N.sup.2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

N.sup.2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

EXAMPLE 1 
(A) N.sup.2 -(2-phenoxathiinylsulfonyl)-L-arginine: 
To a well stirred solution of 83.6 g of L-arginine in 80 ml of 10% 
potassium carbonate solution was added 14.9 g of 2-phenoxathiinylsulfonyl 
chloride in 80 ml of benzene. The reaction mixture was stirred at 
60.degree. C. for 5 hours, during which time the product precipitated. 
After one hour at room temperature, the precipitate was filtered and 
washed successively with benzene and water to give 11.8 g (54 percent) of 
N.sup.2 -(2-phenoxathiinylsulfonyl)-L-arginine. 
(B) N.sup.2 -(2-phenoxathiinylsulfonyl)-L-arginyl chloride: 
A suspension of 4.36 g of N.sup.2 -(2-phenoxathiinylsulfonyl)-L-arginine in 
20 ml of thionyl chloride was stirred for 2 hours at room temperature. 
Addition of cold dry diethyl ether resulted in a precipitate which was 
collected by filtration and washed several times with dry diethyl ether to 
give N.sup.2 -(2-phenoxathiinylsulfonyl)-L-arginyl chloride. 
(C) N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine 
tert-butyl ester: 
To a stirred solution of 4.36 g of N-tetrahydrofurfurylglycine tert-butyl 
ester in 20 ml of chloroform was carefully added N.sup.2 
-(2-phenoxathiinylsulfonyl)-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 with a small amount of diethyl ether to give an 
amorphous solid. This was collected by filtration and reprecipitated from 
ethanolethyl ether to give 3.5 g (52 percent) of N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine 
tert-butyl ester. 
I.R. (KBr): 3400, 1740, 1630 cm.sup.-1 
Analysis -- Calcd. for C.sub.29 H.sub.39 O.sub.7 N.sub.5 S.sub.2.1/2H.sub.2 
SO.sub.3 (percent): C, 51.61; H, 5.98; N, 10.38 Found (percent): C, 
51.88; H, 6.03; N, 10.51 
(D) N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine: 
To a solution of 3.5 g of N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine 
tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl 
acetate. The reaction mixture was stirred for 5 hours at room temperature. 
At the end of this period, the reaction mixture was evaporated to dryness. 
The residue was washed several times with dry diethyl ether and 
chromatographed on 80 ml of Daiaion.RTM. SK 102 ion exchange resin 
(200-300 mesh, H.sup.+ form, manufactured by Mitsubishi Chemical 
Industries Limited) packed in water, washed with water and eluted with 3% 
ammonium hydroxide solution. 
The fraction eluted from 3% ammonium hydroxide solution was evaporated to 
dryness to give 1.2 g (40 percent) of N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine as an 
amorphous solid, I.R. (KBr): 3350, 1640, 1250 cm.sup.-1 
Analysis--Calcd. for C.sub.25 H.sub.31 N.sub.7 O.sub.5 S.sub.2 (percent): 
C, 51.98; H, 5.41; N, 12.12 Found (percent): C, 52.13; H, 5.49; N, 12.08 
EXAMPLE 2 
(A) N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ethyl 
ester 
To a stirred solution of 2.0 g of N-tetrahydrofurfurylglycine ethyl ester 
and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an 
ice-salt bath, was added in portions N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl chloride obtained above. The 
reaction mixture was stirred overnight at room temperature. 
At the end of this period, 50 ml of chloroform was added and the chloroform 
solution was washed twice with 25 ml of saturated sodium chloride 
solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The 
oily residue was washed with ethyl ether to give 4.8 g of powdery N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ethyl 
ester. 
Analysis--Calcd. for C.sub.27 H.sub.35 O.sub.7 N.sub.5 S.sub.2.1/2H.sub.2 
SO.sub.3 (percent): C, 48.34; H, 5.41; N, 10.44 Found (percent): C, 48.56; 
H, 5.46; N, 10.33 
(B) N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine: 
A solution of 4.8 g of N.sup.2 
-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ethyl 
ester in 15 ml of methanol and 15 ml of 2N-NaOH solution was warmed to 
40.degree. C. and held at that temperature for 10 hours. At the end of 
this period, the reaction mixture was concentrated and chromatographed on 
200 ml of Daiaion.RTM. SK 102 ion exchange resin (200-300 mesh, H.sup.+ 
form, manufactured by Mitsubishi Chemical Industries Limited) packed in 
water, washed with ethanol-water (1:4) and eluted with 
ethanol-water-NH.sub.4 OH (10 : 9 : 1). The main fraction was evaporated 
to dryness and washed with ethyl ether to give 3.2 g (80 percent) of 
N.sup.2 -(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine 
as an amorphous solid. I.R. (KBr): 3350, 1640, 1250 cm.sup.-1 
Analysis--Calcd. for C.sub.25 H.sub.31 O.sub.7 N.sub.5 S.sub.2 (percent): 
C, 51.98; H, 5.41; N, 12.12 Found (percent): C, 52.25; H, 5.56; N, 12.36 
EXAMPLE 3 
(A) N.sup.G -nitro-N.sup.2 
-(tert-butoxycarbonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester 
To a stirred solution of 23 g of N.sup.G -nitro-N-.sup.2 
-(tert-butoxycarbonyl)-L-arginine in 300 ml of dry tetrahydrofuran were 
added in turn 10 ml of triethylamine and 10 ml of isobutyl chloroformate 
while keeping the temperature at -5.degree. C. After 15 minutes, to this 
were added 30.4 g of N-tetrahydrofurfurylglycine benzyl ester 
p-toluenesulfonate, 10 ml of triethylamine and 50 ml of dry 
tetrahydrofuran, and then the mixture was stirred for 15 minutes at 
-5.degree. C. At the end of this period, the reaction mixture was warmed 
to room temperature. The solvent was evaporated and the residue taken in 
400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 
ml of 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution 
and 200 ml of water. The ethyl acetate solution was dried over anhydrous 
sodium sulfate. Upon evaporation of the solvent, the residue was dissolved 
in 20 ml of chloroform, and the solution was applied to a column (80 cm 
.times. 6 cm) of 500 g of silica gel packed in chloroform. 
The product was eluted first with chloroform, and then 3% 
methanol-chloroform. The fraction eluted from 3% methanol-chloroform was 
evaporated to dryness to give 24.0 g (60 percent) of N.sup.G 
-nitro-N.sup.2 
-(tert-butoxycarbonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester 
in the form of a syrup. 
I.R. (KBr): 3250, 1740, 1700, 1630, 1260 cm.sup.-1 
(B) N.sup.G -nitro-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester 
hydrochloride: 
To a stirred solution of 24.0 g of N.sup.G -nitro-N.sup.2 
-(tert-butoxycarbonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester 
in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 
0.degree. C. After 3 hours, to this solution was added 200 ml of dry ethyl 
ether to precipitate a viscous oily product. 
This was filtered and washed with dry ethyl ether to give 17.5 g of N.sup.G 
-nitro-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester hydrochloride as 
an amorphous solid. 
(C) N.sup.G -nitro-N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglyc 
ine benzyl ester: To a stirred solution of 2.44 g of N.sup.G 
-nitro-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester hydrochloride in 
10 ml of water and 40 ml of dioxane were added in turn 1.26 g of sodium 
bicarbonate, and 2.2 g of 3-cyclohexyl-4-methoxyphenylsulfonyl chloride at 
5.degree. C., and stirring was continued for 3 hours at room temperature. 
At the end of this period, the solvent was evaporated and the residue 
dissolved in 100 ml of ethyl acetate, and washed successively with 10 ml 
of 1N hydrochloric acid solution, 20 ml of water, 20 ml of 5% sodium 
bicarbonate and 10 ml of water. 
The ethyl acetate solution was dried over anhydrous sodium sulfate. Upon 
evaporation of the solvent, the residue was chromatographed on 50 g of 
silica gel packed in chloroform, washed with chloroform and eluted with 3% 
methanol-chloroform. The fraction eluted from 3% methanol-chloroform was 
evaporated to give 2.4 g (71 percent) of N.sup.G -nitro-N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglyc 
ine benzyl ester in the form of an amorphous solid. 
I.R. (KBr): 3300, 1740, 1640, 1255 cm.sup.-1 
Analysis-Calcd. for C.sub.33 H.sub.46 O.sub.9 N.sub.6 S (percent): C, 
56.39; H, 6.60; N, 11.96 Found (percent): C, 56.51; H, 6.58; N, 12.19 
(D) N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglyc 
ine 
To a solution of 2.4 g of N.sup.G -nitro-N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglyc 
ine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of 
water was added 0.5 g of palladium-black and then the mixture was shaken 
in a hydrogen atmosphere for 50 hours at room temperature. At the end of 
this period, the ethanol solution was filtered to remove the catalyst and 
evaporated to dryness. The residue was washed several times with dry ethyl 
ether and chromatographed on 80 ml of Daiaion .RTM. SK 102 ion exchange 
resin (200-300 mesh, H.sup.+ form, manufactured by Mitsubishi Chemical 
Industries Limited) packed in water, washed with water, and eluted with 3% 
ammonium hydroxide solution. The fraction eluted from 3% ammonium 
hydroxide solution was evaporated to dryness to give 1.1 g (57%) of 
N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglyc 
ine as an amorphous solid. 
I.R. (KBr). 3400, 2920, 1630, 1250 cm.sup.-1 
Analysis-Calcd. for C.sub.26 H.sub.41 N.sub.7 O.sub.5 S.sub.1 (percent): C, 
55.00; H, 7.28; N, 12.34 Found (percent): C, 54.86; H, 7.28; N, 12.49 
EXAMPLE 4 
(A) N.sup.2 
-(3-cyclohexyl-4-hydroxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglyc 
ine 
A solution of 1.6 g of N.sup.2 
-(3-cyclohexyl-4-ethoxycarbonyloxyphenylsulfonyl)-L-arginyl-N-tetrahydrofu 
rfurylglycine obtained by a method similar to that described in Example 3, 
in 10 ml of methanol and 10 ml of 1N-NaOH solution was stirred overnight 
at room temperature. The reaction mixture was concentrated and 
chromatographed on 250 ml of Daiaion.RTM. SK 102 ion exchange resin 
(200-300 mesh, H.sup.+ form, manufactured by Mitsubishi Chemical 
Industries Limited) packed in water, washed with ethanol-water (1 : 4) and 
eluted with ethanol-water-NH.sub.4 OH (10 : 9 : 1). The main fraction was 
evaporated to dryness and washed with ethyl ether to give 1.1 g (78%) of 
N.sup.2 
-(3-cyclohexyl-4-hydroxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglyc 
ine as an amorphous solid. 
I.R. (KBr): 3350, 1625, 1380, 1150 cm.sup.-1 
Analysis-Calcd. for C.sub.25 H.sub.39 O.sub.7 N.sub.5 S.sub.1 (percent): C, 
54.23; H, 7.10; N, 12.65 Found (percent): C, 54.25; H, 7.08; N, 12.86 
Various other N.sup.2 -arylsulfonyl-L-argininamides or acid addition salts 
thereof were synthesized in accordance with the procedures of the above 
examples, and the test results are summarized in Table 2. 
3 Table 2 
##STR425## 
Concentrationrequired toprolong thecoagulationtime by a Preparation 
Physical Elemental analysisUpper: Calculated Sample Addition factor of 
two process proper- Lower: Found I.R. (KBr) No. Ar R moiety (.mu.M) 
(Ex. No.) ties C H N (cm.sup.-1) 
1 
##STR426## 
##STR427## 
0.7 3 55.0054.86 7.287.28 12.3412.49 3,4002,9201,6301,250 2 
##STR428## 
" 3 53.7453.81 6.937.04 11.1910.96 3,4001,7601,6301,220 3 
##STR429## 
" 4 54.2354.25 7.107.0812.6512.86 3,3501,6251,3801,150 4 
##STR430## 
" 1.5 3 56.3356.39 6.486.52 12.1712.07 3,3501,6401,260 5 
##STR431## 
" 3 56.4856.47 6.266.08 13.1413.28 3,3501,6301,3851,160 6 
##STR432## 
" 3 57.4457.63 6.125.99 12.8812.76 3,4001,6301,150 7 
##STR433## 
" 1 51.7852.13 5.415.49 12.1212.08 3,3501,6401,250 8 
##STR434## 
##STR435## 
3 57.2356.95 6.476.45 12.8412.76 3,4001,6301,160 9 
##STR436## 
##STR437## 
2 55.4055.27 6.626.81 12.4312.25 3,4001,6301,260 10 
##STR438## 
##STR439## 
1/2H.sub.2 
SO.sub.3 2 48.3448.56 5.415.46 10.4410.33 3,4001,7401,630 
Having now fully described the invention, it will be apparent to one of 
ordinary skill in the art that many changes and modifications can be made 
thereto without departing from the spirit of the invention as set forth 
herein.