CS236757B2 - Processing of n2-arylsulphonyl-l-argininamide - Google Patents

Description

The invention relates to a process for the preparation of N ² -arylpulfonyl-L-argininamides and pharmaceutically acceptable salts thereof having excellent antithrombotic properties and low toxicity.

Many efforts have been made in the past to obtain new and improved thrombosis treatments. N ² - (p-tolylsulfonyl) -L-arginine esters have been found to be one type of preparation that can be used and are effective in dissolving blood clots (US Patent No. 3,622,615). that particularly useful as a highly effective thrombin inhibitor in the treatment of thrombosis is an ester or amide of N ² -dansyl-L-arginine. (U.S. Pat. No. 3,978 045j. However there is still a need for a highly specific thrombin inhibitor for treating thrombosis, which has a lower toxicity.

It has now been discovered that N ² -arylsulfonyl-L-arginine amides exhibit antithromtootic activity as well as lower toxicity levels at the same relative potency as N ² -dansyl-L-arginine esters or amide.

The present invention provides a process for the preparation of N ² -arylsulfonyl-L-argininamide of formula I

HN

............... \ ...... ...................... ·

O - N - CH 2 CH 2 CH 2 CHCOR / 1.1

HaN H HSO 2

Ar (I) where R is group (1)

Ri /

—N \

CH (CH 2) _n COOR 5

R2 where

R1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinyl-alkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 atoms carbon, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, tetrahydro-4-pyranylmethyl, 2-or-3-pyridylmethyl and phenyl,

R2 is hydrogen or (C1-C10) alkyl;

Ra is hydrogen or alkyl of 1 to 10 carbon atoms, and n is an integer of 0 or 1, (2)

wherein R 1 is -COOR 6 wherein R 6 is hydrogen or alkyl of 1 to 10 carbon atoms, R 5 is hydrogen or alkyl of 1 to 10 carbon atoms and m is an integer of 0 or 2, R 1 is substituted at the 2 or 3 position and R 5 may be substituted at the 2, 3, 4, 5 or 6 position;

(3)

COOH

where p is an integer of 1 or 2, (4)

COOH

or (5)

COOH

and Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyl, C 7 -C 10 phenylalkyl and C 1 -C 10 hydroxyalkoxy , phenyl substituted with at least one hydroxy, C 1 -C 5 alkyl, C 1 -C 10 alkoxy and at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl and phenyl, phenoxyphenyl, dibenzothienyl, 9.9 -dioxodibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolimyl, phenazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted by at least one alkyl group; C 1 -C 10 alkoxy, C 9 -C 16 cycloalkylíenyl, fluorenyl, thioxantenyl or ZH-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10alkyl, C1-C10alkoxy, C2-C10alkoxycarbonyl and oxo groups ,

3-cyclohexyl-4-ethoxycarbonyloxyphenylorphenyl substituted with at least one alkyl, alkoxy, lialogenoalkoxy, alkoxyalkoxy and alkoxycarbonylalkoxy group, said substituents containing from 3 to 7 carbon atoms and said substituted phenyl group further optionally substituted with at least one methyl methoxy, ethoxy, hydroxy and halogen, and pharmaceutically acceptable salts thereof, characterized in that the N ^{1 2} -arylsulfonyl-L-arginyl halide of the formula II is reacted

HN

O - N - CH 2 CH 2 CH 2 CHCOX / III

H2N H HNSO2

Ar (II) wherein Ar is as defined above and X is halogen, with an amino acid derivative of the general Formula III

RH (III) wherein R is as defined above, and optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt, or liberated by reaction of a salt with a base or an acid amide.

Typical compounds obtained by the process of the invention include:

1- [N ² - (quinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

1- [N ² - (3-methylquinoline-8-sulfonyl) -1-argininyl] -4-methyl-2-piperidinecarboxylic acid,

1- [N ^2- (3-ethylquinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, 1- [N ^2- (3-sec-butoxybenzene-1-sulfonyl)] - arinyl] -4-methyl-2-piperidinecarboxylic acid,

1- [N ² - (3,5-dimethyl-4-isopropoxybenzyl, n-1-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid,

1- [N ² - (2,4-dimetlioxy-3-butoxybenzene-1-sulfonyl) -L-arginyl | -4-nitro-2-piperidinecarboxylic acid,

1- (N ² - (3-isopropylaminopropoxy opoxybehzen-l-sulfonyl) -L-arginine ^d hyl] -4-methyl {ethyl-2-piperidinecarboxylic acid,

N ² - (2-phenoxathiinylsulfonyl) -L-arginyl-N-tetrahydrofurfuryl-glycine,

² 2- (2-fluorenesulfonyl) -1-arginyl-N- (2-methoxyethyl) glycine,

1- [N ² - (4-methoxy-3-cyclohexylbenzene-1-sulfonyl) -1-arginyl] -4-methyl-2-piperidinecarbonyl acid, and pharmaceutically acceptable salts of the above compounds.

The condensation of N ² -arylsulfonyl-L-arginyl halide with an amino acid derivative can be shown as follows:

HN 1-1 \ I.

C — N — CH2CH2CH2CHCOOH. / I

H2N NH2 (IV) + ArSO2 (V)

HN Ή

C - N - CH 2 CH 2 CH 2 CHCOOH.1

HzN HNSO2

Ar (VI)

HN H

C-N- CH2CH2CH2CHCOX, I

H2N HNSO2

Ar (II) + RH->

(III)

HN H \ I ........

C — N — CH2CH2CH2CHCOR. / I

H2N HNSO2

Ar (I)

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

N ² -arylsulfinyl-L-argininamide (I) is prepared by condensation of an N ² -arylsulfonyl-L-arginyl halide of formula II, preferably chloride, with at least a maximum amount of an amino acid derivative of formula III,

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

The amount of solvent used is not critical and may range from 5 to 100 times the weight of the N ² -arylsulfonyl-L-arginyl halide of formula II.

The preferred reaction temperature is in the range of -10 to 80 ° C and preferably 20 to 50 ° C. The reaction time is not critical but varies according to the amino acid derivative of formula III used. Generally, the reaction time is from 5 minutes to 10 hours.

The resulting N ² -arylsulfonyl-L-argininamide can be isolated and purified by trituration or recrystallization from a suitable solvent such as a mixture of diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol, or chromatographed on silica gel.

N ² -arylsulfonyl-L-arginyl halide of formula II, the starting material required for the condensation reaction, can be prepared by reacting N ² -arylsulfonyl-L-arginine of formula VI with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide. The halogenation may be carried out with or without a solvent.

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 may range from 5 to 100 times the weight of N ² -arylsulfonyl-L-arginine of formula VI.

The preferred reaction temperature is between -10 ^DEG C. to room temperature. The reaction time is not critical but varies with the halogenating agent and the reaction temperature. Generally, the reaction time is in the range of 15 minutes to 5 hours.

The N ² -arylsulfonyl-L-arginines of formula VI, which are starting materials for the preparation of the N ² -arylsulfonyl-L-arginyl halide of formula II, can be prepared by condensation of L-arginine of formula IV with substantially equimolar amounts of arylsulfonyl halide of formula V.

The coupling reaction is generally carried out in a suitable inert solvent in the presence of an excess of a base such as an organic base (triethylamine, pyridine) or an inorganic base solution (sodium hydroxide, potassium carbonate) at 0 ° C - the boiling point of the solvent for 10 minutes to 15 hours. Preferred condensation solvents include mixtures of benzene-diethyl ether, diethyl ether-water and dioxane-water.

It is well known in the literature that the N ² -arylsulfonyl-L-argininamide ester derivative (I) wherein R 2, R 5, R 5, R 9, R 10 or R 11 is alkyl, aralkyl or aryl can be prepared from the carboxylic acid derivative N ² - The arylsulfones of < 11 > ^L -argininamide, wherein R < ^{21 &} gt ;, R < 5 >, R < 8 > It is also well known that a carboxylic acid derivative can be prepared from an ester by conventional hydrolysis or acid hydrolysis. The conditions under which esterification, hydrolysis or acid hydrolysis would be carried out are given in the literature.

The arylsulfonyl halides of formula V, which are starting materials for the preparation of the N ² -arylsulfonyl-L-argininamides of formula I, can be prepared by halogenation of the desired arylsulfonic acids or their salts, for example sodium salts, by conventional methods known in the literature.

In practice, the halogenation is carried out without a solvent or in a suitable solvent, for example halogenated hydrocarbons or dimethylformamide, in the presence of a halogenating agent, for example phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus trichloride, at a temperature of -10 ° ^C to 200 ^° C. 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 or the like.

The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, benzene or the like. The N ² -arylsulfonyl-L-argininamide of the formula I obtained by the process according to the invention forms addition salts with various inorganic or organic acids. Some N ² -arylsulfonyl-L-argininamides containing a free carboxyl group wherein R 2, R 5, R 6, R 9, R 10 or R 11 is hydrogen form salts with various inorganic or organic bases.

The product prepared according to the above reactions can be isolated in free form or in salt form. Further, the product can be obtained as a pharmaceutically acceptable acid addition salt by reacting the free base with an acid such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic acid. , ethanesulfonic, benzenesulfonic, p-toluenesulfonic or the like. In the same way, the product as a pharmaceutically acceptable salt can be obtained by reacting the free carboxylic acid with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-efenamine, N-N‘-dibenzylethylenediamine, N-ethylpiperidine or the like.

Similarly, the reaction of salts with a base or acid regenerates the free amide.

As mentioned previously, N ² -arylsulfonyl-L-arginine amides and their salts obtained by the process of the invention have a highly specific thrombin inhibitory effect in mammals and a substantially lower toxicity, and therefore these compounds are useful as diagnostic reagents for the determination of thrombin in blood and / or as medicaments for treating or preventing thrombosis.

The compounds obtained by this method of the invention are also useful as platelet aggregation inhibitors.

The antithrombotic effect of N ² -arylsulfonyl-L-argininamide obtained by the process of the invention was compared with the effect of the known N ² - (p-tolylsulfonyl) -L-arginine methyl ester ammonium compound by determining the coagulation time of fibrinogen. The fibrinogen coagulation time was measured as follows:

A 0.8 ml aliquot of a fibrinogen solution prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Arrnour Inc, in 40 ml of borate buffer (pH 7.4J) is mixed with 0.1 ml of borate buffer, pH 7.4 (control) or sample solution in the same buffer and 0.1 ml of thrombin solution (5 units / ml) supplied by Mochida Pharmaceutical Co., Ltd., Japan are added to the ice bath solution.

Immediately after mixing, the mixture was transferred from an ice bath to a bath maintained at 25 ° C. The coagulation time is determined as the period between the time of transfer to a bath of 25 ° C and the time of the first appearance of fibrin fibers. In cases where no samples of the active substance are added, the coagulation time is 50 to 55 se10 kunds. The experimental results are shown in Table 1. The term "concentration required to increase the coagulation time by a factor of 2" is the concentration of active agent required to extend the normal coagulation time from 50 to 55 seconds to 100 to 110 seconds.

The concentration required to increase the coagulation time by a factor of two for the known antithrombotic N ² - (p-tolylsulphonyl) -L-arginine methyl ester was 1,100 μία Inhibitors are listed in Table 1 of indications R and Ar in formula I and other groups .

When an intravenous solution containing N ² -arylsulfonyl-L-argininamide obtained by the method of the invention is administered to animals, a high antithrombotic effect in the bloodstream is maintained for 1-3 hours. The half-life for the antithromotic compounds obtained by the method of the invention in the blood content has been shown to be approximately 60 minutes; the physiological conditions of the hosts (rats, rabbit, dog and chimpanzee) are well maintained. The experimental reduction of fibrinogen in animals caused by thrombin infusion is satisfactorily controlled by the simultaneous infusion of the compounds of the invention.

The acute toxicity (LD 50) values determined by intravenous administration of the compounds of formula I in mice (male / 20 g) range from 150 to 600 milligrams per kilogram of body weight.

Selected LD 50 values for some of the compounds obtained by the process of the invention are shown in the following table.

Compound

HN

C — NH— (CH2ZCHCOR LD50 (mg / kg)

HzN HNSChAr

COOH

In contrast, the LD 50 values for N ² -dansyl-N-butyl-L-argininamide and N ² -dansyl-N-methyl-N-butyl-L-arglninamide are less than 10 milligrams per kilogram.

The therapeutic compositions of the invention may be administered to mammals, including humans, alone or in combination with pharmaceutically acceptable carriers, the amount of which is determined by the solubility and chemical nature of the compound, the route of administration and standard pharmaceutical practice.

For example, the compounds may be administered by injection, paremterally, i.e., intramuscularly, intravenously, or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutions, for example, sufficient saline or glucose to render the solution isotomous. The compounds may be administered orally in the form of tablets, capsules or granules containing suitable carriers such as starch, lactose, white sugar, and the like. The compounds may be administered in the form of lozenges in suhlingal form, in which then it is sufficiently dehydrated to obtain a mixture suitable for compression into a solid form. The compounds may be administered orally in the form of solutions which may contain coloring or flavoring agents. The dose of the therapeutic composition that would be more inhospitable to humans is determined by the physician and will vary with the route of administration and the particular compound selected. In addition, the dose depends on the patient's condition.

For oral administration of the composition, more active ingredient is required to achieve the same effect as that achieved with less parenterally.

The therapeutic dose per day is 10 to 50 mg / kg for parenteral administration, 10 to 500 mg / kg for oral administration.

The following examples illustrate the invention.

Example 1

A. N ^2- (2-Dibenzothienylsulfonyl) -L-arginine

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

Β. N ² - (2-dibeinzothienylsulfonyl) -L-arginyl chloride

A suspension of 4.21 g of N ² - (2-benzothienylsulfonyl) -L-arginine in 20 ml of thionyl chloride was stirred at room temperature for 2 hours. Addition of cold dry diethyl ether gives a precipitate which is filtered off and washed several times with dry diethyl ether to give N ² - (2-dibenzothienylsulfonyl) -L-arginyl chloride.

C. N ² - (2-Dibenzothienylsulfonyl) -1-arginyl-N-butylglycine tert-butyl ester

To a stirred solution of 2.67 g of N-butylglycine tert-butyl ester in 20 ml of chloroform was carefully added the above-obtained N ² - (2-dibenzothienylsulfonyl) -L-arginyl chloride. The reaction mixture was allowed to stand for 1 hour at room temperature.

At the end of this time, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness.

The residue is eluted in a small amount of diethyl ether to give an amorphous substance. This was filtered and reprecipitated from ethanol-ethyl ether to give 3.1 g (49%) of N- ^2- (2-dibenzothienylsulfonyl) -L-arginyl-N-butylglycine-tert-butyl ester.

Infrared spectrum (KBr):

3350, 1740, 1625 ^cm-first

Analysis for G28H39O5N5S2.1 / 2 H2SO3

238757 calculated:

H, 6.39; N, 11.10. Found:

% C, 53.21;% H, 6.46;% N / 10.89.

D. N ² - (2-Dibenzothienylsulfonyl) -L-arginyl-N-butylglycine

To a solution of 2.00 g of N- ^2- (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 at room temperature for 5 hours. At the end of this time, the reaction mixture was evaporated to dryness. The residue is washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion ^(K) SK 102 ion exchange resin ⁽ 200-300 mesh, H ⁺ form, manufactured by Mitsubishi Chemical Industries Limited) filled with water, washed with water and eluted with 3% hydroxide solution. ammonium.

The fraction eluted with 3% ammonium hydroxide solution was evaporated to dryness to give 0.9 g (53% of N ² - (2-dibenzothiemylsulfonyl) -L-arginyl-N-butylglycine as amorphous).

Infrared spectrum (KBr):

3350, 1640, 1270 ^cm-first

Analysis for C 24 H 31 N 5 O 5 S 2 calculated:

% C, 54.01;% H, 5.86;% N, 13.12.

% C, 53.78;% H, 5.97;

Example 2

A. N ^2- (2-Dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) 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 7.0 grams of the above N ' ² - ( The reaction mixture is stirred overnight at room temperature, at which time 50 ml of chloroform are added and the chloroform solution is washed twice with 14 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and dried in anhydrous sodium sulphate. The oily residue was washed with ethyl ether to give 5.5 g of powdery N ² - (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine ethyl ester.

Calcd for C25H23O6N5S2.1 / 2 H2SO3:

H, 4.07%, N 11.78%, found:

H, 4.18; N, 11.51.

B. N ² - (2-Dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine

A solution of 5.5 g of N ² - (2-dibenzothienylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine-ethyl ester in 1/5 ml of methanol and 15 ml of 2 N sodium hydroxide solution is heated to 40 " C and held at this temperature for 10 hours. At the end of this time, the reaction mixture was concentrated and chromatographed on 200 ml Daiaion ^(R) SK 102 ion exchange resin ⁽ 200-300 mesh) (H ⁺ form, manufactured by Mitsubishi Chemical Industries Limited) filled with 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 N- ^2- (2-dibenzothienylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as an amorphous substance.

Infrared spectrum (KBr):

3400, 1630, 1280 ^cm-first

Analysis for C23H29O6N5S2 calculated:

51.57 ° C, 5.46 θ / ο H, 13.08% N, found *

% H, 5.63;% N, 12.86.

Various other N ² -arylsulfonyl-L-arginine amides or acid addition salts thereof were prepared according to the procedures described in the previous examples and the results are shown in Table 1.

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ArSO2Cl or ArSO3H Starting material HN Product or salt Amino acid ester \ (literary reference) C — NH— (CH2) 3CHCOR

Ber., 86, 951 (1953).

J. Chem. Eng. Data 12,610 (1967)

Ex. (2)

ArSOžCl or ArSO3H Starting material HN Product or salt Amino acid ester \ (literary reference) C — NH— (CH2) 3CHCOR

ArSOaCl or ArSCUH Starting material HN Product or salt Amino acid ester \ (literary reference) C — NH— (CH2) 3CHCOR

J. Am. Chem. Soc., 57, 1533 (1935).

238757

Example 3

PREPARATION

Tablets suitable for oral administration

Tablets containing the ingredients listed below may be prepared in conventional manner.

Ingredient Quantity per tablet (mg)

N ^2- (3-cyclohexyl-4-methoxy- 250 ’ phenylsulfonyl-L-arginyl-N-butylglycine lactose 140 cornstarch 35 talc 20 May magnesium stearate 5 total 450 mg Example 4 Capsules for oral administration The capsules of the composition below are made by thoroughly mixing the ingredients and filling hard gelatin capsules mixtures. Component Quantity per capsule (mg) N ^2- (3-cyclohexyl-4-methoxy- 25.0 phenylsulfonyl) -L-arginyl-N-butylglycine lactose 250 total 500 mg Example 5 Sterile solution for infusion The following components are dissolved in water for intravenous perfusion and the resulting solution is then sterilized. Folders Amount (G) N- ^2- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl- -N-butylglycine 25 buffer system according to requirement glucose 25 Distilled water 500

Arylsulfonyl chlorides

A. Sodium 3-butoxy-2,4-dimethoxybenzenesulfone

To a well stirred solution of 50.8 g of 2-butoxy-1,3-dimethoxybenzene in 160 ml of carbon tetrachloride was added 16.1 ml of chlorosulfonic acid dropwise at 0-4 ° C. The reaction mixture was stirred at room temperature for 1 hour, poured onto crushed ice and then diluted to 300 mL with water.

After evaporation of the carbon tetrachloride, the resulting aqueous layer was extracted with ether and then neutralized with 2N sodium hydroxide solution and white crystals precipitated, which were filtered off and dried, yielding 63.3 g (85.1 (%)) of 3-butoxy-2, Sodium 4-dimethoxybenzenesulfonate.

B. 3-Ibutoxy-2,4-dimethoxyhenzenesulfonyl chloride

To a stirred suspension of 60.0 g of dry, powdered sodium 3-butoxy-2,4-dimethoxybenzenesulfonate in 150 ml of dry dimethylformamide was added dropwise 69 ml of thionyl chloride over 20 minutes at room temperature.

The reaction mixture was stirred for 15 minutes and gradually poured into 1,000 mL of ice water and stirred vigorously. After 1 hour, the aqueous layer was decanted and the residual oil was extracted with benzene, washed with water, dried over anhydrous sodium sulfate, distilled to remove the solvent and then distilled in vacuo to give 47.5 g (80.1%). butoxy-2,4-dimethoxybenzenesulfonyl chloride (mp 154-155 ° C / 133 Pa).

Analysis calculated for: C12H15ClO5S:

46.68 ° C, 5.56% H, found ¹ :

% C, 46.71;% H, 5.60.

The following arylsulfonyl chlorides, not yet reported in the chemical literature, were prepared as described above.

Boiling point (melting point)

_Ar-SO2 C1

165 to 106 ° C / 1330 Pa (57.5 to 58.5 ° C)

112 to 115 ° C / 133 Pa (33 to 35 ° C)

127 DEG-129 DEG C./0.6 mbar

148-150 ° C / 133 Pa

143-145 C / 133 Pa (48-51 ° C)

(41 to 42 ° C)

139-140 ° C / 133 Pa

129.5-132 ° C / 133 Pa

145-148 ^and C / 133 Pa

151.5 to 153.5 ^C C / 199.5 Pa

Boiling point (melting point)

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Ar

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210 to 220 ° C / 133 Pa

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160-102 ° C / 266 Pa

154-155 ° C / 133 Pa

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111-116 ° C / 133 Pa

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Ar

Number

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133-134 ° C / 133 Pa

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121-122 ^C C / 133 mm Hg

133-135 ° C / 133 Pa

136 to 139 C / 133 Pa (95 to 96 ° C)

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Claims (10)

OBJECT OF THE INVENTION 1,2,3,4-tetrahydroquinolinyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkyl and C 1 -C 10 alkoxy, C 9 -C 16 cycloalkylphenyl group carbon, fluoroinyl, thioxantenyl or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10alkyl, C1-C10alkoxy, C2-C10alkoxycarbonyl and oxo, A process for the preparation of N ² -arylsulfonyl-L-argi- wherein R is a group of ninamides of the general formula I (1) HN \ / Q — N — CH2CH2CH2CHCOR - N / 11 \ H2N H HNSO2 Ar Boiling point (melting point) (101-103 ° C) 142-144 ° C / 133 Pa (50-51Cl) 158-160 ° C / 133 Pa 159-160 ° C / 133 Pa 151-152 ^Q C / 133 Pa 158-159 ° C / 133 Pa Ri OH (CH 2) _n COOR 3 R2 (I) 2. The process of claim 1, wherein the N ² -arylsulfonyl-L-argyl halide of formula II is reacted with at least an equimolar amount of an amino acid derivative of formula III at a temperature in the range of -10 ° C to + 80 ° C. 2 3 Β 7 5 7 where R1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl (C 3 -C 10) cycloalkylalkyl (C 4 -C 10) cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-4-pyranylmethyl, 2-or-3-pyridylmethyl and phenyl, R 8 is hydrogen or C 1 -C 10 alkyl, R3 is hydrogen or alkyl of 1 to 10 carbon atoms, n is an integer 0 or 1, (2) wherein R / is -COOR _f, wherein _R is hydrogen or alkyl having 1 to 10 carbon atoms, ·, R is hydrogen or alkyl of 1 to 10 carbon atoms and m is an integer of 0 or 2, R 1 is substituted at the 2 or 3 position and R 5 may be at the 2, 3, 4, 5 or 6 position, (3) wherein p is an integer of 1 or 2, (4) COOH or (5) COOH and Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl, C 7 -C 10 phenylalkyl and C 1 -C 10 hydroxyalkoxy phenyl, substituted with at least one hydroxy, C 1 -C 5 alkyl, C 1 -C 10 alkoxy and at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl and phenyl, phenoxyphenyl, dibenzothienyl, 9, 9-dioxodibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl, phthalazinyl, 3. A process according to claim 1, wherein the N ² -arylsulfonyl-L-arginyl halide of the formula II is reacted. HN \ G — N — CH2CH2CH2CHCOX Z I I H2N H HNSO2 Ar (II) wherein Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl and phenyl, phenyl substituted with at least one hydroxy, C 1 alkyl C 1 -C 10 alkoxy having at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl , phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl, or fluorenyl, thioxanthenyl or 2H- a chromenyl group, any of which is unsubstituted or substituted by at least one hydroxy group, an alkyl of 1 to 10 carbon atoms u, C 1 -C 10 alkoxy, C 2 -C 10 alkoxycarbonyl and oxo, and X is halogen, with an amino acid derivative of the general formula III RH (III) wherein R is Ri Z —N \ CH (CH 2) n COOR 3 R 2 wherein R 1 is C 2 -C 10 alkyl, C 2 -C 10 alkoxy, C 2 -C 10 alkylthioalkyl, C 2 -C 10 alkylsulfinylalkyl, C 7 -C 15 aralkyl, C 3 -C 10 cycloalkyl C 4 -C 10 cycloalkylalkyl, R 21 is hydrogen or alkyl of 1 to 5 carbon atoms, R 5 is hydrogen or C 1 -C 10 alkyl, n is 0 or 1, and optionally the above reaction product is converted by treatment with an inorganic or organic acid into a pharmaceutically acid addition salt or is liberated by reaction of a salt with a base or an acid amide. 3-cyclohexyl-4-ethoxycarbonyloxyphenyl or phenyl substituted with at least one alkyl, alkoxy, haloalkoxy, alkoxyalkoxy and alkoxycarbonylalkoxy group, said substituents having from 3 to 7 carbon atoms and said substituted phenyl group being further optionally substituted with at least one methyl, ethyl, ethoxy, hydroxy and halogen, and pharmaceutically acceptable salts thereof, characterized in that N ² -arylsulfomyl-L-arginyl halide of formula II is reacted HN \ G - N - CH 2 CH 2 GH 2 CHCOX / III HeN H HNSO 2 Ar (II) wherein Ar is as defined above and X is halogen, with an amino acid derivative of the general Formula III RH (III) wherein R is as defined above, and, optionally, the reaction product obtained above is converted by treatment with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or is liberated by reaction of a salt with a base or an acid amide. 4. Process according to claim 1 or 2, characterized in that the N ² -arylsulfonyl-L-arginyl halide of the formula II is reacted. HN G - N - CH 2 C H 2 CH 2 CHCOX Z I I 11.N H HNSO2 Ar (II) wherein Ar is phenoxyphenyl, dibenzothienyl, phenoxathiinyl, ind-indazolyl, quinolyl, phenazinyl, chloroxalinyl, phthalazinyl or acridinyl, any of which is unsubstituted or substituted with at least one hydroxy, C 1 -C 10 alkoxy group And X is halogen, with an amino acid derivative of the general formula III RH (III) where R is group (1) COOH and optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or liberated by reaction of a salt with a base or an acid amide. 5. Process according to 1 or 2, characterized in that the N ² -arylsulfonyl-L-arginyl halide of the formula II is reacted. HN Cl - N - CH2CH2CH2CHCOX Z I I H ₂ NH HNSO ₂ Ar (II) wherein Ar is a phenoxyphenyl, dibenzothienyl, phenoxathiinyl, ind-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydro236757 quinolyl or acridinyl group, at least one of which is unsubstituted or substituted; hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl, or fluorenyl, thioxanthenyl or 2H-chromenyl, any of which is unsubstituted or substituted with at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkyl up to 10 carbon atoms, alkoxycarbonyl of 2 to 10 carbon atoms and oxo, and X is halogen, with an amino acid derivative of the general formula III R 1 -I (III) wherein R is wherein R 1 is -COOR 5 wherein R 6 is hydrogen or alkyl of 1 to 10 carbon atoms, R 5 is hydrogen or alkyl of 1 to 10 carbon atoms and m is 1 or 2, R 6 is substituted at the 2 or 3 position and R 5 may be substituted at the 2, 3, 4, 5 or 6 position, and optionally the reaction product obtained above is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or a. is liberated by reaction of the salt with a base or an acid amide. 6. A process according to claim 1, wherein the N ² -arylsulfonyl-L-arginyl halide of the formula II is reacted. HN \ C, - N - C FLCH 2 CH from C HCOX / I HM H HNSO 2 Ar (II) wherein Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl and phenyl, phenyl substituted with at least one hydroxy, C 1 -C 10 alkyl C 1 -C 5 and C 1 -C 10 alkoxy with at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, indolinyl, phenolinyl , quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl or fluorenyl, thioxanthenyl or a 2H-chromenyl group, any of which is unsubstituted and substituted with at least one hydrox C1-C10alkyl, C1-C10alkoxy, C2-C10alkoxycarbonyl and oxo, and X is halogen, with an amino acid derivative of formula III RI-I (III) where R is group (1) Ri / —N \ CH (CH 2) n COOR 3 R2 wherein R1 is tetrahydrofurfuryl or tetrahydro-4-pyranylmethyl, R2 is alkyl of 1 to 10 carbon atoms, R 5 is hydrogen or alkyl of 1 to 10 carbon atoms, n is 0 or 1, and cgghy-x And wherein optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or liberated by reaction of a salt with a base or an acid amide. 7. A process according to claim 1, wherein the N ² -arylsulfonyl-L-arginine halide of formula II is reacted. HN N c n -cHrCl 2: ghgox / III 11. \ H HNSO,.; AND Ar (Π) wherein Ar is a phenyl group substituted with at least one amino, C 1 -C 10 alkylamino, acylamino. (C 1 -C 10) alkyl, (C 1 -C 10) hydroxyalkyl and phenyl, phenyl substituted with at least one hydroxy, (C 1 -C 5) alkyl, and (C 1 -C 10) alkoxy (at least one C 7 -C 12 aralkyl) carbon, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, femazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or any unsubstituted n-alkyl, or acridinyl group or substituted with at least one hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl, or C 9 -C 16 cycloalkylphenyl, fluorenyl, thioxanthenyl or 2H-chromenyl, any of which is unsubstituted or substituted with at least one hydroxy group, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 and carbon atom, C 2 -C 10 alkoxycarbonyl and oxo, and X is halogen, with an amino acid derivative of the general formula III RH (III) wherein R is Ri / —N \ CH (CH 2) _n COOR 3 R 2 wherein R 1 is C 2 -C 10 alkyl, C 2 -C 10 alkoxyalkyl, C 2 -C 10 alkylthioalkyl, C 2 -C 10 alkylsulfinylalkyl, C 7 -C 15 aralkyl, C 3 -C 3 cycloalkyl C 10, C 4 -C 10 cycloalkylalkyl and phenyl, R 2 is alkyl of 1 to 5 'carbon atoms, R 3 is hydrogen or alkyl of 1 to 10 carbon atoms, and n is 0 or 1, and optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or is liberated by reaction of a salt with a base; · Acid amide. θ. 1. A process according to claim 1, wherein the N ² -arylsulfonyl-L-arginyl halide of formula II is reacted. HN G - N - CH 2 CH 2 CH 2 CHCOX 1; H2N H HNSO2 Ar (Π) wherein Ar is phenyl substituted with at least one amino, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl and phenyl, phenazinyl, quinoxalinyl, phthalazinyloxathiinyl, 1H-indazolyl, 1H-indazolyl, 1H-indazolyl quinolyl, phenazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted with at least one hydroxy, C 1 -C 10 alkoxy and C 1 -C 10 alkyl, cycloalkylphenyl C až-C 16 fluor, fluorenyl, thioxanthenyl or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C až-C alky alkyl, C až-C alko alkoxy, C až-C alko alkoxycarbonyl and X is halogen, with an amino acid derivative of the general formula III RH (III) where R is group (1) Ri / —N \ CH (CH 2) _n COOR 3 R2 wherein R1 is furfuryl and tetrahydrofurfuryl, R2 is hydrogen or alkyl of 1 to 10 carbon atoms, R 3 is hydrogen or C 1 -C 10 alkyl, and n is 0 or 1, (2) COOH 235757 and optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or is liberated by reaction of a salt with a base or an acid amide. 9. A process according to claim 1 or 2, wherein N ² -arylsulfonyl-L-arginyl halide of formula II is reacted. HN \ C - N - CH 2 Cl 2 .CH 2 CHCOX Z I I I-hN H HSO 2 Ar (Π) wherein Ar is phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, chimoxalinyl, phthal azinyl or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy group having 1 to 10 hydroxyl, and C 1 -C 10 alkyl, or C 9 -C 16 cycloalkylphemyl, fluorophenyl, thioxanthenyl or 2H-chromenyloyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkyl, C 1 alkoxy up to 10 carbon atoms, an alkoxycarbonyl of 2 to 10 carbon atoms and an oxo group, and X is halogen, with an amino acid derivative of the general formula III R H (III) wherein R is wherein R 4 is -COOR 6 wherein R 8 is hydrogen or alkyl of 1 to 10 carbon atoms, R 5 is hydrogen or alkyl of 1 to 10 carbon atoms and m is 1 or 2, Rd is substituted at the position 2 or 3 and R 5 may be substituted at the 2,3,4,5- or 6 position, and optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or is liberated by reaction of a salt with a base or acid amide. 10. A process according to claim 1, wherein the N ² -arylsulfonyl-L-arginyl halide of formula II is reacted. HN \ C — N — CH2CH2CH2CHCOX H2N H HNSO2 Ar (II) wherein Ar is phenyl substituted with at least one alkyl, alkoxy, haloalkoxy, alkoxyalkoxy, and alkoxycarbonylalkoxy group, said substituents containing from 3 to 7 carbon atoms and said substituted phenyl group optionally optionally substituted with at least one methyl, ethyl, methoxy, ethoxy hydroxy and halogen, and X is halogen, with an amino acid derivative of formula III RH (III) where R is group (1) Ri Z —N \ CH 1 (CH 2) n COOR ₅ wherein R 1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, -alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 4 to 10 carbon atoms, furfury-1, tetrahydrofurfuryl and tetrahydro-4-pyranylmethyl, (2) wherein R 4 is -COOR 6, where R e is hydrogen or alkyl of 1; up to 10 carbon atoms, R 5 is hydrogen or alkyl of 1 to 10 carbon atoms and m is 1 or 2, R 4 is substituted at the 2-position or o-3 and R 5 may be substituted at the 2,3,4,5-position or 6 (3) where p is the number 1 or 2, (4) COOH 236737 and (5) Severography, n. P., Plant 7, Most and optionally the above reaction product is converted by reaction with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt or liberated by reaction of a salt with a base or an acid amide. Price 2,40 KSs