FI72316B - PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL ACTIVATED N2-ARYL SULPHONYL-L-ARGININAMIDER AND PHARMACEUTICAL ACCEPTABLE SALTER DAERAV - Google Patents

Description

7231 6 2

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

The present invention relates to a process for the preparation of certain novel N-arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts, which compounds are of particular value due to their excellent anticoagulant 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-thrombotic agent is N-dansyl-L-arginine ester or amide (U.S. Patent No. 3,978,045). In addition, N-naphthylsulfonyl-L-arginine esters and amides are known from DE-A-2,550,088, which are very specific anti-thrombotic agents.

2,72316

However, there is a continuing need for highly specific anti-vascular agents with low toxicity.

2

It has now been found that certain novel N-arylsulfonyl-L-arginine amides have anticoagulant activity and lower toxicity than the compounds known from the above-mentioned US-3,978,045 and DE-2,550,088 when used in equally effective amounts as will be apparent from the description below.

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): C - N - CHoCH_CH 2 CHCO (I) I 2 2 2 | H_N ^ H HNS0o 2 t 2

Ar where R is (1) COOR,: r? (RC) -D m wherein R 9 is hydrogen or -C 1-4 alkyl, each R 6 is hydrogen or C 1 -C 4 alkyl and m is an integer from 0 to 2, wherein R 6 may be in the 4- or 6-position; or

(2) COOH

Ό or 7231 6 3

(3) COOH

-N 0 or

(4) COOH

-N 10 and Ar is a phenyl group substituted with at least one substituent selected from amino, -C 1-6 alkylamino, hydroxyalkyl, C 1-6 C 1-6 phenylalkyl or -C 1-6 hydroxyalkoxy; tax

Ar is a phenyl group substituted with at least one substituent selected from hydroxy, C 1 -C 4 alkyl or C 1 -C 6 alkoxy, and at least one substituent selected from C 2 -C 8 alkylcarbonyl or phenyl; or

Ar is a dibenzothienyl, 9,9-dioxodibenzothienyl, 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 ^ -C ^ alkyl group; 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 -C 6 alkyl, C 1 -C 6 alkoxy or oxo groups; or

Ar is a phenyl group substituted with at least one substituent which is a C1-C4 haloalkoxy or C2-C7 alkoxyalkoxy group and an optionally substituted phenyl group is further substituted with at least one substituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy or halogen.

7231 6

In the formula (1) of the group R, the group R 8 is, for example, hydrogen, methyl, ethyl, propyl, butyl or tert-butyl, and each R 1 is separately, for example, hydrogen, methyl, ethyl, propyl, iso-propyl or butyl.

Typical compounds of formula I include e.g. the following: 1- [N- (quinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, 1- [N- (3-methylquinoline-8-sulfonyl) -L-arginyl] -4 -methyl-2-piperidinecarboxylic acid, 1- [N- (3-ethylquinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, 1- [N- (4-methoxy-3-cyclohexylbenzene) 1-sulfonyl) -L-arginyl--4-methyl-2-piperidinecarboxylic acid, and pharmaceutically acceptable salts of these 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

X.

C - N - CH, CH, CH., CHCOR (XX) ^ I 2 2 2 | HN R "HNSO II II R 'Ar wherein R and Ar are as defined above, R' and R" are hydrogen or a guanidino group protecting group, and at least one of R 'and R "is a guanidino group 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 formula

MJ

X

C - N - CH.CH.CH.CHCOX (XXII)

/ I 2 2 2I

H „N H HNSO-, 2 I 2

Ar

II

7231 6 wherein Ar is as defined above and X is halogen is reacted with an amino acid derivative of formula RH (IV) wherein R is as defined above and, if desired, hydrolyzing the resulting reaction product, and if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt.

In process a) the acid hydrolysis is generally carried out by contacting G-2 N-substituted N -arylsulfonyl-L-argininamide (XX) and an excess of acid, e.g. hydrofluoric, hydrochloric, hydrobromic or trifluoroacetic acid, without solvent or in a solvent such as ether. (tetrahydrofuran, dioxane), alcohol (methanol, ethanol) or acetic acid at a temperature between -10 and 100 ° C, preferably 10-60 ° C, and even more preferably at room temperature for 30 minutes to 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.

Due to the use of excess acid, the products are generally acid addition salts of 2 N -arylsulfonyl-L-argininamides (I) which can be readily 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 ° C. 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 of the 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.

G 2 The starting N-substituted N-arylsulfonyl-L-argininamides (XX) can be prepared as follows: HN.

C - N - CH_CH_CH_CHCOOH (II) -> / I 22 2! H2N h NH2 il 7 7231 6 HN \ + RH (IV) C - N - CH „CH_CH„ CHCOOH (III) I 2 2 2, -> HN '1

I R "HN

I I

R 'R' "HN ^ - N - CH ^ CH ^ CH ^ CHCOR (V) ^ I 2 2 2. -> HN 1 1

I R "HN

I I

R 'R "'

HN

.C - N - CH_CH-CH9CHCO0 (XIX) ArSO? X (VII)

I I

I R ”NH9

R * Z

HN

- N - CH_CHnCH ~ CHCOR (XX) / I 222.

HN 1 1 I R "HNS02 R '1

Ar

In the above formulas, R, Ar, X, R 'and R "are as defined above. When the groups R' and R" are guanidino protecting groups, they are preferably nitro, tosyl, trityl or oxycarbonyl. R "1 is a protecting group for an α-amino group such as benzyloxycarbonyl or tert-butoxycarbonyl.

In the above scheme, L-arginine amides (XX) can be prepared by protecting the guanidino and α-amino groups of L-arginine (II) by nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzylcarbonylation, benzoylation, benzoylation, by butoxycarbonylation or tritylation, and condensation of the G 2 then formed N-substituted N-substituted L-arginine 7231 6 (III) with the corresponding amino acid derivative (IV) using a conventional method such as acid chloride method, azide method and carbide method, mixed anhydride method, mixed anhydride method, then selectively removing only the N-substituent of the N-substituted 2 N-substituted L-argininamide (V) by hydrogenation or acid hydrolysis and then condensing the N-substituted L-argininamide (XIX) thus obtained with the arylsulfonyl halide (VII) , preferably with chloride, base ol as a solvent. Amino acid derivatives (IV),

G

which are starting materials for the preparation of N-substituted N-substituted L-argininamides (V) can be represented by the following formulas:

COOR, COOH

) \ (^ H-N) (X) H-N ^ -O (XII) (R.) b m

COOH

COOH j H-N ^) (XI) Η "θθ <XIII)

In the above formulas, R 1 and m are as defined above.

Of the amino acid derivatives, amino acid tert-butyl ester derivatives are most preferred because they can be easily converted to other ester derivatives by acid hydrolysis in the presence of the corresponding alcohol using an inorganic acid (HCl, SO 2, etc.) or using an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.). According to the process used for the preparation of 2-piperidinecarboxylic acid derivatives (X), the process is described by the following scheme: 11 7231 6 (^ <vmJäa2 £ ^ O-'V .- '08- »1» H Cl (XIV) (XV) (XVI)

^ N ^ CN (H +) ^ N ^ CO, H

', 2

H H

(XVII) (XVIII)

According to the first reaction of the above scheme, the appropriately substituted piperidine (XIV) is contacted with an aqueous solution of sodium hypochlorite at a temperature between -5 and 0 ° C. The product (XV) obtained is isolated by extraction as a solvent, e.g. diethyl ether, and then treated with potassium hydroxide in a lower alkanol solvent to give 1,2-de-7231 6 hydropiperidine (XVI). Under the influence of cyanogenating agents, e.g. hydrogen cyanide or sodium cyanide, 1,2-dehydropropidines (XVI) are converted into the corresponding 2-cyano analogues (XVII). In the hydrolysis of 2-cyanopiperidines (XVII) to give 2-piperidinecarboxylic acids (XVIII), this is done by treating 2-cyanopiperidines (XVII) with an inorganic acid such as hydrochloric acid or sulfuric acid.

The arylsulfonyl halides (VII) which are the starting materials 2 for the preparation of N-arylsulfonyl-L-argininamides (I) can be prepared by halogenation of the corresponding arylsulfonic acids or their salts, e.g. sodium salts, by conventional methods well known to those skilled in the art. .

In practice, the halogenation is carried out without solvent or in a suitable solvent, eg halogenated hydrocarbon ’

or in DMF, a halogenating agent, e.g. phosphorus oxychloride, J

thionyl chloride, phosphorus trichloride, phosphorus tribromide! or in the presence of phosphorus pentachloride at a temperature between -10 and 200 ° C for a period of 5 minutes to 5 hours.

After completion of the reaction, the reaction product is poured into ice water and then extracted with 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-argininamide (I) 2 is prepared by condensing N-arylsulfonyl-L-arginyl halide (XXII), preferably chloride, with at least an equimolar amount of the amino acid derivative (IV).

* i

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 ti 11 7231 6 (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.

2 The starting N-arylsulfonyl-L-arginyl halide (XXII) can be prepared as follows: HNX f - N - CH2CH2CH2CHCOOH (VII) + ArSQ2X ^ H2N NH2 ”

HN. B

X I

C - N - CH2CH2CH2CHCOOH (XXD _> H2N hLo, I 2

Ar HN% f - N_ - CH2CH2CH2CHCOX (XXII) h ~ n ti * λ 2 HNS0o I 2

Ar

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

12 7231 6 2

In the above scheme, N-arylsulfonyl-L-arginine (XXI) can be prepared by condensing 11a L-arginine (II) with a substantially equimolar amount of arylsulfonyl halide (VII) using a method similar to that described for condensing L-argininamide with arylsulfonyl halide.

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, phosphorus oxychloride, phosphorus trichloride, phosphorus trichloride or phosphorus pentacid chloride. The halogenation can be carried out with or without a solvent.

The most preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, methane 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).

The most preferred reaction temperature 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.

It is well known in the art that an ester derivative of N-arylsulfonyl-L-argininamide (I) in which 2

Rg is alkyl can be prepared from a N-arylsulfonyl-L-argininamide derivative wherein Rg is 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 blocking, hydrolysis or acid decomposition can be carried out are known to the person skilled in the art.

tl 2 13 7231 6

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 an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, succinic acid, succinic acid, lactic acid, succinic acid, with ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. 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. 1

As mentioned above, the N-arylsulfonyl-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 are therefore useful as diagnostic reagents in the determination of vascular occlusion or .

7231 6 14

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-coke agent N - (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. The coagulation time was taken to be the time from the transfer to the 25 ° C bath to the time the first fibrin fibers appeared. In those cases where drug samples were not added, the coagulation time was 50-55 sec. The experimental results are shown in Table 1. The term "concentration required to double the coagulation time" is the concentration of the active ingredient required to increase the normal coagulation time, from 50 to 55 seconds, to 100 to 110 seconds.

The concentration required to double the coagulation time using the known anticoagulant N1- (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.

y

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 to 3 hours. The circulating half-life of the anti-thrombotic compounds of the invention was approximately 60 minutes. The physiological 4 * 15 7231 6 physiological conditions of the experimental animals (rats, rabbits, dogs and chimpanzees) 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.

The acute toxicity values (LD ^ q) determined by intravenous administration of the compounds of formula (I) to mice (male-mouse 20 g) are about 150-600 mg / kg body weight.

Typical LD 2 values for the compounds of the invention are shown in the following table.

Compound

HN

X

C - NH - (CH ~) CHCOR

/ 2 3i H2N HNS02Ar LD50 (mg / kg)

With R

CH3 / - \ I - N V- CH_ 270 \ / 3 '

1 COOH

Cl J '"> _V CH3 300

I COOH

Similarly, the following LD50 values were obtained when N-dansyl-L-arginine derivatives disclosed in U.S. Patent No. 3,978,045 were administered intravenously to mice.

16 7231 6

Compound HN.

V

C - NH - (CHO) oCHCO

/ 2 3I

h2n hnso2 / v / ^ l

{JLJ

n (ch3) 2

Compound R LD50 (mg / kg) 2 N-dansyl-L-arginine-O (CH2) 3CH3 60 n-butyl ester 4-methyl-1- (N2-dansyl-N-VCH8 L-arginyl) piperidine -ethyl-1- (N, N-dansyl) -. Ν (Λ-ΟΗ, α, 8 L-arginyl) piperidine (2 - (N2-dansyl-L-arginyl) -0-isoindoline)

The corresponding LD50 values for oral administration of the above compounds are> 6000, 1310, 1375 and 1360 mg / kg, as shown in U.S. Pat. No. 3,978,045, column 13, lines 36-44.

On page 31 of DE-A-2 550 088 it is shown that the LD 2 values determined by oral administration to mice (male mouse 20 g) of N 2 -naphthylsulfonyl-L-arginine derivatives are about 1000-10,000 mg / kg body weight. It should be noted that these LD50 values have been obtained by oral administration of the compounds, so that they are not directly comparable to the LD50 values obtained by intravenous administration of the compounds of the invention to 17,731 6 mice. It is generally accepted that the LD50 value of an orally administered compound is much higher than if the same compound is administered intravenously. In general, the LD50 value of an intravenously administered compound differs from the LD50 value obtained by oral administration by a factor of 100. This means that the LD50 values obtained by oral administration in DE-A-2,550,088 are 1000-10,000 rag. / kg for intravenous dosing correspond to approximately LD 1 -Q values of 10-100 mg / kg.

It is clear from the above that the 2 novel N-arylsulfonyl-L-argininamides according to the invention have substantially lower toxicity than the compounds known from U.S. Pat. No. 3,978,045 and DE Application No. 2,550,088.

It is apparent that the carboxylic acid group attached to the 2-position of a nitrogen-containing ring, such as piperidine, in the compounds of the invention contributes to a surprisingly low toxicity.

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 and the like. The compounds may also be administered sublingually in granular or liquid form, each active ingredient being mixed with sugar and corn syrup. with flavors and colorants and then sufficiently dehydrated to make the mixture suitable for compression into a solid form. 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 as with a lower parenteral dose.

The therapeutic dose is generally 10 to 50 mg / kg of active ingredient parenterally and 10 to 500 mg / kg orally per day.

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

Example 1G2 (A) Ethyl 1- [N-nitro-N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate.

Q

To a well-stirred solution of 2.05 g of ethyl 1- (N-nitro-L-arginyl) -4-methyl-2-piperidinecarboxylate hydrochloride and 1.26 g of NaHCO 3 in 10 ml of water and 40 ml of dioxane, 2.2 g of 3-cyclohexyl-4-methoxybenzenesulfonyl chloride were added portionwise while maintaining the temperature at 0 ° C. The reaction mixture was stirred overnight at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was dissolved in 50 ml of ethyl acetate and the ethyl acetate solution was washed successively with 10% citric acid, saturated NaCl, saturated tl 19 7231 6

NaHCO 3 and saturated NaCl solution. The ethyl acetate solution was evaporated and the residue was chromatographed on silica gel packed in chloroform and eluted with chloroform containing 3% methanol. The main fraction was evaporated to dryness to give 2.6 g of ethyl 1- [G 2 / N-nitro-N- (3-cyclohexyl-4-methoxybenzenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate.

I.R. (KBr): 3400, 1735, 1635, 1250 (cm-1).

(2) Ethyl 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate.

_G 2

To a solution of 2.6 g of ethyl 1- [N-nitro-N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid, 0.5 g of palladium black were added, and then the mixture was shaken under a hydrogen atmosphere for 15 hours at room temperature. The solution was filtered to remove the catalyst and evaporated to give an oily product.

Recrystallization from ethanol-diethyl ether gave 2.4 g of ethyl 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate.

(2) 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid.

_2

A solution of 2.4 g of ethyl 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of 1-n NaOH solution, stirred overnight at room temperature.

The reaction mixture was then concentrated and dissolved in 10 ml of water. The solution was neutralized with 2N HCl to give a white, gummy precipitate which was dissolved in 150 mL of chloroform. The chloroform solution was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.52 g of 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4- methyl-2-piperidinecarboxylic acid as an amorphous solid.

I.R. (KBr): 3350, 2920, 1620, 1250 cm -1.

Analysis - Calculated for C 26 H 41 O 6 N 5 S (%): C, 56.60; H 7.49; N 12.70 Found (%): C 56.51; H 7.53; N 12.68

Example 2 This example provides a general description of how N-arylsulfonyl-L-argininamides of formula I 2 can be prepared by Method b.

2 (A) N- (trisubstituted phenylsulfonyl) -L-arginine.

To a well-stirred solution of 16.7 g of L-arginine in 150 ml of 10% potassium carbonate solution was added 26.1 g of trisubstituted phenylsulfonyl chloride in 150 ml of benzene. The reaction mixture was stirred at 60 ° C for 5 hours at which time the product precipitated. The reaction mixture was allowed to stand for one hour at room temperature, after which the precipitate was filtered off and washed successively with benzene and water to give 31.4 g (81%) of N- (trisubstituted phenylsulfonyl) -L-arginine.

2 (B) N- (trisubstituted phenylsulfonyl) -L-arginyl chloride.

2

A suspension of 3.93 g of N- (trisubstituted phenylsulfonyl) -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 filtered off and washed several times with dry diethyl ether to give N- (trisubstituted phenylsulfonyl) -L-arginyl chloride.

li 2 21 7231 6 (C) Ethyl 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate.

To a stirred solution of 1.7 g of 4-methyl-2-piperidinecarboxylic acid ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt 2 bath, was carefully added the N - (tri - substituted phenylsulfonyl) -L-arginyl chloride. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform were 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-2-ether to give 2.1 g of a powdery ethyl-1 / N- (trisubstituted phenylsulfonyl) -L-arginyl / -4-methyl-2-piperidinecarboxylate.

2- (D) 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid.

_2

A solution of 2.0 g of ethyl 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate in 10 ml of methanol and 10 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 (r) 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 and washed with ethanol / water (1 : 4), eluting with ethanol / water / NH 4 OH (10: 9: 1). The main fraction was evaporated to dryness and washed with ethyl ether to give 1.2 g (69%) of 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid as an amorphous solid.

2

Various other N-arylsulfonyl-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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Claims (4)

A process for the preparation of a pharmaceutically active 2 N -arylsulfonyl-L-argininamide or a pharmaceutically acceptable site thereof, the compound having formula (I): HN. %> C - N - CH.CH ^ CH.CHCOR (I) / · I 2 2 2 [H-N H HNS0o 2 | Ar is where R is (1) COOR- (R c) - 5 m where r 6 is hydrogen or C 1-6 alkyl, each R 5 is hydrogen or C 1-6 alkyl and m is an integer 0-2, where R 1 is. may be in the 4 or 6 position; or (2) COOH or N, - or (3) COOH N> - \ -NO or (4) COOH -00 7231 6 and Ar is a phenyl group substituted by at least one substituent consisting of amino, C alkylamino, C ^-C ^-hydroxyalkyl, C ^-C 0-phenylalkyl or C ^-C ^-hydroxyalkoxy; or Ar is a phenyl group substituted but at least one substituent consisting of hydroxy, C C 1 -C 6 alkoxy, and with at least one substituent consisting of C 1 -C 4 alkylcarbonyl or phenyl; or Ar is a dibenzothienyl, 9,9-dioxodibenzothienyl, phenoxathienyl, 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 2 alkyl groups, or Ar is a C 6 -C 6 cycloalkylphenyl -, fluorenyl, thioxanthenyl or 2H-chromenyl group, each of which is unsubstituted or substituted by one or more C 1 -C 4 -alkyl, C 1 -C-alkoxy-1b or oxo groups; with at least one substituent consisting of a C ^-C ^ haloalkoxy or C₂-C ^ alkoxy alkoxy group, and possibly the substituted phenyl group is further substituted by at least one substituent consisting of methyl, ethyl, methoxy, ethoxy, hydroxy or halogen, characterized in that the a) N-substituent is removed from an N -substituted N - arylsulfonyl-L-argininamide of the formula: HN C - N - CH-CHOCH »CHCOR (XX) I 2 2 2 H H R" HNSO-II 2 R 'is where R and Ar are defined above, R' and R "are hydrogen or a protecting group for the guanidino group, and at least one of the groups R 'and R" is a protecting group for the guanidino group, by acid hydrolysis or hydrogenation and if desired, the reaction product obtained is hydrolyzed, or 2 b) an N -arylsulfonyl-L-arginyl halide of the formula HN C - N - CH 2 CH.CH.CHCOX (XXII) | Z Z Z j H ~ N H HNSO- 2. Process according to claim 1, characterized in that the acid hydrolysis is carried out by contacting the N-2-substituted N -arylsulfonyl-L-arginine amide with an excess of an acid at a temperature between -10 and 100 ° C. Ar is defined above and X is halogen, reacted with an amino acid derivative of the formula RH (IV) wherein R is defined above, and, if desired, the resulting reaction product is hydrolyzed and, if desired, compound of formula I to a pharmaceutically acceptable site. 3. 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. 4. A process according to claim 1, characterized in that the N -arylsulfonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature between -10 and + 80 ° C.