N-
pentylbutyrine ' - :~

; N -(6,7-diethoxy-2-naphthylsulfonyl~-L-arginyl-N-
butylalanine

N -(6~7-dimethoxy-2-naphthyl~ulfonyl)-L-arginy].-N-
cycloheptylalanine

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

N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N- :
(2-othoxy~tlly]~alanine




_ 7o _


~C '



N -(7 methoxy-2-naphthylsulfonyl)-L-arginyl-N-
cyclohexyl-~7 -al anine

N -(7-n~ xy-,?-t~ tllyl~ roIly~ -alfri3ly]-N-(2- ~ -
methoxyethyl)norvaline

N -(6,7-dimethoxy-2-naphthylsulforlyl)-I,-argiryl-N-
ben~.ylleucine ,

l-~N -(5-~ethoxy-1-naphthylsulfonyl)-L-arginyl3-1l-
: ethyl-2-piperidinecarboxylic acid

l-[N -(6-methoxy-2-naphthylSulfonyl)~I,-arginylJ-4-
ethyl-2-piperidinecarboxylic acid

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

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

l~[N -(7-ethoxy-2-naphtllylsulfonyl)-L-arginyl)-4-
e-thyl-2-piperi.dinecarboxylic acid

l-CN -(6,7 diethoxy-2-naphthylsulfonyl)-L-arginyl~-4-
ethyl-2~piperidi.Ilecarboxylic acid

l~CN2-(7-metJloxy-2-naphthylsu~follyl)-l,-ar~ yl~-4-
tort~ tyl-2-I)iperi.(l:i.necarhoxy:lic acid :~
.




-- 71 --



Phenyl l-tN -(7-methoxy~2-naphthylsulfonyl)~L-arginylJ-
4-ethyl-2-piperidinecarboxylate

131?ll:r.y~ N2-( 7-mctl~oxy-2-1lap~l tllyl~ `onyl ) ~L-arginyl~
4-ethyl-2-piperidinecarboxylate -~

Ben~y] l-[N -(6,7-dimethoxy-2-naplltllylsulfonyl)-L-
arginyl~-4-methyl-2-piperidinecarboxylate

l-~N -(5-nitro-1-naphthylsulfonyl)-L-arginyl~-4-
methyl-2-piperidinecarboxylic acid

l-tN -(7-hydroxy-2-naphthylSulfonyl)-L-arginyl~-4-
ethyl-2-piperidinecarboxyllc acid

l-[N -¦5-cyano-1-naphthylsulfonyl)-L-arginyl~-4-methyl-
2-piperidinecarboxylic acid

l-~N ~(7-methyl-2-naphthylSulfonyl)-L-arginyl3-4-
ethyl-2-piperidinecarboxylic acid

1-tN2-(5--~imetllylamillo~l-naphthyls~llrollyl)-L-arginyl~-
ll-ethyl-~ )o~ ccarboxy.i.ic aci<l

l-~N -(2-nap~ltllylsulf`onyl)-L-arginyl~ -ethyl-2-
pi~eri.dillccarboxylic aci~

L-~N -(5,~),7,~-Lotral~y(lro-2-na~ thyl~ lrollyl)-1,-
ar~ yl~ etllyl-2-~iperidinecarl)oxylic acid :



-- 7~ --


s~
.,~ ...... .



l-~N -(5-dimethylamino-1-na.ph-thylsul.fonyl)-L-arginylJ-
4-fnethyl-2-piperidinecarboxylic acid

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

l-CN -(7-methyl-2-naphthylsul~onyl~-L-arginyl~-4-tert-
butyl~-2-piperidinecarboxylic acid

1-~N -( 5-nitro-1-naphthyl~ulfonyl)-L-arginylJindoline-
2-carboxylic acid

2-~N2-(5-cyano-1-naphthylsulfonyl)-L-arginyl~isoindoline--
l-carboxylic acid

4- [N -( 7-methyl-2-naphthylsul~onyl)-L arginyl~thio
morpholine~3-carboxylic acid

4-~N -(6,7~dimethyl-2-naphthyl.sul~onyl)-L-arginyl~
morpholine-3-carboxylic acid

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

4-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~morpho7ine- :
3-carboxylic acid

4 ZN -(7-chloro-2-naphthylsulfonyl) L-arginyl~morpholine-
3-carboxylic acid




~ 73 -
~ . .
.
~" .

~ ~.,,
~, ~ ~



4~N -(7-hydroxy-2-naphthylsulfonyl)-L arginyl~
morpholine-3~carboxylic acid

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

4-~N -(5-cyano--1-naphthylsulfonyl)-L-arginyl~thio-
morpholine-3-carboxylie acid

~ CN -( 5-methoxy-l-naphthyl3ulfonyl)-L-arginyl3
morpholine-3-carboxylic acid

Ethyl 4~N -(4,6-dimethoxy-2-l~aphthyl~ul~onyl)-L-
arginylJ morpholine-3-carboxylate

4-~N -(5 ethoxy-l-naphthylsulfonyl)-L-arginyl~
morpholine-3-earboxylie acid

4 - rN - ( 5-dimethylamino-1-naph1;hylsulfonyl)-L-arginyl~
thiomorpholine-3-carboxylie acid

3-~N2-(l-naphthyl9ul~onyl)-L-arginyl~t.hiazolidine-4-
earboxylie aeid

2-~N -(7-methoxy~2-naphthylsulfonyl~-L-arginyl~ :
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid ~ :~

2-tN2-~7-methoxy-2-naphthylsulfonyl)-L-arginyl~ :
isoindoline-l-earboxylic acid




?


2-[N2~ ,6~imet}loxy-2-napllthylSulf`ony]~)-L-ar~in
1,2,3,4~tetrally~Iro.iso~ inoline-3-carboxylic acid

?-~N~-(rj-n~ o~y~ ly~ rollyl)-]~ rilly:
isoi.ndo]ille-l-carbo~.ylic acid

2-~N -(5-etho~y-1-naphthylsulfonyl)-I-aIglnyl~-l,Z,3,ll-
tetrahydroisoquinoline-3-carboxylic acid

EXAMPLE

(A) NG-nitro-N -(ter-t-butoxycarbo~yl)-L-arginyl-N-(2-
methoxyethyl)glycine ethyl ester:
To a stirred solution of 28.3 g of N -nitro-N -(tert-
butoxycarbonyl)~L-arginine in 450 ml of dry tetrahydrofuran
were added i.n turn 12.4 ml of triethylamine and 12.4 ml
of isobutyl chloroformate while keeping the temperature
at -5 C. ~fter 15 minutes, to th.is was added 11~.2 g of
. N-(Z-metlloxyetIIyl)glycine ethyl ester~ and the mixture
was stirred Ior 15 minutes at -5C. At the end of this
io-l, tlle l'eaCtiOIl miXtllre was warme~l to room tempera-
~III`C. 'l`lle solvellt was cvalora~ed alld tllc resi(llIe taken
up in lIOO mI Or ethyl acetate~ and washed successively
with 200 ml of water, 100 ml of 5% sodillm bicar~onate
.sol~ iol~, 1()() ml ot` 109~, c,:i l;ric aci(l sollll,:io~ d 200 ml.
of wal;cr. Tllc etllyl acctatc solllt.ioll was ~Iric(l ovcr




~ 7S -


.

lla~2316

an}ly(lrolls sod:i11m sulfate. Upon ovaporati.ol1 of -the
solven~;, the residue was disso:l.ved in 20 ml of chloro-
form9 alld the .so1utio~ as app:I.ied to a co:lllnu-l (80 cm
x 6 cnl) o t` 500 ~r o l` gilica ~ a(~lie(l ill clllorof
The procltlct wa9 eluted firSt wi th chlorol'orm, a3ld the
3% mel;l1a~lo~.-ch:Loroform. The fracti.on e:lute(l from 3%
methanol-C]l.1o]:~oform was evaporated to dryness to give
25,8 g (63 perce11t) o.f NG-nitro-N -(tert-b1ltoY~ycarbonyl)
L-arginyl-N-(2-n1ethoxyethyl )glycirle ethyl ester in the
form Or a syr~lp,
I.R. (ISBr)- 3,300, l,7L~o, 1,690 cm

(~) N --ni tro-L-aIginyl-N--(2--methoxyetllyL )g.lycine ethyl ester
h~dro chlo ri de:
To a stirred solution of 29.8 g of NG-nitro-N2-(tert-
butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl~glycine
ethyl es ter in 50 ml of ethyl acetate was added 80 ml
of 10% dry ~ICl-ethyl acetate at 0C. Af`ter 3 hours,
to this so.l.utiorl was acklecl 200 m.l of dr~ ethyl ether to
precipitate a viscous oily product.
This Wlls fi.ltered and w~shecl wi th dry etllyl ether to
give 24.l g Or N -nitro--L-arginyl-N-(2-methoxyethyl)
glycine et~1yl ester hydrochloride as a~1 amorphous solid.

(C) N -ni. tro-N -(6,7-dimet}loxy-2-rlaplltllylsul fonyl )-L-arginyl-
N-(2-metlloxyel;hyJ )glycine el;hyl ester:



1~)
_ , ... ... _.
,...
,
'~ ,"'' .

~$~

To a stirred solu-tion of 4.0 g o~ N ~nitro-L-arginyl-
N-(2-methoxy~-thyl)glycine ethyl ester hydrochloride in
20 ml of water and 20 ml of dioxane were added in turn
2.5 g of sodium bicarbona-tc7 and 3.5 g of 6,7-dimethoxy-
2-naphthalenesul~onyl chloride in 30 ml of dioxane at
~C, and stirring was continued for 3 hours at room
temperature. At the end of this period, the solvent
was evaporated and the r~sidue dissolved in 40 ml oP
chloroform, and washed with 10 ml of lN hydrochloric
acid solution and 20 ml of water.
The chloroform solution was dried over anhydrous sodium
sul~ate D Upon evaporation of the solvent, the re~idue
wa~ chromatographed on 50 g of silica gel packed in
chloroform, wa3he~ with chloroform and eluted with 3%
S methanol-chloroform. The fraction eluted from 3%
methanol-chloroform was evaporated to give 5.3 g ~87
percent) of NG-nitro-N -(6,7-dimethoxy-2-naphthyl-
sulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in th~
form of an amorphous solid.
I.R. ~KBr): 3,Z40, 1,740, 1~630 cm 1

(D) N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-
(2-methoxyethyl)glycine ethyl ester:
To a 901ution of 3.00 g of NG-nitro-N -(6,7 dimethoxy-
2-naphthylsulfonyl)-I,-arginyl-N-(2-methoxyethyl)glycine




~ 77 ~

. . .. , .. . . . ......... ... ,.. , . .. ..... .. . .. , ., ., . . .. ~. . .. . .. ~ .. .....

.
.

2~


etlly] ost~r i.n 50 ml of etllarlol alld 0.5 ml Or acetic
aci(l was aclcl~(l 0.5 g Or palla(tiurn-black ancl then the
mi.xture w~ shalien in a llycirogen atmospllere ror 100
llo~lrs at l~oom tc~ml)cratllrc. At tlle ollcl Or tl~i4 period,
the ethano] solution was fi.ltered to remove the catalyst
and evaporated -to give an o.ily product. Reprecipitation
with ethanol-ethyl ether gave 2 53 g (91%j of N -(6,7-
dimethoxy-2-naphthyl5ulfonyl)--L-argi.nyl-N-(2-methoxyethyl)
glycine ethyl ester.
~or analysis of the product~ a portion Or the product
was converted to the flavianate; M.P. 185 C, I.R. (KBr):
3,375, 3,200, 1,71~0 cm 1.
Analysis - Calcd- for C25H37N58S ClOH6 2 8 (P
C, 47.67; H, 4~92; N~ 11.12 ~ound (percent)~
C, 47.64; H, 4.81; N, 11.12

(E) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2
methoxyethyl)g~.ycine~
A soltltloll of 2.5 g of N -(6,7--dimethoxy-2-naphthyl-
~111ro~lyl.)~L-ar~iny.l.-N-(2-me-thoxyotlly.l)gl.ycine etllyl
esl;er i.ll 5 ml. Or etll.~nol alld 7 m~. o~ l.N ~odium hydroxide
~O lUtiOII was stirre(l ror 30 hours at room temperature.
At the encl of` tlliS ~eriod, the solution was concentrated
to 5 ml, chromatograpllecl on 80 ml Or ~aiaion ~ ~K 102
ion excllan~e resill (200 - 300 melh, ll t`orm manu~acture~ :




~ 7~ -


.~,` ' .


by Mi tsubishi Chemical Industries Limited) packed in
water, washecl with water, and elutecl with 3% ammonium
hyclroxide solution. The fraction e]uted from 3%
amnlo~ nl ~Iy~lro~;i dc solution was evaporat(3d to dryne~s,
and the res:idue l~as purified by reprecipitation with
ethanol-ethyl ether to give 1.32 g (72 percent) of
N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-a~ginyl--N (2-
methoxyethyl)glycine as an amorphous solid.
I.R. (KBr): 3,380, 3,180, 1,630 cm 1
10 Ana]ysis -- Calcd. for Cz3H33N508S (percent): C, 51.20;
H, 6.17; N, 12.98 Found (percent): C, 50.93;
H, 6.02; N, 12.63

The foilowing compounds are prepared ~n a similar manner:
N -(5,6,7,8--tetrahydro-2-naphthylsulfonyl)-L-arginyl- ~-
N--(2--ethoxyethyl)glycine

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

N --(7--ethyl--2--naphthylsulfonyl)--L--arginyl--N--(2--
metho2~yethyl)glycine

N --(5-methoxy-1-naphthylsulf`onyl)-L-arginyl--N-
cyclohexylglycine




~ 79 --



~. , .

~z~


N -(7-me-thoxy-2-naphthylsulfonyl)-L-arginyl-N-
(3-cyclollc~yl31~ropyl~1ycine

2-tN2-(7-nlethyl-2-llaphthylsulfonyl)-L-areinyl~-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid

2-~N2-(7-~ethyl-2-nap~lthylsulfonyl)-L-argin
isoindoline-l-carboxylic acid

2-tN~-(6~7-dimethyl-2-naphthylsulfonyl)~L-arginy~
isoindolirle-l-carboxyllc acid

2-~N -(2-naphthylsulfonyl)~L-arginylJisoindoline~
carboxylic acid

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

2- ~-(5,6,7,8-tetrahydro-1-naphthylsulfonyl~-L-
argilly1~:isoi.l~lo~ lc-1-cQrhoxyli.c aci~l

2-~N -(~-cl~10ro-l-rla~lltlly:lslll rO~Iy~ ~ar~ yl3-
I,2,'3,~ ctr;ll)y(lroiSog~ lolinc-3-carl~oxylic acid

.L-[N~-(5-l~y~lroxy-l-lla~lltlly.lsulrollyl)-1,-argillyl3 ~
].~2~3~1l-tt?~rally(lroqlli.rlolin~-2-carl)oxylic acid




- 8~ -

33~


2-~N -~5-climethylamino-1-naphthylsu]fonyl)-L-arginyl~
isoindo~ine-l-carl~oxylic acid

2-~N2-(l-nal~htllylsl~lforlyl)-L-arginyl~-lJ2~37ll-
tetrahydroisoq~linoline-3-carboxylic acid

EXAMPLE ~l

(A) L-arginyl-N-(2-methoxyethyl)glyclne ethyl ester
hyclrochl.oride:
To a so~.ution of 4.0 g of N -nitro-l,-arginyl-N-(2-
methoxyethyl)glycine ethyl es-ter hydrochloride in 50 ml
of ethanol was added 0.5 g of palladium-black and then
the mixture was shaken in a hydrogen atmosphere for
150 hours at room temperature. At the end of this
period~ the ethanol solution was filtered to remove
the catalyst and.evaporated to give an oily product.
; 15 Reprecipitati.on with ethanol-etllyl ether gave 3.0 g
(81%~ of L-arginyl-N-(2-metlloxyethyl)glycille ethyl
e~ter llydrochl.oride in tlle form o~` a pow~er.

(B) N -(4,6-dimetlloxy-2~napllthylSulfonyl~-L,-arginyl-N-(2-
metlloxyethyl)glyci.ne ethyl ester:
To a well stirred solu-tion of 2.00 g Or L arginyl-N-
(2-methoxyethyl)glycine ethyl estor lly(lrochloride and
1,95 g of K2C03 in 20 ml of water and .10 ml of dioxane



-- 81 --


''~
~ .




~ras added c1ropll/ise a solution of 2.17 g of 4~6-
dimethoxy--2-naphtllaleneslllfonyl chloride in 30 ml of
dioxane over a period of 30 minlltes wllile maintainillg
llle t;e~ erlt(lr~ ut 0 C. Tlle reacl;ioll nuxture was ~'
stirred for an additional 5 hours at room temperature.
At the end of t~liS period, the solvent was evaporated
and the residue taken up in 50 ml of chlo'roform.
The chloro-form solution was filtered to remove the
insolllble material and dried over anhydrous sodium
slll`ate. ~ddi tiOIl of 150 ml of etllyl e-ther to tlle
chloroform solution resulted in a precipitate whic'h was
separated by decantation and purified by reprecipitation
with ethanol--ethyl ether to glve 2.31 g (72 percent) of
N -(4,6-dimethoxy-2-naphthylsu:Lfonyl)-L-arginyl~N--
(2-methoxyethyl)glycine ethyl ester.
For analysis of the product, a portion of the product
was converted to the flavianate; M.P. 225-227 C,
I.R. (Kl~r): 3,375, 3,200, 1,742 cnl
Analysis - Calc<l. for C251l37N508S C101 6
N208S (percent): C, 47.67; 'H, 4.92; N, 11.12
F`ound (percent): C, 47.62; 1l, 4.84; N, 11.18

(n) N --(4,6-dimetlloxy-2-naplltllylsulfolly~)-L--arginyl-N-(2-
nletl~oxyollly] )~lycillc:




- B2 -


~'



N -(4 ,~-dimethoxy-2-naphthylSulforlyl)-L-ar~inyl-N-(2-
methoxyethyl)glycine was obt~ined in the ~orm of an
amorpllous solid in a manner similar to that deseribed
in Exanlpl~ 3 (E)-
I~R. (KBr): 3,360, 3,180, 1,610 cm


~A) N2-(6,7-dimethoxy-2-naphthylSùlfonyl)-L-arginyl-N-
phenethylglycille:
N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-
- 10 arginyl-N-phenethylglycine b.enzyl ester was prepared
by the procedure described in Example 3, and has a
mel-ting point o~ 133-5C.
To a solution of 3.00 g Or N -nitro-N -(6,7-dimethoxy-
2-naphthylsul~onyl~-L-arginyl-.N-phenethylglycine benzyl
ester i.JI 50 ml of ethanol and 0.5 ml o~ acetic aeid was
aclded 0.5 g Or palladinm-black and then t~le mixture was
shakerl in a llydrogen atmosphere for 100 hours at room
tempera!llro. ~t tlle encl o~ this pcli.o(l, I:lle ethanol
~ollltion wag f`ilterecl to remov~ the cata.lyst and
evaporated to dryness. The residue was washed several
times with dry cthyl ether and cl~romatograplle(l on 80 ml
o~ I)ai.aion ~ SK 102 ion exchange resi.n (200 - 300 mesh,
Il form, manufactured by M.i.tsubishi Chemieal Industrie.s



- ~3 -



,


Li mited) packed jJI water, washed wi th water~ and eluted
with 3~ ammonium hydroxide solution. The fraction
e:Lutcd f`rom 3% ~mmonium hy(lroxi(le solution was evapo-
ratecl l;o (IrY11eS9 to give 1.71 g (709~0) of N --~6,7--
dimethoxy-2-naphthylsulfonyl)~l -arginyl-N-phenethyl-
glycine as an amorphous solicl.
I.R. (KBr): 3,360, 3,200, 1,590 cm
Analysis - Calcd. for C28H35N507S (percent): C, 57 ll2;
H7 6.02; N, 11.97 Found (percent) C, 57.09;
0 119 6.l)6; N, 11.74

EXAMPIE 6

(A) N -(6~7-dimethoxy-2-r~aphthylSulfionyl)-L-arginyl-N~(2-
methoxyethyl)glycyl chloride hydrochloride:
A suspension of 2 00 g of N -(6,7-dimethoxy-2-naphthyl-
sulfonyl)-L--arginyl-N-(2--me~thoxyethyl)glycinein 20 ml ;~
of` thionyl chloride was stirred for 2 hours at room
temperature. Addition of cold dry ethyl ether resulted ;
in a precipitate which was collectecl hy fi ltration and
wasllc(l several timcs with dry ethyl ether to give N -
(6~7--dimethoxy-2-naphthylsulf`onyl)-L-argillyl-N-(2--
methoxyethyl)glycyl chloricle hydrochloride. ` ~'




~ 84 ~ :



(~) N -(6,7-d:Lmethoxy-2~napht}ly~sulfony])-L-argiJlyl-N-(2-
met;hoxyetllyl)glycirle m-tolyl ester l~yclrochloride:
A mixtllre of 2.00 g of m-cresol and N ~(6,7-dimethoxy-
2-nal~lltllyls-llrollyl)-L-argillyl-N-(2-nlotlloxye-tllyl)glycyl
chloride hydrochloride obtained above was heated at
90C for 50 minu-tes. At the end o-f this period, -the
reaction mixture was cooled, washed sever~l times with
dry ethyl ether, and then dissolved in lO ml of dry
e-thyl alcohol. ~ddition of cold dry etlly] ether
resulted in a precipitate which was washed several
times with dry ethyl ether to give 2.12 g (86 percent)
of N -(6,7-dirnethoxy-2-naphthylsulfonyl)~L-arginyl-N-
(2-methoxyethyl)glycine m-tolyl ester hydrochloride in
the form of a powder.
I.R. (KBr): 3,250, 3,100, 1,740, 1,640 crn 1
The following compounds are prepared in a ~imilar manner:
N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-
etllyl~h:ioet~lyl)glycitle phenyl ester

N -(~,7-dimetlloxy-2-n~plltllylslllf`ollyl)-1,-~r~jnyl-N-(2-
etl)ylt;llioetlly:l)glycille be~zyl ester

N -(6,7-dimethoxy-2-naph-thylsulfonyl)-L-arginyl-N-
benzylglycine phenyl ester




-- 8~ --


~,~




N -(6,7 dimetho~y 2~napllthyls~l1f'ollyl)-L,-argillyl-N-
furf`llry:lgrlyci.lle ~enzyl ester

N -(~),7-~linlcl,llo~y~ plltllyl~ lrollyl)-l,-argilly.L-N-
tetrallyclrofurfuryl~.l.ycille phenyl. ester

Phellyl 1 ~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-
4-ethyl-2-piperidinecarhoxylate

BenZY1 1- [N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~ -
~-ethyl-2-pipericl.inecarboxylate

~enzyl 1- LN -(6-chloro-2-llaphthylsulfonyl)-L-arginyl~-
4-methyl-2-p~peridinecarboxy1.ate

Ethyl l~-[N -(7-me-thyl-2-naphthylslllfollyl)-L-ar6inyl~ `
morpholllle-3-carbo~cylate :'

Various other N -arylsulfonyl-L-argininamides or
sa~ts thercof were syntheSizecl in accor~ance
with tlle procedllre oL` tlle abOVQ exanlpl~s, ~ld tlle ~test
re~ltb a~ ullmlari~ed in T~bl~ 1.




.


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-- 89 --

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~ 92 --



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-- 96 --




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,~ ~ ,. - ----1- ---



_ a_ ~ O _ _ .
~ r l I r~ r~ ~ l ~ : ~
^~ . '
_ , _ ___ ,_~ __ ___ _.

~ =~1'^1 ~~ Q^ ^ ~J~
r u ~ ~ (~ 8 C~ ~ u ~ ; ~3 a
- - ? _ 1 i l i
~ rl __._ ___ , _
~ c a ~ r ~ O ~ ~ a
~ ~ ,u,l ~ ~ ~ ~D

_ rD rJ~ o rl r 7
E; r~ rl rl - rr~ rl r l

-118-

~23~a~


____ ~_, _ _ _ ._ ._ __ ~ _ O Cr O ~ O O O
E _, ~) r--l ~D ~ ~ ~D
;~,U ~ ~ I ,,,~, ,~0~ _, ~ ~
l ~_ _ '~ l~ _ _ r~ _ --r t r~ rr~ u~ c~ O

~ _ _ _ ___ ~ _,_ ` b~ `C ~ t
L _ rr r~ ~ t ! . -T ~ ur~ r~ ~O ~ O
_ ~ _ __ -t '- J~ 't~ ~O ~O 3 ~ rl ~ r~ ~ O
_ ~ I_ : __ _ ._ ~_
' J ~1~ Ir~ Ir~ _l ~1 _~ _
_ o, _ ___
a c ~ _ ~ O,




e ~ ~ _




_ ~i ~ ~ d~ 2
l _~ .
-119 -



~,~
. j .

23~6

_ _ _ __

". o o un o o Ln ,n o O O O O
U h~ n ~Ln ~ ~ I~ In ~- ~ ~ ~1
h. _ ~) ~1 ~D 1~ ~1 ~D ~ ~ O ~ . I ~D
~ ~^~^~î~ ~ ~ ~ ~ ~ ~ ~ ~
__ __ _
n ~ ;~. I h ~r~ ~ . .~ Ln
. o __ , ~ ~ ~ i
a , ~ 0~ r~t ~ h~ ~O ~
a ~. ~: ~i ~O ~ ~ o
~ u ~ ~ l ~
14 ~ I _ ~ _ _ O O .:


'C'OZ 'I ~ Il~ ,~
_ O




O O ~
L. O L`D '` O ~.
a 3 LJ E
.~ r




Or\o ~9 . ~ $

.~ ~ ~ ~~ b~
__ I_ _ __
d ' N r
-120-

~ 23~

E_A~LE 7


Tablets suitable ~or oral ad~inistration
Tablets contain:ing the ingredients indicated below may be
prepared by conventional techniques.

_ ...
.~ IngredientAmount per tablet
,,, ,~ , .
N -(7-methoxy-2-naphthylSulfonyl)- 250
L~arginyl-N-(2-methoxyeth-yl)glycine .

Lactose 140

Corn starch 35

Talcum 20

Magnesium stearate 5
_ ~ ~ ~ ~
_450 mg
: ::

F,XAMPLE 8


Capsules for oral administration
.- :
Caps~le5 of the below were made up by thoroughly mixin~
together batches of -the ingredients and filling hard
gelatin capsule~ with the mixture.



~ _~
_ _ _ Ingredient (mg)


i N -(7-methoxy-2-naphthylsulfonyl)- 250
L-arginyl-N-(2-methoxyeth~l)glycine .

Lactose 250 .
_ _ . - . __ .
: Total 500 mg ,:




- 121 -


, ..
..
.
, ,'.~.


EXA~U'I~E ?

Sterile Sol.UtiOIl for infusion
r~l~ f~OllOwi,~f~ te~ t.~ r~ S~io:l~rc~cl ~ at~l l`or
.~ intravellous perfusion an~l the resulting solutioll is then
.~ s terili Y.ed .

~ . _..... .
lngredi en ~sAnlo~ln t ( ~r)
. ._ ____ _...... _ __
N~-(7-metlloxy-2-l1aplltlly:Lsul ronyl )- 25
L--ar~rinyl-N-(2-1lle~l~oxyotl~yl)glycille
Buffer sys tem As clesired
Glucose 2 5
Dis tillecl l~ater 500

.
~;.

;
o
'''




, ., . . ., , _.. .. . ~
7~
i.
1 .'',

Z~


- - -

A L~Y ~ f`olly l ci~ l o:r.i~les

io(l:i~lnl G,7-rl.i.lllctlloxy-2-~ E)llt:lla:L(3l~c~ 1t`ol~al:c
To a ~.~c:l:l gt;irre~l so:Lution of 70.8 gr of so(li.llm 6,7-
di.llyrllo~;y~ i;11l1el~esu:lr`ol-late a~l~l 77.2 ~r of~ soclium
lly~lro~ lr~ 50 nnl ol` ~Yal;e:r ~rag .l(l(lC(l rlrop~ i se 230 nll.
ol (linlct,llyI. su~ rat;c at 60C over a l)ori ocl of ol-le hour~
rill~ t~llLcll tilllO tlle l~rocl~lct proc~ ll:r(l, To tllis ~:
react:i.oll m-i~;tllre ~as ackle(l i.ll l)ortloJls ~3c3.~ ~ oL` so~ rn ~i
l1ydro~ le, and stirring was conti.rltlecl f`or ol~e hollr. ~:
After olle llour at room temperaturo, tlle prec:ipitlte was
rilterecl, t~rasllo(l wi.th etllallol and clriocl to ~i.ve 50 g Or ,~
socliun1 6J7-clinletlloxy-2-llapl~tllalelles~ `ol~atQ~

( B ) 6, 7 -(linle t;llo~cy-2-llal~htlI11ellesll:l f`on~ L cll:l o r:i(lc .
'rO a s tirre~I sus~-)ellsiol1 of 50 ~ of :fille.l y (liviclcrl so~lium
,, ~.
6,7-(limotllo.~y-2~ plltha:l.el-leslllrollato in 1,()() nll 0~` climetllyl~
rorrllanl.irle ~ ; a~l(l(?(1 (Iro~ r:isc 62., nll Or` 1;11iollyl cll:l.oricle
; r()()~ `1111)(.! r1 1,11 t`C . ~ ;c~ 1` 3() nl~ C3~C tioll :
Ill:i. ~c ~; l l r e ~ .i l l tO .l. ~ o ~` i c (~ < l l l (l 1; 11(3 l) rc! ci ~
tate l`:i I tcre(l a~l(l t;hl?ll ~Iissolv(3(l illtO 2so nlL Or l~ell~clle.
~rllc l.~ .C~o L~ oll ~ lg :~ tc~ Llll~
~I :r.i. ~ ( l o v ~ y( l t o l l s ~; o cl i l l rll ~ ; o .l. v cl l t ~ ly `~ ~

:
.

, .
~23

3L3L~2;~


rec:rysta~ .e(l from l)e~ elle-JI-llexalle (1: 1) to grive
32 g of 6~7-(Iimetl1oxy-2~napIltha1enesul[`o~Iyl cllloricle,
~I.I'. l27.5 -- :I2').5 C
ArIaIy.~; - C.lIc(I. I~ol CL2II~ lOI~.';C:I. (poIcol~ C, 5().26;
H, 3,87; Cl".2.37 Found (percent): C, 50.45;
~J ~.00; Cl, 12.33
The following ary1s~1fol1yl ciLlorides not previously
reported ln tlle cllemical ].i terature were syntIlesi~ed by
the a~orenIelltlolled procedure which is eYserltia:L1y -that
as cIescr:ibed irl E. Il. I~od-l, "Chemistry Or Carbol1 Compourlds",
Elsev:ier Publislung Company, 1954, Vol :[II, P, 4~ 469.
. - ............... ~ . .. .
,` No. Ary:lsulfollyl Chloride l`l.P. ( C)
_ ... ~ .... .... _.. _~

~ 1 ~ ~lOz~ [ O~ 8 -- 119.S ~ :

~ ~: C.l 2~; ~
2 ~ OCII,31 3~ . 5 - ~I.38.5
.... _ .
15 ~ ~('I0,~

.
:




-- ] 211 --

, . _- - ., . _ , . ... . . ..... . . _ _ . _ .. .... ... _ .. ~
. '
,
,.,~

r~~
31~


1'1~1~,l'AI~ ()N ll

A ~ O a c :i ( l ( 10 r:i. va l; :i V

( /~ ) N ~ l t y .l ~; l y c i l l c l; e ~ u t y:L e ~: t e :r
~`o ~G.5 ~r 0l` hlll;yl.alni,lle was added w:il;h stirr:i.ncr :L5.05 g
Or terl,-l)lll;y.1 cllloroQcetate ovc,~r a poriod o~' 30 mill~,lte.s,
wll:i.le nn.~ l{r l;lle ten~,peratu.re i,lt 30-7(')C. 'I`lle
rcclcl,ioll n~ tllre ~ras 11eJ.cl at 70C ~o t' a3l arl(:li.tio~la:L 03le

was c~r,ll)c) r~l,od ~ VaC:I10, .l~ld tlle rcsi.clue was talccll up iJI
40 nl1, Or ,N NaOII so lutioll and 50 m.L ol' I)e3~i~.enr3, tr~n~1`erreci
illtO a sel)aratory r~nllel alld ~rcl,.1 shalcell. The berl~ene
so,i~ll;io~ ra.~ sr;~l:)a.ratecl~ wasllccl Wi tll ~r~.-tcr~ clrlcd over
al~llyllr(>lls so(.l~ Lt'ate al~cl r:iLtcre(l. Al`tcr evul~oratio
of l~en:~e~lc, tlle r e~si clue was ciisti.Ll.cd ullcler r e(.lucecl .
,
r~ ~; 9 ~ I o ~ i v(~ 1 7 . 0 ~ ,) ( 3 . ~) I) c` r`c (' ll l, ) 0 ~' N -~ ,'C :i. l l C
tct l -l)lll.y~ ,t(~ .1'. 7~iC'/I~ 1Illlllll,. ~ '
'1`11(~ 1`oJ 10\~ O .l(,~ C~ ; llot ~ violl;ly .
t'C`~)O I`i.(`~l :i 11 1,ll(' Cll(`tlli C~l I .I.. i l.C`l`ill,ll J`(! W(`J`(J ~`:;yJI l,lI(',';i `~c(l l~y . ~ ~
tll-.~ al'orcnlc~ll;:iollc(l l)roco(l~lrc Wll,iCIl :is o~s~elltia:l:l.y l,llat .-~ ' .
a~; ta~l~,rl~t l.~y A . J . Spc,~,:i,a,le et al ., J . Org. Chenl. 2 r~ 7
(19t')0) .




- ~25 - .

I .

r~



- - -
N o . ~ nl i l l o ~ i v~ t~ 13 .1~ .
_ _ __ _ _
:LI I N - ' .3 9 5 C/ 2 ( ) nllltl l g
\(,~ o)~ c~ _ _

2 IIN~ 2 ( 3)2 G5 C/ 5 mmllg
\CII"CO,~ C11119
_ _
3 /( (~1~2 )~ 11,3 8~ )O C/2 . 5 nlrrlllg
\('II,,CO,~-t:-Cllll()
_ _~ _ _I
1l I IN / ( 2 ) 5 3 8 3 - 5 ( ' /.1. . 5 mntl 1 g
\(:~12C2 -t -c~l1l9 . .
_ _ _ _ .
~ ( C112 ) 7 C~ ~ 3 12 5--:l 3 0 C /~1 mn~l gr
(,11 ? C ? ~ t--(, / 1-19 .
__. ~ __ . .
6 ~lN/Cl 2Cll~ C113 6:1- 2 C/2 mn~lg
\(,II?CO~--t--C~1119 . . :
7 /(,11~C112()('113 9/1 C/ '3 nln~lg
~ . \(,112(~112C02-t-c1~ll9 _ , ...... : . ,

8 /~ ,C112()C11,3 60- 3 C/'3 nlnlllg
(~112~ CII,_C02 ~ t-cll1l9
_ ~
/~ll )cll~ ,o~ll
~IIN\ '~ 3 ~r)_ 7(,/5 I)~ r
('II,CO~ )
~_ ~_ _
Cll"CII ,OCII"(~II, o
10IIN/ ~ -3 1():' C/ ~I nlmllg


. , .



- 1~6 -
'' .



- - -
No, Anli 1l(1 Ao:i (l l)(~liv~lt:.i vo 11.1' .
__ _ __ ~
:l l./ (, l I;, C l 1" -~ :I G G C / I O nln~l g
(~112(~2 1;~ (,)
_ .................... _
Cll,CII ~;CIl Cll, o
2 ~ IN/ '- 2 2 3 1 oG - ~ c ~ l. . 5 m~ ,r
(~ t-('11ll(3
__
:L ' 3/ ( ' I I ~ C 112 ~ C 1~ ,3 ( ) ~7 (~ , r~ ;
('112CO"~ __ .
__ ,D _ _ ~

1ll IIN 1(.)1 C~ 5 mnJIg : -
\'C112C112C112C02-t-C1113~
_ . _ . "
1 5 IIN~l J :1. OJ. C~ 5 Illl~ g
_ \Cll,~C02~ 119 ',.~' '

. 1G ILN--O Lo5 C~ 11 nilnllg ;~
\ C112CI-l2c02 - t ~cl~ . _
~ O ' . ___ . : ~

17 IIN~ 12~-:l 30 C/.'3 nmlllg
. ('Il ,C(),,-~;-C~ ___
___ . . ;~
I ~¢ I I N \ I / l r~ ~ ~ C ~ I r~ g
~`I1"('0" -~ ~ .. _
. (`11 -O
L'J IIN/ ~ 1 5G C/l() mrllllfr
\ (' 112 (' 11~ --L -(~ _ ~ .~




-- l27 -
. , ,

3~6


_~ _ ~ ____
. _
; ' O I I N ` ~ ' 3 o
\(~ ~ /(~ ;

.. _ ~ _

I I N 2 ) 3 '~ n
~' I ( ,11(, 0, --I --(~ 11 I 1 0 (, /2 7 1~ ,

_ . _

IIN /( ( I 2 )~(,11,3
22 \(~1l(,o2_~ (3 .L21l 'C/2G r

_ , . _ ~
IIN/ Cl12CI120(,113
2 3(~ ~X-90(,/6

._ ~ . ~ _ __
, ~ (,112--

- . 21~Cl13 1:16- 8C/2 mmllg .
~ __ _

11 N ;- ;~ ~ . .
5\( ~ o ~ 11 . ~ '7(' /' I ~ "1"~
_ ~\ ._

,~G (~ O?~I; ,~ ] ? 5 (,/: G 11mlllo




:.

;
~'

3~


No. Amino Acid Deriv~tive ~
_ __ ............................ . . ~
~ CH2--~
27 ~CHCO -t C4H 141 C/~.5 mn~g
CH3
. _ . ~
28 ~(CH2)3CH3 89 C/ 3 mmHg
CEI2CH2C02--t--C4Hg :
_ _ _ . . _.,........ . _ . _ I , .
/ 2 (~ o . ,
29 HN~ 111 C/ 1 mmHg
CH2C02--t -C I~H9 I - .

3 O . ~ _ _ 91-- 2C /1 mmH
CH2C2--t--C4H
~ _
31 CH2CH2C02C2H5 115 C/ 2 mmHg
CH C O --t--C 4H
.. . ._ ,, ~,_ . ~ ,,
OH
32 ~N~CH2CH2CHCH3 82-- 84 C/2 mn~g
CH2C2 t C4Hg
~ __ . .~ . __ --
~CH2cH2socH3 .
33 HN\ 150C/ 0.5mmHg
CH2 ~ 2--t--C 4H .
. ,, ,,, __ _ ~.~ _ . _ , , ,... ~ .. _
34 E~N~ 2 2 95-- 6 C/2 mn~Ig
CH C02--t--C4H .
. ~ __ _ . . , . _ _
. 35 ~ CH2C -=CH
_ 2C 2 CI~EI




-- 129 _

. 3 ... ~ .... ,.................. .... ,........ , . ~;
,.,
.
'.~
. .,

r~




r 0l` I.I`~ y.l.Lll~ lO ill I ,e ol` ~ 110 Wtl; a(~
ll~O~ OI~";~ 3~1 .() ~J' ol ('~ y.~ OlllO-lC(~Lc~
2()0 n11. 0r l)(~ llt! :i" olle IIOlI:t` at l~()olll t(?r~ t~lre. At
tllc ClICI oJ` tl~ e-r:iocl, tlle nlixtu.r(~ waS ILe~cltec1 at rer~ x
t`or ~ l1ol1r.~ to conl1~:1.ete tlle re.1ct:ioll~ Upoll clLil1:irlg, the
l;l.ictl1yl allli llo hyclrob.~omid~ .IS l (~nlo~ c(l l~ i I t r~l t; i oll .1l~l
~,lS~ r:i 1;11 I)cll.~ . AL`t;e:L l.'C,`llIOVLI.I. Or tll~ so:lvt~llt~ tllo
pro~lllct ~as clist.i.l I.ocl i.ll vacuo to y:ie:l(l ~ll2.8 g (75.3
perccllt) Or N-(2-nletlloxyet;lly:L)glyc:illc etlly:L cst-?r,
- B.l~. 73--5 (Y/ll rlmlll~
l~c L`o:l:10~ lg ~1n1.illo aci.c1 otl~yl o~;l;c:r.~i llol, l)reviol1cily ~ -
rel)ortcl1 :i ll. I;lle cllell1:ica:1. :I:i teratlll c ~iere ciy1lt]lc~ .ec1 l~y
L5 tll(~ cl~ o~ l1 t:i o1l(a~-l Z~l oc~ :L~ca, ~l1icl1 i i e~ (?l1 ti.l:l:l y l,¦l~t
as tall~ t l)y A. J. S1)o~:ia:Le cl. al ., J. ()rg. Cllc'lll.~ ~r~

7~1 ( I '~f;O) -
,... . _ (
N o, A nl i l ~ o /~ c i ( I 1~`1 l l y 1 I~`s l c r ( ( ' ~ ;n l~ )
_~ ~_ ~ .
L IIN\ - ~ .) 57~ /.3 n~nl11g
(~11,>~ ,;,11 r) .
._ , ~
2 / C11~ ()('11,3 G ~- 11~/~3 mrl~1g
('ll,,C'~I,)(~()~)C2ll,5 __ ~




1 30 --

.
,.

~ .
. . ~.

~23~



. ,' .
N o, ~\ IIN I I O ~ o i ( l l;~ y l. I~s t o l ( (, /nlllll l g ) ~ :
_ ~ ~
',~

'3 ~ (~11 ~'() (: 1-1 () 1 ~ /2 n~ :
~
~ _~_ . ~: .

1~ i I ,11 " (,1~,~ C 2115 1 IC 1 L () 1. ~2 C

CO~C,~115 .
,.__ ~ _ 1
(1'()2(`2~15
5ilN /CII~C,II~(,II;~C113 L 1.3-- G c/3 mnlllg
, . _\ ('112(~0~,~C~115 . _ ' .'

6 C 11 -Cl 12 ~ l I o - 7 C /:l nlmll g

.~ ~........... ~ .
, ~ . _ .:
7 1lN/(~ llcll3 78-8()~'C/~
(~1~12C02C2115 . .
----llN/(C112 ) ,3C113 ~ ! ;
8 ~ 1C~()"C21l5 . ]ICI. (i3-11 C
_ (,II"~,O"C"II ~ . . _
.' : ..

(C) N-(2-nlel,llo,~yotl~l )g,lyc:inc L)c~ .y:l. csl,o~ l)-t(~ ellcs1l:if`0llat:c To a solllt;:io]l oL` 55.8 g of` N-(2-moll~o,~cyot,llyl)gLycill(3
-tert-l)utyl estor ill 200 ml of l)ell:~el~(? W-IS acl(:le(l 63.8 ~
oL` hell~,y:l. alcoJIol. alld 72.9 g Or p-tolllellesu:Lrorli.c aci~l
n~ollolly(l-~ to, ~rl~O nl.i.~l;uro Wil~i llcal;c(l .~1; rolNl.u~c ror 1,0

:.; , .
''' '
,;' ,
-- 13 1 -- ~ .


~ '
.. ~ .

3~6

hollrs ~lritll tlle conti.nuous reniova:l of` l~aLer through a
3~ea~ ;tarlc water trap. At the end Or tllis pe:riod, tlle
sol~ll ioll w~s concelltrated in vacuo, allcl to the residue
was c~ erl 3()0 m.l ol` dry etllyl cLllor. Arl er 2 hours at
room temperature, the formed precipitate l~ras filtered,
washed wi Ih dry ethyl ether arld then recryY tallized from
etllyl acetate Lo yield 99,2 g (85 percellt) of N-(2- :
methoYye-tlly:L)g.lycine be2lzyl ester p-(;o:llleneslllrorla-te~ -
M.P . 95--6C.
The rOl loltrillg amlllo acid benzyl ester p-toluenesulfonate
not previol~sl.y reported in -the chemica:L ].i terature were
syntllesizc<l by tlle alorementioned procedl.lre. .

~ ~ _
No Amillo Acid Benzyl Eslter M ~' (~ )
. .............. . p-Toluenesul :~onate . . ~
_ . .......... _

1~ CH2 C 2 CH2 ~ 97 -- 9
2~ ~ Cll~ ) lC13 3 1 "~


3llN~ - ( 3 ) ~ 9/1 _ 5
,,,: (,112(~02C112 -~
: _

, u 1l \CI{ C112C02C112 ~




- I 3.' -

r
.,
,...

.

: ~

~ - - - --
1\ 11 1 i I I ( I /~ ( ~ i ( I 1 J c I 1 ~ ~ I 1.~ .; 1; ( ~ I ~ 1 ,
N (~ . I ) -'I `( ~ 1 1 1 (~1 1 ~ .; I 1 1 1 0 ~ ~ ~ )
/(('11" )/1('11~3 ~ :
r~ \ C 1 1 2 (; 2 C 112 4~ I ( ) I ~ 2
_ _ _ _ .... .
~i ~IN~C 2 ~ . 1110 -- 3
\CII"C02C112~~
_ . . _. _

~ 7 C~ CII, CO ~C 12~ ~ 511 -- G~ ~

(-,11, (,11 -(~ .
- 8 IIN/ 2 2 ~ 133 -- 5
~ . \C112C02C112~
. I 0 --

.: 9 ," 2 2 ~ 1 3 3 -- 5
~ --- ~('112-0 ~ ~ ~ .,

] O , \ ~ I 3'3 - 8
r- (~112C 2('112
_ __ _
I I N ~- ~ 3 . ~ :
. I I \~ 2-~ 103 - (~
~.' . (~ '
~ :
~ /(~ LI I ~


',' , ,
', '

,,

,
,
- I 33



~; , ,.
, .

~Z~3~6

.
~muno Acid Benzyl Ester M.P (C)
No. p-Toluenesulfonate _ _




~ '
:
5 ~ CH~ ~ 130 - 1 .




PREPAR~TION C

2-Piperidinecarboxylic acids ~d esters thereoP
... . .
^ (A) 4-methyl-2-piperidinecarbonitrile
To 500 g of 10% 90dium hypochlorite solution cooled in
an ice bath, there was added dropwise a solution of
33.6 g (0 21 mole) o~ 4-methylpiperidine acetate in
10 ml of water over a period of 1 hour. At the end of
. this period, the reaction product was extracted twice
with 500 ml of ethyl ether and dried over anhydrous
sodium sulfate. After evaporation of ethyl ether~ the




: - 134 -
...
;,."~
, ~'' .

2~

resiclue was aclded dropwise to a solution Or lL.8 g (0,21
lO0 ml of
mole) of potassium hydroxide in/ 96q/o e-tllanol urlder rc~lux.
~efluxing was con-tinued for an additional 10 minutes.
Ethanol was evapora-ted, and the residue was di~solved
into 50 ml of` 2N sodium hydro~cide solution and then
extracted with ether.
The ether layer was dried over anhydrous sodiurn 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 hydrochlor:ic acid in 300 ml of
water. The solution was stirred at a temperature of 10
to 20 C 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 I;o give
17 g (66%) of` 4-methyl-2-plperidinecarbonitrile, B.P.
96-97C/10 mmHg.
The following 2-piperidinecarbonitriles not previouSly
reported in the chemical literature were synthesized b-$~
the aforementioned proceclure which is essentially that
as taught by Grundon et al., J. Chem. Soc., 196~j 3898,
Grundon et al~, J. Chem. Soc., ~ 2448, R. Bonnett
et al., J. Chem. Soc., ~, 2092 and H. Bohme e-t al.,
Ber.~ 92 1613 (l959).

..
",' '.


- 135 ~

, ~ ' "

~'
~ ~23~1L6

r~7
1~ CN




N o . ~_ Ll . L' .

--(, 11 2 C l ~, ~ l. () S ~ r,
12 C 1 1 " (, 1 [ 3 :I :I. G c~ /~3 Il"~ r

~_ ~,<1~ ~
2-(,113 _.



(13) ~ letll~L-,'~ er~ ecar~)oxy1ic aci~ (lrocll:l.ori.~lc . ~ ;

/~ SOllltiC)II of :L~ ~ of l~-metllyl-2-r)ipc~r:icl~ c~lrl)ollitri:l.e
il~ 25() nll Or (~N lly~ oclllolic aci(l WLIS rol`:Lllx~(l l`or O
hours, A[ tor ~vaporatioll oI~ the solvcllt, the resiclue
w~s rocry.it~:l.]i~ecl lI~onl water to g.ive 13 g Or /~-methyl--2-
ri~ lor~ o~ .i c aci~l lly(lrocllloL~:i(

(C) 1~,1;1JyI 1~--r~ i l)(Jl~:i(liIIC`(`~ l)O)i.yIi,~
A .~ ( () . ()7,J nlo l e ) o ~ l C- ~:
c ~ o ~ y l :i (~ ( l l o c l l l o ~ (i 5 () lll l o ~ i o l l ~ :l c l l .L o l i ( l o
ill ')()(~ Tlll ol' cLllallo:l w.~s rQL':luxo(l l`or ll llollrs. /~t t~
Or t~ oriocl? tl~(! so:l.vellt was e~rar)orato(l url(lc~r rcducecl
~ro~i.s~lre, all(l tll(! ro~ 3 wai extracto(l ~ri.l;ll a sol~ltiorl Or
Clll.OrOf'Ol'lll clll(l S..I.tlll'al;Q(l pOI;asSillnl CalL'i)Oll'ltQ sO.l.lltiOn,




"
.~,



'I`he cll:Loro:ro~ Layer was ciri.ecl over anllyclrolls sodium
silll ato a~(l tllen chlororornl was evar~oral;od . Disti].].a(;ion
Or tlle ros:i.(lllc ~;avc 7,11 g (Go~O) Or etlly~ mcl;}lyl-2-
piperid:i.lloc.~ ylatc, 13.1'. 76-77C/3 mlllll,~.

(D) Benzyl ll-metllyl-2-pipericliIlecarboxy:Late p--toluQnesulfollate
i~ solution oi` 20 g (0.112 mole) of ll-metlly~.-2-pi.peridine-
carl)oxy:li.c acid llydrochloride, 211 g (0.22l~ nlole) of` benzyl
alcollol al~d 25.6 g (().1.3l~ mole) Or p-l;oluerlesulfonic acid
moJIolly(ira~e in :lO0 m.I. Or berlzl3rle was rc~rluxed for 5 hours
wi th the continuous removal of water throllgll a Dean-Stark
water trap. Al; tlle end of this period, tlle solvellt was
clistille(l of ~, an(l tlle residue was wasllocl wi th etller-n-
llexane and recrystal1ized to give 10 g ( '2%) of l~erlzy1 :~
4-methyl-2-piperidinecarboxylate p-tol.uenesul.fonate~
M.P. 160--163C .
The following 2-piperidinecarboxylates no t previously
reportecl i.n tlle cllemical l:iterature were syllthesized by
tlle arol~enlellt.ioIled p.rocedure.




I ~)7 _
. ~ ~
~ ..
~ . ~' .
,.......................................... ..

~23

. N C2C2~5
-r ~ _
No. ~ Addition B.P.
~ _ ......... ~
1 ~ CH2C~3 . 82-4 C/3.5 m~Hg
__ ~ _ ___
2 4-C~2CH2CH3 HCl


¦ 3 ~ 4 C~ 3 _95-6~C/2 mmHg ¦
_ . ~__ . - . . __ _ . .
4 2-C~3 . _ ~7~
,

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


. _ ., , _ . ~ _
. Compound Litera-ture
_~ .. .. . . ~ . . ~

HN ~ J. Org. Chem., 29 2203 (1964)
___ . _. ~ ~
C02H




J. Org. ~ "
,


- 138 - :
,
, . .. . . , .,, . ~ ~ r ~ - ~ ~:
...
~ ,..~
",'''
~ ~, ' .

3 ~i


c o ~ o ~ I i ~; e r l l l l r c
_ ~ _ . .
(~o~
IIN ~ ~ J Am. Cl~em. ~oc., r~') 2()0 (:L937)
. . - . . _ _ _ ~
C0211
IIN ~ ~I Obsllcl~ llim.~ 2 22l~5 (1973)
._. ._.. . .. _ _ _
C02ll Ber , ~ 20311 (]9LI)




~ ; ) 0~ (L) Ber. ~ ~ 9Z7 ( L93~)




Tlle methyl or ethyl ester of` the aforemen-tiorlecl compounds
were prepared by a eonventional esterifiea-tisn proeedure.
Ethyl tiliomorplloline-3-earboxylate has a boiling point of
108C/4 mmllg.
Diethyl pipericline-2,6-diearboxylate llydroehloride was
preparecl by the eonventiollal esterif`icat:ioll of piperi~ine-
2,~-cliearbo~ylie aeicl and has a melting pO illt O~ 1811-6C .
lsoindoline-L-ear~oxylic acid was prepc-re(l by a proeeclure
irni:lar to thaL- ~or the preparation of isoquinoline-3-
carboxyLic acid described in Ber., 4ll 2034 (1911). Ethy:L
isoindoLille-]-c.lrboxylate hydrochlori(le wa5 prepare~ y




....

;,,

2~


the convcn t:i.ona:l es teri:fi cation of isoin(lolirle-l-
carl)oxylic ~cid and has a melting pOillt of 139-1110.5 C.
Ilavin~ l~o~ l y clescribed the :inventioil~ i t will be
al~l>al cllt to ollo Or Or(~ ary slcill ill tll~ ~rt tll~t m~lly
changes alld moclifications can be macle thereto without
del)artill~ :t`rom tlle spirit of thc invention a9 Set rorth
,~ ; herei]l.

~ ' , ,




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