FI74455B - PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL ACTIVATED N2-ARYLSULFONYL-L-ARGININAMIDER OR PHARMACEUTICAL ACCEPTABLA SALTER DAERAV. - Google Patents

Description

1 74455 2

Process for the preparation of pharmaceutically active N-arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts

Divided by application 780073 (patent 72316)

The present invention relates to a process for the preparation of certain novel 2 N-arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts, which compounds are of particular value due to their excellent anti-thrombotic properties and low toxicity.

To date, several attempts have been made to obtain new and better agents for the treatment of vascular thrombosis. N- (p-tolylsulfonyl) -L-arginine esters have been identified as substances that can be used for this purpose and have been found to be effective in dissolving blood clots (see U.S. Patent No. 3,622,615). One class of compounds that has been found to be very useful as a specific anti-occlusive agent is N-dansyl-L-arginine ester or amide (U.S. Patent No. 3,978,045). However, there is a continuing need for highly specific anti-thrombotic agents with low toxicity.

2

It has now been found that certain novel N-arylsulfonyl-L-arginamine amides have anticoagulant activity and lower toxicity than the N-dansyl-L-arginine esters and amides known from the aforementioned U.S. Pat. No. 3,978,045 when used in equally effective amounts.

2 74455

The present invention relates to a process for the preparation of a novel pharmaceutically active N-arylsulfonyl-L-argininamide or a pharmaceutically acceptable salt thereof, which has the formula (I): HN 2 O - C - N - CH CH CH CHCOR (I) / l 2 2 21 Η „ΤΓ h HN $ On 2 I 2

Ar where R is

R

-N ^ ^ CH-COOR I 3

R

2 wherein R is C 1-4 alkyl, C 1 -C 4 alkoxyalkyl, C 1 -C 4 alkyl-1 2 7 2 8 2 8 1thioalkyl, C 1 -C 4 alkylsulfinyl and C 1 -C 4 alkylalkyl, C 1 -C 6 cycloalkyl, furfuryl, tetrahydrofurfuryl or tetrahydro-4-pyranylmethyl, R is hydrogen or C 1-4 alkyl,:: 16 is hydrogen or C 1 -C 4 alkyl, and

Ar is a phenyl group substituted with at least one substituent 11a selected from amino, C 1 -C 4 alkylamino, C 1 -C 16 alkanoylamino, C 1 -C 4 hydroxyalkyl, C 1 -C 6 phenylalkyl or C -C-hydroxyalkoxy; or 1 5

Ar is a phenyl group substituted with at least one substituent 11a of hydroxy, C 1 -C 4 alkyl or 16 C 1 -C 6 alkoxy, and at least one substituent 11a of which is C 1 -C 4 alkyl. C 1-4 alkylcarbonyl or phenyl; or

Ar is a biphenyl, phenoxyphenyl, dibenzothienyl, 9,9-dioxodibenzothiyl, phenoxathinyl, quinolyl, phthalazinyl, phenazinyl or acridinyl group, each of which is unsubstituted or substituted by one or more hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkyl groups; or

Ar is a C 1 -cycloalkylphenyl, fluorenyl, thioxan-9-yl or 2H-chromenyl group, each of which is unsubstituted or substituted by one or more C 1 -C 6 alkyl, C 1 -C 4 or coxy or an oxo group; or

Ar is a phenyl group substituted with at least one substituent 11a which is a C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxyalkoxy or C 1 -C 6 alkoxycarbonylalkoxy group, and an optionally O-substituted phenyl group is substituted further with at least one substituent 11a selected from methyl, ethyl, methoxy, ethoxy, hydroxy or halogen.

In the formula for the group R, the group R 1 is, for example, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, methoxymethyl,: ethoxymethyl, propoxymethyl, 2-methoxymethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl. , 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthiethyl, 3-methyl, 3-methyl thiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4-methylthibutyl, 4-ethylthiobutyl, methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylethyl, 2-methylethylsulfyl 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, 2-phenylpropyl, cyclopropyl, cyclobutyl, cyclo cycloececyl and R 1 are, for example, hydrogen, methyl, ethyl, propyl, butyl or tert-butyl and R 1 is, for example, hydrogen, methyl, ethyl, propyl, butyl or tert-butyl.

4 74455

Typical compounds of formula I include e.g. the following: N- (2-phenoxathiylsulfonyl) -L-Arginyl-N-tetrahydrofurfurylglycine, N- (2-fluorenesulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, and pharmaceutically acceptable salts of the compounds.

Compounds of formula (I) may be prepared by removing the G G 2 a) N substituent from an N-substituted N-arylsulphonyl-L-argininamide of formula:

HN

^ \ C - N - CH CH CH CHCOR (XX) / I "2 2 21 HN R" HNSC)

: 'Γ: I I

R 'Ar wherein R and Ar are as defined above, R' and R "are hydrogen or a guanidino protecting group, and at least one of R 'and R" is a guanidino protecting group, acid hydrolysed by maltol or by hydrogenation and, if desired, hydrolysis of the reaction product thus obtained, or 2 b) N-arylsulfonyl-L-arginyl halide having a ca-

HN

^ C - N - CH CH CH CHCOX (XXII) / I 2221 H N H HNSOft

9 I

Ar wherein Ar is as defined above and X is halogen is reacted with an amino acid derivative of formula RH (IV) 5 74455 wherein R is as defined above and, if desired, hydrolyzing the resulting reaction product, and optionally converting the resulting compound of formula I to a pharmaceutically acceptable salt.

In process a) the acid hydrolysis is generally carried out by contacting N-substituted N-arylsulfonyl-L-arginine amide (XX) and an excess of acid, e.g. hydrofluoric, hydrochloric, hydrobromic or trifluoroacetic acid, without solvent or in a ether such as ether. rofuran, dioxane), in alcohol (methanol, ethanol) or in acetic acid at a temperature between -10 and 100 ° C, preferably at -10 ° C to 60 ° C, and even more preferably at room temperature for between 30 minutes and 24 hours. The products are separated by evaporation of the solvent and excess acid or by trituration with a suitable solvent, followed by filtration and drying.

: 2 Due to the use of excess acid, the products are generally acid addition salts of N-arylsulfonyl-L-argininamides (I), 6 74455 which can be easily converted to the free amide by neutralization.

Removal of the nitro group and the oxycarbonyl group, e.g., the benzyloxycarbonyl group and the p-nitrobenzyloxycarbonyl group, is easily accomplished by hydrogenation.

At the same time, the benzyl ester group which may be included in the R group is converted into a carboxyl group by hydrogenation.

The hydrogenation is carried out in an inert reaction solvent, e.g. methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activated catalyst, e.g. Raney nickel, palladium or platinum, in a hydrogen atmosphere at a temperature between 0 ° C and the boiling point of the solvent: and preferably 10 -80 ° C, within 2-120 hours.

* * *: Hydrogen pressure is not critical and atmospheric pressure is sufficient.

The ‘2 N-arylsulfonyl-L-argininamides (I) are separated by filtration on a catalyst followed by evaporation of the solvent.

The 2 N-arylsulfonyl-L-argininamides (I) can be purified by trituration or recrystallization from a suitable solvent such as diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol, or by chromatography on silica gel.

'. * Q 2 The N-substituted N-arylsulfonyl-L-argininamides (XX) used as starting materials can be prepared as follows:

HN

- N - CH-CH 2 CH 2 CHCOOH (Π) - ^ / I 222.

H N 1 1 2W H NH2 7 74455 HNX + RH (IV) C - N - CH2CH2CH2CHCOOH (III) _ ^

HN I I

I R "HN

I I

R 'R "· ΗΝχ C - N - CH„ CH „CH„ CHCOR (V) I 2 2 2. -? HN I'

I R "HN

I I

R 'R' "

HN

yZ - N - CH2CH2CH2CHCOR (XIX) ArSO9X (VIJ)

HN ^ I I

I R "NH„ R '1 ·: · HN v

X

::: C - N - CHoCHoCHoCHCO0 (XX) / \ l 2. 2. - WKT I 1 I R "HNS02

R 'I

Ar: ** · In the above formulas, R, Ar, X, R 'and R "are defined •} above. When the groups R' and R" are guanidino protecting groups,. they are preferably nitro, tosyl, trityl or oxycarbonyl. R "'is an α-amino protecting group such as benzyloxycarbonyl or tert-butoxycarbonyl.

** '. In the above scheme, L-arginine amides (XX) can be prepared by protecting the guanidino and? by butoxycarbonylation or tritylation, and condensation of the G 2 then formed N-substituted N-substituted L-arginine 8 74455 (III) with the corresponding amino acid derivative (IV) using a conventional method such as the acid chloride method, the azide method, the mixed anhydride method, the mixed anhydride method imide method and then selectively removing only the N-substituted 2 2 N-substituted L-argininamide n (V) N substituent

by hydrogenation or acid hydrolysis and then condensation G

the N-substituted L-argininamide (XIX) thus obtained with an arylsulfonyl halide (VII), preferably with a chloride, with a base as a solvent. Amino acid derivatives (IV) which are starting materials for the preparation of N-substituted N-substituted L-arginine amides (V) can be represented by the following formula: X R 1 H-N (VIII)

^ CH-COOR

.::: | 3 ·: r2

In the above formula, R ", R" and R "are as defined above.

Amino acid derivatives of formula (VIII) above may be prepared by condensing a haloacetate, 3-halopropionate or 4-halobutyrate with a suitable amine of formula R NH (see J. Org.

Chem., 25, 728-732 (1960).

... The condensation or 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 pyridine at a temperature of 0 to 80 ° C for 10 minutes to 20 hours. After completion of the reaction, the formed amino acid derivative is separated by conventional methods such as extraction with a suitable solvent or evaporation of the reaction solvent, followed by purification by distillation under reduced pressure.

9 74455

Of the amino acid derivatives, amino acid tert-butyl ester derivatives are most preferred because they can be readily converted to other ester derivatives in the presence of an alcohol corresponding to acid hydrolysis using an inorganic acid (HCl, H 2 SO 4 Etc. Etc. +) or using an organic acid .).

The arylsulfonyl halides (VII) which are the starting materials 2 for the preparation of N-arylsulfonyl-L-argininamides (I) can be prepared by halogenating the corresponding 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 out without solvent or in a suitable solvent, e.g. halogenated hydrocarbon or DMF, halogenated, e.g. phosphorus oxy k 1 ori di n, thionyl ori di n, phosphorus trichloro di n, phosphorus tri bromo di n or in the presence of phosphorus pentachloride at a temperature between -10 and 200 ° C for 5 minutes to 5 hours. After completion of the reaction, the reaction product is poured into ice water and then extracted as a solvent such as ether, benzene, ethyl acetate, chloroform and the like.

The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, benzene and the like.

2

In process b) N-arylsulfonyl-L-Arginyl amide (I) is prepared by condensing a N -arylsulfonyl-L-arginyl-halide (XXII), preferably chloride, at least equimolar. with an amount of the amino acid derivative (IV).

The condensation reaction can be carried out without using an added solvent in the presence of a base. However, satisfactory results are obtained when using a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).

The amount of solvent used is not critical and can vary from about 5 to 100 times the weight of N-arylsulfonyl-L-arginyl halide (XXII) used.

The most preferred condensation reaction temperatures are in the range of -10 to 80 ° C, and preferably 20 to 50 ° C. The reaction time is not critical, but varies depending on the amino acid derivative (IV) used. Generally, a time between 5 minutes and 10 hours is appropriate.

2

The resulting N-arylsulfonyl-L-argininamide can be isolated and purified as described above.

The starting N-arylsulfonyl-L-arginyl halide (XXII) can be prepared as follows: HNx ": - N - CH 2 CH 2 CH 2 CHCOOH (VII) + ArSQ 2 X 2 H 2 N NH 2

HN H

X I

C - N - CH2CH2CH2CHCOOH (XXX) _ ^ h2n hnso,: · i 2:. · Ar HN% f

/ C - N - ch2ch2ch2chcox (XXID

H-N TT1 * 2 HNSO ~ i 2

Ar

In the above formulas, R, Ar and X are as defined above.

11 74455 2

In the above scheme, N-arylsulfonyl-L-arginine (XXI) can be prepared by condensing L-arginine (II) substantially equimolar with an amount of arylsulfonyl halide (VII) using a method similar to that described for condensing L-argininamide with arylsulfonyl.

2 N-Arylsulfonyl-L-arginyl halide (XXII) can be prepared by reacting N-arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride di a, phosphorus oxychloride, phosphorus trichloride dichlorophosphate, or phosphorus tri bromo di a. Halogenation can be carried out with or without a solvent.

The most preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane and ethers such as tetrahydrofuran and dioxane.

The amount of solvent used is not critical and can vary from about 5 to 100 times the weight of N-arylsulfonyl-L-arginine (XXI).

o

The most preferred reaction temperature 1a is from -10 ° C to room temperature. The reaction time is not critical, but varies depending on the halogenating agent and the reaction temperature. Generally, a time of between 15 minutes and 5 hours is appropriate.

2

It is well known in the art that an ester derivative of N-arylsulfonyl-L-argininamide n (I) in which R

O

12 74455 2 is alkyl can be prepared from a N-arylsulfonyl-L-argininamide derivative having hydrogen by conventional esterification methods well known to those skilled in the art. It is also well known in the art that a carboxylic acid derivative can be prepared from an ester derivative by a conventional hydrolysis or acidolysis method. The conditions under which esterification, hydrolysis or acid hydrolysis can be carried out are known to the person skilled in the art.

2

The N-arylsulfonyl-L-argininamide (I) of the invention forms an acid addition salt with various inorganic and 2 organic acids. A few N-arylsulfonyl-L-argininamides containing a free carboxyl group form salts with various inorganic and organic bases.

The reaction products described above can be isolated in free form or in the form of salts. In addition, the product can be obtained in the form of pharmaceutically acceptable acid addition salts by reacting a free base with a sulfuric acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid. ; acid, phosphoric acid, acetic acid, citric acid, maleic acid, succinic acid, lactic acid, tartaric acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid Similarly, the product can be obtained in the form of a pharmaceutically acceptable salt by reacting a free carboxylic acid with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, N-N-dibenzylethylenediamine.

Similarly, treatment of salts with a base or acid provides for regeneration of the free amide.

As mentioned above, the N-arylsulfinyl-L-argininamides of the invention and their salts are characterized by their highly specific inhibitory effect on vascular thrombosis in mammals as well as their substantial non-toxicity, and consequently these compounds are useful in the prevention of vascular thrombosis.

13 74455

The compounds of the invention are also useful in inhibiting platelet aggregation.

2

The vasoconstrictive activity of the N-arylsulfonyl-L-argininamide of the invention was compared to the effect of the known anti-thrombotic agent N2- (p-tolylsulfonyl) -L-arginine methyl ester by determining the coagulation time of fibrinogen. Fibrinogen coagulation time measurements were performed as follows: A 0.8 ml aliquot of fibrinogen solution prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) manufactured by Armor Inc. in 40 ml of borate-salt buffer (pH 7.4) was mixed. With 0.1 ml of borate salt buffer, pH 7.4 (comparison), or with a sample solution in the same buffer, and 0.1 ml of thrombin solution (5 units / ml) manufactured by Mochida Pharmaceutical Co., Ltd. was added. to these solutions in an ice bath.

Immediately after stirring, the reaction mixture was passed from an ice bath to a bath maintained at 25 ° C. Coagulation. the gul time was taken to be the time elapsed from the transfer at 25 ° C; ; to the moment when the first fibrin fibers appeared. In those cases where drug samples were not added, the coagulation time was 50-55 sec. The test results are shown in Table 1. The term "concentration required to double the coagulation time" is the concentration of the active ingredient required to prolong the normal coagulation time, from 50 to 55 seconds, to 100 to 110 seconds.

The concentration required to double the coagulation time when using the known anticoagulant * 1-2 N- (p-tolylsulfonyl) -L-arginine methyl ester was 1100. The inhibitors are shown in Table 1 by showing R and Ar in formula (I) and the addition group.

"2

When a solution containing the N-arylsulfonyl-L-argininamide of the invention was administered intravenously to animals, strong anticoagulant activity was maintained in the circulating blood for 1-3 hours. The circulating half-life of the anti-thrombotic compounds of the invention was approximately 60 minutes. The physiological conditions of the experimental animals (rats, rabbits, dogs and chimpanzees) 14 74455 could be well maintained. Experimental degradation of fibrinogen in animals by infusion of thrombin could be satisfactorily controlled by co-administration of the compounds of the invention.

Acute toxicity values (LD) of the compounds of the invention as determined by intravenous administration of formula (I)

5 O

compounds for mice (male hili 20 g) are about 150-600 mg / kg body weight.

The typical LD value of the compounds of the invention is shown in the following table.

Combine ste HN v.

: ^ C - NH - (CH) CHCOR

::: X 2 31 H N HNSO Ar:. 2 2 · **; Ar R LDgO (mg / kg) N-X'S CH - - ^ 0 ^

Il 1 (i I / 2 "N 260

XCH COOH

. ·. * 2

Accordingly, the following LD 1 values were obtained when N-dansyl-L-Arginine derivatives known from U.S. Patent 3,978,045 were administered intravenously to mice.

15 74455 Y h diste

HV

C - NH - (CH) CHCOR / 2 3 |

H N HNSO

ΑΧ N (CH 1 3 2

Compound R LD (mg / kg)

oU

2-N-dansyl-L-arginine-O (CH) CH 60

b v O

n-butyl ester 4-methyl-1- (N2-dansyl-N-CH2-L-arginyl) piperidine: 4-ethyl-1- (N2-dansyl-> N - H2) (H3 8 L-arginyl) piperidine 2- (N2-dansyl-L-arginyl) - - N and J10 isoindoline

The corresponding LD values for oral administration of the above compounds 50 are> 6000, 1310, 1375 and 1360 mg / kg, as shown in U.S. Pat. No. 3,978,045, column 13, lines 36-44.

It is clear from the foregoing that the novel N -aryl sulfonium compounds of the present invention have substantially lower toxicity than U.S. Pat. 978 045 with known compounds.

16 74455

Therapeutic agents of the invention may be administered to mammals, including humans, alone or in combination with pharmaceutically acceptable carriers, the amount of which will be determined depending on the solubility and chemical nature of the compound, the mode of administration, and conventional pharmaceutical practice.

These compounds can be injected e.g. parenterally, i. intramuscularly or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other soluble substances, e.g., enough salt or glucose, to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules or granules containing suitable excipients such as starch, lactose, sugar, etc. The compounds may also be administered ... also sublingually in granular or liquid form, each active ingredient being mixed with sugar and corn syrup; · 'With flavor and colorings and then sufficiently dehydrated to make the mixture suitable for compression into a solid ·. shape. The compounds may also be administered orally in the form of solutions which may contain coloring and flavoring agents. The physician will determine the dosage of these therapeutic agents which will be most suitable for humans, and these dosages may be varied depending upon the mode of administration and the compound employed. In addition, the dosage may be varied depending upon the host treated.

When the mixture is administered orally, a larger amount of active substance is required to achieve the same effect obtained with a lower parenteral dose.

. The therapeutic dose is usually 10-50 mg / kg of active ingredient. parenterally and 10-500 mg / kg orally daily.

In the following, the invention will be described in more detail by means of exemplary embodiments.

17 74455

Example 1 2 (A) N- (2-dibenzothienylsulfonyl) -L-arginine:

To a well-stirred solution of 83.6 g of L-arginine in 800 ml of 10% potassium carbonate solution was added 112.7 g of 2-dibenzothiophenesulfonyl chloride in 300 ml of benzene. The reaction mixture was stirred at 60 ° C for 5 hours during which time the product precipitated. After standing for 1 hour at room temperature, the precipitate was filtered and washed successively with benzene and water to give 127 g (76%) of N2- (2-dibenzothienylsulfonyl) -L-arginine.

... (B) N- (2-dibenzothienylsulfonyl) -L-arginyl chloride: '': 2; ; A suspension of 4.21 g of N- (2-dibenzothienylsulfonyl) -L-: arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold, dry diethyl ether gave a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N- (2-dibenzothienylsulfonyl) -L-arginyl chloride.

2 (C) N- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycol. toxin-tert-butyl ester:

To a stirred solution of 2.67 g of N-butylglycine tert-one

- O

butyl ester in 20 ml of chloroform, N- (2-:: dibenzothienylsulfonyl) -L-arginyl chloride obtained above was carefully added. The reaction mixture was allowed to stand at room temperature for 1 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 at 74455 and precipitated from ethanol-ethyl ether to give 3.1 g (49%) of N2- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine tert-butyl ester.

I.R. (KBr): 3350, 1740, 1625 cm-1

Analysis - calculated for C-OH, nCr '], S- · 1/2 H-SO-, (¾): Zö jy u b Z Z 5 C 53.31; H 6.39; N 11.10 Found (¾); C 53.21; II 6.46; N 10.89.

(D) N2- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine

To a solution of 2.00 g of N- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred 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 w SK 102 ion exchange resin (200-300 mesh, H + form, manufactured by Mitsubishi Chemical Industries Limited) 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 0.9 g (53%) of N- (2-dibenzothienyl-: sulfonyl) -L-arginyl. -N-butylglycine as an amorphous solid.

I.R. (KBr): 3350, 1640, 1270 cm -1

Analysis - Calculated for C 24 H 31 N 5 O 5 S 2 O 2: C, 54.01; H 5.86; N 13.2 Found (%): C 53.78; H 5.97; N 12.96.

*. Example 2 (A) N2- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxy-; ethyl) glycine ethyl ester: *. To a stirred solution of 2.42 g of N- (2-methoxyethyl) -glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added portionwise 2 7.0 g of N- (2-dibenzothienylsulfonyl) -L-arginyl chloride obtained as described above. The reaction mixture was stirred overnight at 19 74455 overnight at room temperature. At the end of this period, 50 ml of chloroform and chloroform solution were added twice to 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 5.5 g of a powdery N2- (2-dibenzo) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester.

Analysis; Calcd for C25H23O6N5S2 * 1/2 n2SO3 (? o): C 50.49; H 4.07; N 11.78 Found (S): C 50.22; H 4.18; N 11.51.

(B) n2- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine:

A solution of 5.5 g of N2- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester in 15 ml of methanol and 15 ml of 2N-NaOH solution was heated to 40 ° C and maintained at this temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H + form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1: 4) and eluted with ethanol-water-NH 4 OH: (10: 9: 1).

The main fraction was evaporated to dryness and washed with ethyl ether to give: * 3.05 g (62%) of n2- (2-dibenzothienylsulfonyl) -L-arginyl-: N- (2-methoxyethyl) glycine as an amorphous solid. .

I.R. (KBr): 3400, 1630, 1280 cm-1

Analysis - Calculated for C 23 H 28 O 9 N 2 S 2 (%): C, 51.57; H 5.46; N 13.08 Found (%): C 51.35; H 5.63; N 12.86.

::: Example 3 G o (A) N-Nitro-N '- (tert-butoxycarbonyl) -L-arginyl-N-butyl-glycine benzyl ester!

To a stirred solution of 28.4 g of N, N-nitro-N2- (tert-butoxycarbonyl) -L-arginine in 450 ml of dry tetrahydrofuran was successively added 12.4 ml of triethylamine and 12.4 ml of isobutylamine. Chloroformate while maintaining the temperature of the solution at -5 ° C. After 15 minutes, 35.0 g of N-butylglycine benzyl ester p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran were added, and the mixture was then stirred at -5 ° C for 15 minutes. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated off and the residue was dissolved 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. After evaporation of the solvent, the residue was dissolved in 20 ml of chloroform, and the solution was added to a column (80 x 6 cm) of 500 g of silica gel packed in chloroform.

The product was eluted first with chloroform and then with 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform

G

evaporated to dryness to give 26.0 g (56%) of N-nitro-N2-tert-butoxycarbonyl) -L-arginyl-N-butylglycine benzyl ester in the form of a syrup.

I.R. (KBr): 3300, 1740, 1690 cm -1.

• · t · «

* · · G

: V (B) N-Nitro-L-arginyl-N-butylglycine benzyl ester-::: hydrochloride:

• * G

To a stirred solution of 26.0 g of N-nitro-N '- (tert-butoxy - * .carbonyl) -L-arginyl-N-butylglycine benzyl ester in 50 ml of ethyl acetate was added 80 ml of 10% ethyl acetate. dry HCl-ethyl acetate at 0 ° C. After 3 hours, 200 ml of dry ethyl ether was added to this solution to precipitate a viscous oily product.

This was filtered and washed with dry ethyl ether to give 20.8 g of N-nitro-L-arginyl-N-butylglycine benzyl ester. hydrochloride as an amorphous solid.

G 2 (C) N-Nitro-N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L - '** · arginyl-N-butylglycine benzyl ester:

G

To a stirred solution of 2.33 g of N-nitro-L-arginyl-N-21 74455 butylglycine benzyl ester hydrochloride in 10 ml of water and 40 ml of dioxane were successively added 1.26 g of sodium bicarbonate and 2.2 g of 3-cyclohexyl chloride. 4-methoxyphenylsulfonyl chloride at 5 ° C and stirring was continued for 3 hours at room temperature. At the end of this period, the solvent was evaporated and the residue was 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 solution and 10 ml of water.

The ethyl acetate solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3 ml of methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to give 2.6 g (77%) of N-nitro-N - (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine benzyl ester. in the form of an amorphous solid.

I.R. (KBr): 3300, 2920, 1740, 1640, 1250 cm -1

Analysis - Calculated for C 32 H 24 N 2 O 2 • 6: C, 56.95; H 6.87; N 12.46 Found (¾): h '*: C 56.49; H 6.63; N 12.38.

i (D) N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine.

To a solution of 3.00 g of N-nitro-N '- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water, 0.5 g of palladium black was added and then the mixture was stirred under 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.

was dried. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion ® SK

. ·· *. 102-ion exchange resin (200-300 mesh, H + form, manufactured by Mitsu- • Bishi 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 1.5 g (72%) of N2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl-N-butylglycine as an amorphous solid.

22 74455 I.R. (KBr): 3350, 2920, 1630, 1250 cm-1.

Analysis - calculated for C H N 0 $ (%).

2541 651 C 55.63; H 7.66; N 12.98 Found (%): C 55.32; H 7.39; N 12.84.

2

Various other N-arylsulfonyl-1-L-argininamides or their acid addition salts were prepared synthetically by the methods described in the above examples, and the experimental results are shown in Table 1.

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k> Ή »H iH ry» H »H» H

.. “O O

. τ 'OO OO OO OO O CO., LTD

tv-'a me »ΟΌ mm O m -CT c £>. g m PJ -7 CJ m vo m u- \ »*

Lvi ty * “** * * *" * * frt - ^ rv »h rv ^ rv * - <rv *. <'* - \ 5 00 CO CV .T CO -T .T oo« - oo ζ O t "* co CsM rv. .

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ΓΙ * 7T S ~ -H -t Ή m VO Cv VO Cv ΠΝ ON

g «-g X CMM CO VO VO c ~ \ VOt ^ -.

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s s s >> <u en rv I o «o s r- ^ s os« L · s = "§ L? § 8 • ·. U * o O O I o o o

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The compound shown in Table 2 below was prepared in a similar manner. The reference to the prior art in this table (in the second column of the table) shows the production method of the compound shown in the second column.

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Claims (6)

32 2 74455 A process for the preparation of a pharmaceutically active N-arylsulfonyl-L-argininamide or a pharmaceutically acceptable salt thereof, which has the formula (I): HN '^ C - N - CHoCH ,, CH_CHCOOR (I) 2 2 2. H * 1 Process according to Claim 1, characterized in that the acid hydrolysis is carried out by contacting the N-2-substituted N-arylsulfonyl-L-argininamide with an excess of acid at a temperature between -10 and 100 ° C. 2. HNSO „Ar wherein R 1 is / R 1 -N'-CH-COOR R 2 wherein R 1 is C 2 -C 4 alkyl, C 2 -C 8 alkoxyalkyl, C 2 -C 8 alkylthioalkyl, C 2 -C 8 alkylsulfinylalkyl, C 1 -C 4 aralkyl, C 3 -C 10 cycloalkyl, furfuryl, tetrahydrofurfuryl or tetrahydro-4-pyranylmethyl, R 2 is hydrogen or -C 8 alkyl, and R 1 is hydrogen or -C 1-4 alkyl, and Ar is a phenyl group substituted with at least one substituent selected from amino, -C 1 -C 4 alkylamino, C 1 -C 4 alkanoylamino, C 1 -C 6 hydroxyalkyl, C 7 -C 6 phenylalkyl or -C 1 -C 4 hydroxyalkoxy; or Ar is a phenyl group substituted with at least one substituent selected from hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and at least one substituent selected from C 1 -C 6 aralkyl, C 2 -C 6 alkylcarbonyl, or phenyl; or Ar is a biphenyl, phenoxyphenyl, dibenzothienyl, 9,9-dioxodibenzothienyl, phenoxathinyl, quinolyl, phthalazinyl, phenazinyl or acridinyl group, each of which 74455 33 is unsubstituted or substituted by one or more hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkyl; or Ar is a C 8 -C 6 cycloalkylphenyl, fluorenyl, thioxanthenyl or 2H-chromenyl group, each of which is unsubstituted or substituted by one or more C 1-6 alkyl, -C 1-6 alkoxy or oxo groups; or Ar is a phenyl group substituted with at least one substituent having a C 1 -C 4 haloalkoxy, C 2 -C 7 alkoxyalkoxy or C 1 -C 4 alkoxycarbonylalkoxy group, and the optionally substituted phenyl group is further substituted with at least one substituent , which is methyl, ethyl, methoxy, ethoxy, hydroxy or halogen, characterized in that GG 2 a) the N-substituent is removed from the N-substituted N-arylsulfonyl-L-argininamide of the formula: mi ^ C - N - CH_CH 2 CH 0 CHCOR (XX) 2 I 2 '2 "2 H 2 O 2' Ar wherein R and Ar are as defined above, R 'and R" are hydrogen or a guanidino protecting group, and at least one of R' and R "is a guanidino protecting group , by acid hydrolysis or hydrogenation and, if desired, hydrolysis of the reaction product thus obtained, or 2 b) N-arylsulfonyl-L-arginyl halide of the formula HN v% C - N - CH „CH„ CH_CHCOX (XXII) I 2 2 2 | h2nX h hnso2 Ar wherein Ar is as defined above and X is halogen, rea with an amino acid derivative of formula 34 7445 5 RH (IV) wherein R is as defined above, and, if desired, hydrolyzing the obtained reaction product, and if desired, converting the obtained compound of formula I into a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that the hydrogenation is carried out in an inert reaction solvent in the presence of an activating hydrogen catalyst in a hydrogen atmosphere at a temperature between 0 ° C and the boiling point of the solvent. Process according to Claim 1, characterized in that the N-arylsulphonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature between -10 and + 80 ° C. 35 7 4 4 5 5 Patent patent K For the preparation of a pharmaceutical active ingredient N-or 1-sulfonyl-L-Argi ni namid or ett pharmaceutisk accep-tabelt sait därav, vilken förening har formuleln (I): HN - N - CH CH CH CHCOR (I) / I 2221 HNH HNSO 2 i 2 Ar color R är / R1 -N ^ CH-COOR I 3 R 2 color R är C -C alkyl, C -C alkoxyalkyl, C -C alkylthioal-1 27 28 28 yes, C 1 -C 4 -alkyl-alkyl, C 1 -C 6 -alkyl, C 1 -C 4 -cycloalkyl, furfuryl, tetrahydrofurfuryl or tetrahydro-4-pyranylmethyl, R 1 or C 1 -C 4 alkyl; is selected from the group consisting of C 1-4 alkyl, and C 1-4 alkyl substituted with a substituent selected from amino, C 1-4 alkyl, amino, C 1-4 alkanoylamino, CC-hydroxy , CC -phenylalkyl or C -C -hydroxy- 15 7 10 15 coxy; e 11 is an aryl phenyl group substituted by a substituent having a hydroxy, C -C -alkyl or C -C -alkoxy, and 16 16 with a substituent selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl arbonyl or phenyl; or 2 6 The biphenyl, phenoxyphenyl, dibenzothienyl, 9,9-dioxodibenzothienyl, phenoxathiin, quinolyl, phthalazinyl, phenazinyl or acridinyl groups are optionally substituted with 36 7 ^ 455 substituents. or hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkyl groups, or C 1 -C 6 cycloalkylphenyl, fluorenyl, thioxanthenyl-9-yl or 2 H-chromium groups, which may be substituted or substituted. with C 1-4 alkyl, C -C ..... 1 10 J 1 10 alkoxy or oxo; wherein the phenyl group is substituted by a substituent having the substituent C 1-4 haloalkoxy, C -C alkoxyalkoxy or 14 C 7 -C 1-4 alkoxycarbonylalkoxy, and optionally by the substituents of the phenyl group having other substituents and substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy and hydroxy or halogen, having the following substituents: - N - CH CH CH CHCOR (XX) / »„ 2 2 2i HN R "HNSO / 1 2 / Ar R 'color R och Ar Ar definierade ovan, R' och R" är väte eller en skyddsgrupp för guanidinogroupen, och atminstone the group of R 'and R "groups in the guanidino group, which is a hydrolyser or a hydrolyser, and which are self-contained, a hydrolyser of the reaction products, or