Method for preparing N.sup.2 -arylsulfonyl-L-argininamides

A method for preparing N.sup.2 -(3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine which comprises the step of condensing N.sup.G -nitro-L-arginine and 3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl chloride. The method achieves an extremely efficient and high yield preparation of N.sup.2 -arylsulfonyl-L-arginineamides that are useful as active ingredients of medicaments. Also provided is a novel N.sup.2 -(3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine compound which can be used as synthetic intermediate for the manufacture of (2R,4R)-4-methyl-1-N.sup.2 -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine -carboxylic acid.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a method for preparing N.sup.2 
-arylsulfonyl-L-arginineamides which are useful as active ingredients of 
medicaments such as anti-thrombotic agents. 
2. Related Art 
The Japanese Patent Publication (KOKOKU) No. (Sho) 61-48829/1986 discloses, 
as Compound No. 6 in Table 1, (2R,4R)-4-methyl-1-N.sup.2 
-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine 
-carboxylic acid. As taught by the publication, this compound has highly 
specific inhibitory activity against thrombin that exists in a mammalian 
body, and is useful as an agent for therapeutic and preventive treatment 
of thrombosis, and as a platelet aggregation inhibitor. Monohydrate of 
this compound has been used as a selective anti-thrombotic agent for the 
treatment of chronic arterial occulsive diseases, cerebral thrombosis or 
other. 
As a method for preparing the N.sup.2 -arylsulfonyl-L-arginineamides such 
as mentioned above, the method set out in the scheme below was known so 
far, as disclosed on pages 2 and 3 of the Japanese Patent Publication 
(KOKOKU) No. (Hei) 1-35000/1989 and on page 3 of the Japanese Patent 
Publication (KOKOKU) No. (Hei) 2-31055/1990. In the scheme, Ar represents 
1,2,3,4-tetrahydro-8-quinolyl group whose 3-position is substituted with 
methyl group or ethyl group; Q represents 8-quinolyl group whose 
3-position is substituted with methyl group or ethyl group; R.sup.1 
represents a hydrogen atom or a C.sub.1-5 alkyl group; X represents a 
halogen atom; R.sup.2 represents a hydrogen atom, a C.sub.1-10 alkyl 
group, or a C.sub.7-15 aralkyl group; at least one of R' and R" represents 
a protective group of the guanidino group; and R"' represents a protective 
group of the .alpha.-amino group. 
##STR1## 
This method comprises the steps of condensing a piperidine-2-carboxylic 
acid derivative (Compound (IV) in the scheme) with an arginine derivative 
whose guanidino group and amino group on the .alpha.-carbon atom are 
appropriately protected (Compound (III) in the scheme); removing the 
protective group of the amino group on the .alpha.-carbon of the 
condensate obtained (Compound (V) in the scheme) and then allowing the 
resulting amino group react with a quinolinesulfonyl halide (Compound 
(VII) in the scheme); followed by removing the substituent on the 
guanidino group such as nitro group, and then reducing the quinolyl group 
and deblocking the carboxyl group to obtain the desired compound (Compound 
(I) in the scheme). 
The Japanese Patent Publication (KOKOKU) No. (Sho) 61-48829/1986 discloses, 
as Example 2 on page 7, a specific process for preparing 
(2R,4R)-4-methyl-1-N.sup.2 
-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine 
-carboxylic acid according to the aforementioned method. The publication 
discloses that the ethyl ester of (2R,4R)-1-N.sup.G -nitro-N.sup.2 
-(3-methyl-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxyli 
c acid was prepared in the three-step process by using N.sup.G 
-nitro-N.sup.2 -(tert-butoxycarbonyl)-L-arginine as a starting material, 
and the yield of step (A) was 74.5%. 
The Japanese Patent Publication (KOKOKU) No. (Hei) 1-35000/1989 discloses 
the reaction scheme on pages 4 and 5 that relates to a process comprising 
the steps of condensing unprotected L-arginine (Compound (II) in the 
scheme) with an approximately equimolar amount of a quinolinesulfonyl 
halide (Compound (VII) in the scheme) to obtain N.sup.2 
-quinolinesulfonyl-L-arginine (Compound (IX) in the scheme), and then 
allowing the resulting product react with the piperidine-2-carboxylic acid 
derivative (Compound (IV) in the scheme), followed by reducing the 
quinolyl group and deblocking the carboxyl group to obtain the desired 
compound, which will be shown in the scheme below. However, this method is 
not specifically demonstrated by any working example given in the 
publication, and moreover, it is impossible to obtain the desired compound 
with high selectivity, because the publication fails to teach any specific 
means to control the sulfonylation of the unprotected guanidino group 
which must be expected as an inevitable side reaction. Therefore, this 
method is of no significance to industrial applications. In addition, the 
publication neither teaches nor suggests a process of reacting an arginine 
having a protected guanidino group, e.g., Compound (III) shown in the 
scheme, with a quinolinesulfonyl halide according to the aforementioned 
method. 
##STR2## 
Therefore, an object of the present invention is to provide a method that 
enables efficient preparation of N.sup.2 -arylsulfonyl-L-arginineamides on 
an industrial scale. Another object of the present invention is to provide 
a synthetic intermediate compound which is useful for efficient 
preparation of N.sup.2 -arylsulfonyl-L-arginineamides. 
SUMMARY OF THE INVENTION 
The inventors of the present inventor conducted various researches to 
provide a more efficient method to prepare N.sup.2 
-arylsulfonyl-L-arginineamides than those disclosed in the aforementioned 
patent publications. As a result, they found that each of the reactions 
can be completed with high efficiency by first condensing L-arginine 
having a nitro-protected guanidino group with a quinolinesulfonyl halide, 
and then allowing a piperidine-2-carboxylic acid derivative react with the 
.alpha.-amino group in the presence of a certain compound, thereby the 
process is successfully simplified and overall yield can be remarkably 
improved. 
The present invention thus provides a method for preparing N.sup.2 (3-(a 
hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G 
-nitro-L-arginine which comprises the step of condensing N.sup.G 
-nitro-L-arginine and 3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl chloride. According to another embodiment of 
the present invention, there is provided a novel N.sup.2 
-(3-methyl-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine compound which 
is useful as a synthetic intermediate for the preparation of N.sup.2 
-(3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G 
-nitro-L-arginine compounds, preferably (2R,4R)-4-methyl-1-N.sup.2 
-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine 
-carboxylic acid, that are useful as active ingredients of medicaments. 
According to a further embodiment of the present invention, there is 
provided a method for preparing a lower alkyl ester of 1-N.sup.G 
-nitro-N.sup.2 -(3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxylic 
acid which comprises the step of condensing N.sup.2 -(3-(a hydrogen atom 
or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine and a 
lower alkyl ester of 4-methylpiperidine-2-carboxylic acid. According to a 
still further embodiment of the present invention, there is provided a 
method for preparing a lower alkyl ester of 1-N.sup.G -nitro-N.sup.2 
-(3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxylic 
acid which comprises the steps of (a) preparing N.sup.2 -(3-(a hydrogen 
atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine by 
reacting N.sup.G -nitro-L-arginine with 3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl chloride; and (b) condensing N.sup.2 -(3-(a 
hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G 
-nitro-L-arginine obtained in the above step (a) with a lower alkyl ester 
of 4-methylpiperidine-2-carboxylic acid. 
DETAILED EXPLANATION OF THE INVENTION 
Best Mode for Carrying out the Invention 
In the specification, the description of "3-(a hydrogen atom or a lower 
alkyl)" used in the names of compounds means that the substituent at the 
3-position is either a hydrogen atom or a lower alkyl group. As to N.sup.2 
-(3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G 
-nitro-L-arginine, i.e., a novel compound provided by the present 
invention, a straight- or branched-chain C.sub.1-4 alkyl group, preferably 
methyl group or ethyl group, and most preferably methyl group, may be used 
as the substituent at the 3-position. 
N.sup.2 -(3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G 
-nitro-L-arginine can be prepared by condensing N.sup.G -nitro-L-arginine 
and 3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl chloride. An 
example of the method will be detailed in Examples of the specification. 
In general, the reaction may be carried out by dissolving nitroarginine in 
an aqueous solution of a base such as sodium hydroxide, and then adding 
3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl chloride 
dissolved in a water-miscible organic solvent such as tetrahydrofuran or 
acetone to the above-obtained aqueous solution of nitroarginine. A base 
such as sodium carbonate may be optionally used in the reaction. 
The reaction is preferably carried out under cooling, for example, at a 
temperature ranging from about 0 to 10.degree. C. N.sup.G 
-nitro-L-arginine and 3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl chloride, e.g., 3-methyl-8-quinolinesulfonyl 
chloride and 3-ethyl-8-quinolinesulfonyl chloride, that are used as 
starting materials are known compounds. For example, they can be prepared 
according to the method described in the Japanese Patent Publication 
(KOKOKU) No. (Hei) 4-984/1992, or alternatively, they can be readily 
obtained as commercially available products. N.sup.2 -(3-(a hydrogen atom 
or a lower alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine can be 
isolated and purified by applying ordinary post-treatments, and if 
required, by applying additional purification processes including 
chromatography and recrystallization. The above reaction can be conducted 
with an extremely high yield and results in little by-products. Therefore, 
a crude product contained in an extract or other material that is obtained 
by ordinary post-treatments, can usually be applied to the reaction in the 
next step without further isolation and purification of the resulting 
product. 
N.sup.2 -arylsulfonyl-L-arginineamides which are useful as active 
ingredients of medicaments, preferably 4-methyl-1-N.sup.2 -(3-(a hydrogen 
atom or a lower 
alkyl)-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine-car 
boxylic acid and the like, can be efficiently prepared by using the 
aforementioned N.sup.2 -(3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine. For example, 
4-methyl-1-N.sup.2 -(3-(a hydrogen atom or a lower 
alkyl)-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine-car 
boxylic acid can be prepared in a high yield by the steps of condensing 
N.sup.2 -(3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine with a lower alkyl 
ester of 4-methyl-2-piperidine-carboxylic acid to obtain a lower alkyl 
ester of 1-N.sup.G -nitro-N.sup.2 -(3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxylic 
acid; hydrolyzing the lower alkyl ester group of the resulting compound; 
and then subjecting the resulting carboxylic acid derivative to catalytic 
hydrogenation. 
As lower alkyl ester groups that are comprised of the lower alkyl esters of 
the 4-methyl-2-piperidine-carboxylic acid used in the above reaction, for 
example, a straight- or branched-chain C.sub.1-4 alkyl group, preferably 
methyl group or ethyl group, most preferably ethyl group, may be used. The 
aforementioned piperidine derivatives have two asymmetric carbon atoms, 
and accordingly, their optical isomers and diastereoisomers can exist. 
These isomers in pure forms may be used in the method of the present 
invention, or alternatively, any mixtures thereof can also be used. Where 
optically active isomers are used, their stereostructures are not 
particularly limited. For example, lower alkyl esters of 
(2R,4R)-4-methyl-2-piperidine-carboxylic acid may preferably used. Ethyl 
(2R,4R)-4-methyl-2-piperidine-carboxylate is most preferably used as the 
ester compound. These piperidine derivatives can be easily obtained, for 
example, according to the methods described in the Japanese Patent 
Publication (KOKOKU) Nos. (Sho) 61-25029/1986 and (Sho) 62-34035/1987, as 
well as in the Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 
2-212473/1990. 
For the condensation of the aforementioned lower alkyl ester of 
4-methyl-2-piperidine-carboxylic acid with N.sup.2 -(3-(a hydrogen atom or 
a lower alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine, any methods 
can be applied so far that they are applicable as methods for condensation 
between an amino group and a carboxyl group by dehydration, whose examples 
include acid halide methods, mixed acid anhydride methods, activated ester 
methods, and methods using condensing agents. As a preferred embodiment of 
the present invention, a method for the condensation using phosphorus 
oxychloride will be detailed in Examples. This reaction can be generally 
carried out in an organic solvent such as tetrahydrofuran at a temperature 
of not higher than 10.degree. C., preferably not higher than 5.degree. C., 
and most preferably not higher than 0.degree. C., by adding phosphorus 
oxychloride dropwise to a solution of N.sup.2 -(3-(a hydrogen atom or a 
lower alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine, and then 
adding a lower alkyl ester of 4-methyl-2-piperidine-carboxylic acid and an 
appropriate base such as triethylamine successively to the reaction 
mixture. 
Where condensing agents are used to carry out the reaction, the condensing 
agents are not particularly limited. For example, 
N',N'-dicycloalkylcarbodiimides such as N',N'-cyclohexylcarbodiimide 
(DCC); carbodiimide derivatives such as 
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAPC); or benzotriazole 
derivatives such as 1-hydroxybenzotriazole (HOBT) may be used. In 
addition, N-hydroxy derivatives, disulfide compounds, succinic acid 
compounds, phosphinic chloride compounds, oxalate derivatives, 
triarylphosphines, N-(a lower alkyl)-5-aryl-isooxazolium-3'-sulfonates, 
diheteroaryl diselenides, arylsulfonyl triazolides, 2-halo-1-(a lower 
alkyl)pyridinium halides, diarylphosphoryl azides, imidazole derivatives, 
dicarboxyimide derivatives and the like may be used. 
Examples of agents for preparing activated esters that are used in the 
activated ester methods include, for example, an N-hydroxy compounds such 
as N-hydroxysuccinimide, 1-hydroxybenzotriazole, or 
N-hydroxy-5-norbornene-2,3-dicarboxyimide; disulfide compounds such as 
dipyridyl disulfide or the like. Where the carboxyl group is converted 
into an acid halide according to the acid halide method, for example, 
phosphorus pentachloride, thionyl chloride, oxalyl chloride or the like 
can be used as a halogenating agent. However, methods for condensation of 
the above compounds and reagents can be suitably chosen by those skilled 
in the art, and accordingly, they are not limited to those explained 
above. 
By subjecting the lower alkyl ester of 1-N.sup.G -nitro-N.sup.2 -(3-(a 
hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxylic 
acid prepared as described above to hydrolysis and catalytic hydrogenation 
according to any one of methods that are known, per se, 
4-methyl-1-N.sup.2 -(3-(a hydrogen atom or a lower 
alkyl)-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine-car 
boxylic acid, preferably 4-methyl-1-N.sup.2 
-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine 
-carboxylic acid, more preferably (2R,4R)-4-methyl-1-N.sup.2 
-(3-methyl-1,2,3,4-tetrahydro-8-quinoline-sulfonyl)-L-arginyl!-2-piperidin 
e-carboxylic acid, and most preferably (2R,4R)-4-methyl-1-N.sup.2 
-(3-methyl-1,2,3,4-tetrahydro-8-quinoline-sulfonyl)-L-arginyl!-2-piperidin 
e-carboxylic acid monohydrate, can be prepared. The reaction may preferably 
be carried out, for example, according to the methods described in the 
steps (D) and (E) on pages 8 and 9 of the Japanese Patent Publication 
(KOKOKU) No. (Hei) 1-35000/1989, and the steps (D) and (E) on pages 7 and 
8 of the Japanese Patent Publication (KOKOKU) No. (Sho) 61-48829/1986.

EXAMPLES 
The present invention will be explained more specifically by referring to 
the following examples. However, the scope of the present invention is not 
limited to the examples. 
(1) N.sup.G -nitro-L-arginine (20 g) was dissolved in 25% aqueous solution 
of sodium hydroxide, and sodium carbonate (9.7 g) was added to the aqueous 
solution. To this reaction mixture, a solution of 
3-methyl-8-quinolinesulfonyl chloride (27.4 g) in tetrahydrofuran (360 ml) 
was added dropwise under cooling. After completion of the dropwise 
addition, the reaction mixture was left at room temperature and stirred 
for two hours. The reaction mixture was adjusted to pH 2.7 with diluted 
hydrochloric acid under water-cooling, and then the solvent was evaporated 
under reduced pressure. Methanol (270 ml) was added to the residue and the 
solvent was again evaporated under reduced pressure and the residue was 
cooled. The resulting slurry mixture was filtered and the precipitates 
collected were washed with water to obtain N.sup.2 
-(3-methyl-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine (35 g). 
Melting point 196-198.degree. C. Angle of rotation a!.sub.D.sup.24 
+116.degree. C. (c=1, 2N HCl). I.R. (KBr, cm.sup.-1) 1700, 1650, 1330, 
1170 
(2) N.sup.2 -(3-methyl-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine (35 
g) was dissolved in tetrahydrofuran (360 ml) and the solution was cooled 
to -10.degree. C. To this solution, a solution of phosphorus oxychloride 
(19.5 g) in tetrahydrofuran (90 ml) was added dropwise at -10.degree. C. A 
solution of ethyl (2R,4R)-4-methylpiperidine-2-carboxylate (20 g) in 
tetrahydrofuran (90 ml) was added dropwise to the reaction mixture at 
-10.degree. C., and then triethylamine (24 g) was added dropwise at 
-10.degree. C. After completion of the dropwise additions, the reaction 
mixture was stirred at -5.degree. C. for one hour. After completion of the 
reaction, the reaction mixture was added with saturated brine (330 ml) and 
layers were separated to give a solution of ethyl (2R,4R)-1-N.sup.G 
-nitro-N.sup.2 
-(3-methyl-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxyla 
te in tetrahydrofuran. The overall yield of the above steps (1) and (2) was 
78%. 
(3) Monohydrate crystals of (2R,4R)-4-methyl-1-N.sup.2 
-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine 
-carboxylic acid were obtained from ethyl (2R,4R)-1-N.sup.G -nitro-N.sup.2 
-(3-methyl-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxyla 
te obtained in the above step (2) according to the method described in 
Examples (D) and (E) on page 7 of the Japanese Patent Publication (KOKOKU) 
No. (Hei)-2-31055/1990. IR spectrum of the resulting monohydrate crystals 
was found to be identical to that of the compound manufactured and sold 
under a non-proprietary name of "argatroban." 
From these results, it can be readily understood that N.sup.2 
-arylsulfonyl-L-arginineamides can be efficiently prepared on an 
industrial scale according to the method of the present invention. It can 
also be understood that N.sup.2 -(3-(a hydrogen atom or a lower 
alkyl)-8-quinolinesulfonyl)-N.sup.G -nitro-L-arginine provided by the 
present invention is useful as a synthetic intermediate for efficient 
manufactures of N.sup.2 -arylsulfonyl-L-arginineamides which are useful as 
active ingredients of medicaments.