CS236773B2 - Process for preparing N2-arylsulfonyl-L-arginine amides i - Google Patents

Abstract

A process for the preparation of N2-arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts, which have been found to be effective pharmaceutical agents for the inhibition and treatment of thrombosis in mammals.

Description

The invention relates to a process for the preparation of N ² -arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts, which have excellent antithrombotic properties and low toxicity.

In the past, much effort has been made to obtain new and improved preparations for the treatment of thrombosis. It has been found that N ² -(p-tolyl-sulfonyl)-L-arginine esters are one type of preparation that can be used and are effective in dissolving blood clots. (U.S. Patent No. 3,622,615.) It has been found that a particularly useful highly effective thrombin inhibitor in the treatment of thrombosis is an N ² -'dansyl-L-arginine ester or amide. (U.S. Patent No. 3,978,045.) However, there remains a need for a highly specific thrombin inhibitor for the treatment of thrombosis that has lower toxicity.

It has now been discovered that N ² -arylsulfonyl-L-arginine amides exhibit antithrombotic activity and also a lower level of toxicity at the same relative potency compared to N ² -dansyl-L-arginine ester or amide.

The subject of the invention is a method for preparing N ² -arylsulfonyl-L-arginine amides of the general formula I “ HN

C—N—CH2CH2CH2CHCOR / I I

HaN H HNSO2 (I)

AND

Ar where R is a group (1)

R /

—Ν \

CH(CH2) _n COOR3

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, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, tetrahydro-4-pyranylmethyl, 2- or 3-pyridylmethyl and phenyl,

R2 is hydrogen or alkyl of 1 to 10 carbon atoms,

R3 is hydrogen or alkyl of 1 to 10 carbon atoms, and n is an integer of 0 or 1, (2)

where

R4 is —COOR6, where R6 is hydrogen or alkyl of 1 to 10 carbon atoms, Rs is hydrogen or alkyl of 1 to 10 carbon atoms and m is an integer of 0 or 2, R4 is in position 2 or 3 and Rs can be in position 2, 3, 4, 5 or 6, (3)

where p is an integer 1 npbo 2, (4)

CO0H

-N O \__v or (5)

and Ar is phenyl substituted with at least one amino group, alkylamino group with 1 to 10 carbon atoms, acylamino group with 1 to 10 carbon atoms, hydroxyalkyl group with 1 to 10 carbon atoms, phenylalkyl group with 7 to 10 carbon atoms and hydroxyalkoxy group with 1 to 10 carbon atoms, phenyl substituted with at least one hydroxy group, alkyl with 1 to 6 carbon atoms and alkoxy group with 1 to 10 carbon atoms and at least one aralkyl with 7 to 12 carbon atoms, alkylcarbonyl with 2 to 6 carbon atoms and phenyl, phenoxyphenyl, dibenzothienyl, 9,9-dioxobenzothienyl, phenoxathienyl, ΙΗ-indazolyl, quinolyl, indolinyl, phenazinyl, chloroxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl group, any of which is unsubstituted or substituted by at least one hydroxy group, alkyl with 1 to 10 carbon atoms and alkoxy group with 1 to 10 carbon atoms, cycloalkylphenyl group with 9 to 16 carbon atoms, fluorenyl, thioxanthenyl or 2H-chromenyl group, any of which is unsubstituted or substituted by at least one hydroxy group, alkyl with 1 to 10 carbon atoms, alkoxy group with 1 to 10 carbon atoms, alkoxycarbonyl with 2 to 10 carbon atoms and oxo group, 3-cyclohexyl-4-ethoxycarbonyloxy-phenyl, or phenyl group substituted by at least one alkyl, alkoxy group, haloalkoxy group, alkoxyalkoxy group and an alkoxycarbonylalkoxy group, said substituents containing 3 to 7 carbon atoms and said substituted phenyl group is further optionally substituted with at least one methyl, ethyl, methoxy, ethoxy, hydroxy and halogen, and pharmaceutically acceptable salts, characterized in that L-argininamide of general formula II is reacted

HN

C—N—CH2CH2CH2—CHCOR (II)

HzN Η NH2 where

R has the meaning given above, with an arylsulfonyl halide of general formula III

ArSOzX(III) where

Ar has the above meaning and X is halogen, 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 is liberated by reaction of the salt with a base or acid amide.

Typical compounds of the invention include:

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

1-[ N ² -(3-methylquinoline-8-sulfonyl j -L-arginyl]-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)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid

1-[N ^{1 2} -(3,5-dimethyl-4-isopropoxybenzene-1-sulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid

1-[N ² -(2,4-dimethoxy-3-hydroxybenzene-1-sulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid

1-[N ² - (3-isopropoxybenzene-1-sulfonyl) -L-arginyl]-4-methyl-2-piperidinecarboxylic acid

N ² -(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

N ² -(2-fluorosulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine

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

The following scheme shows the inventive condensation of L-argininamide with an arylsulfonyl halide and the precursors for the preparation of L-argininamide.

HN

C—N—CH2CH2CH2CHCOOH /1 I

HžN H NHz (IV) ->

HN

IN

C—N—CH2CH2CH2CHCOOH / I I

HN R' HN

R' R"' (V) + RH (VI) HN

C—N—CH2CH2CH2CHCOR / I I

HN R" HN

R' R"' (VII)

HN

C—N—CH2CH2CH2CHCOR / I I

HzN Η NH2 (II)

23B773

+ ArSOzX (III) - in the N ^G -substituted-N ² -substituted-L-argininamide of general formula VII, are expressed by the following general formulas: N—CH2CH2CH2CHCOR / I I Ri / Η—N (VIII) H HNSO2 Ar (I) \ (CH2) _n COOR ₂

R3 (IX)

In the above formulas, R and Ar are as previously defined; X is halogen; R"' is a protecting group for the -amino group, such as benzyloxycarbonyl or tert-butoxycarbonyl; R' and R" are hydrogen and protecting groups for the guanidino group, such as nitro, tolyl, trityl, oxycarbonyl, etc.; and at least one of the substituents R' and R" is a protecting group for the guanidino group.

The N ² -Arylsulfonyl-L-argininamide of the general formula I is prepared by condensing the L-argininamide of the general formula II with an equimolar amount of the arylsulfonyl halide of the general formula III, preferably the chloride.

The condensation reaction is generally carried out in a suitable inert solvent in the presence of an excess of base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate) at a temperature ranging from 0 °C to the boiling point of the solvent for 10 minutes to 15 hours.

Preferred solvents for condensation are benzene diethyl ether, diethyl ether water and dioxane water.

After the reaction is complete, the salt formed is extracted with water and the solvent is removed by standard methods such as evaporation under reduced pressure to yield N ² -arylsulfonyl-L-argininamide I, which can be purified by precipitation or recrystallization from a suitable solvent such as diethyl ether tetrahydrofuran, diethyl ether-methanol and water-methanol mixtures, or it can be chromatographed on silica gel.

L-Argininamides of the general formula II, the starting materials required for the condensation reaction, can be prepared by protecting the guanidino- and α-amino groups of L-arginine of the general formula IV by nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then by condensing the formed N ^G -substituted-N ² -substituted-L-arginine of the general formula V with the appropriate amino acid derivative of the general formula VI such as an acid chloride, azide, mixed anhydride, activated ester or carbodiimide in the usual manner and then by selectively removing the protecting groups from the formed N ^G -substituted-N ² -substituted-L-argininamide of the general formula VII.

Derivatives of the amino acid of general formula VI, which are starting materials for the preparation of Η—N

CH—(CH2) _m COOR5

R4

(XI)

(XII)

COOR"

Η-N (XIII)

In the above formulas, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , Z, n, m, r, q, i, and j have the meanings previously given.

Amino acid derivatives of the above formula VIII or IX can be prepared by condensation of a haloacetate, 3-halopropionate or ^1,4 -halobutyrate with a suitable amine of formula R1NH2 or R3NH2. (see J. org. chem. 25 728-732 /1960/).

The condensation 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 8d °C for 10 minutes to 20 hours. After the reaction is completed, the formed amino acid derivative is separated by conventional methods such as extraction with a suitable solvent or evaporation of the solvent, and then purified by distillation under reduced pressure.

Among the amino acid derivatives, tert-butyl esters of the amino acid are preferred because they are easily converted into other esters by acidic hydrolysis in the presence of the appropriate alcohol and using an inorganic acid (HCl, HCl, etc.) or an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.). The procedure used for the preparation of 2-piperidinecarboxylic acid derivatives of general formula X can be illustrated by the following scheme:

R.

KOH

R, (XVI)

HCN ——

(XVII)

H _from 0

ΪΗ+)

and

H ρςνιπ)

CO^H

In the first reaction of the above reaction scheme, an appropriately substituted piperidine of formula XIV is contacted with an aqueous solution of sodium hypochlorite at a temperature of -5 to 0°C. The resulting product of formula XV is isolated by extraction with a solvent, for example diethyl ether, and then reacted with potassium hydroxide in a lower alkanol as solvent to give the 1,2-dehydropiperidine of formula

XVI. By the action of reagents such as hydrogen cyanide or sodium cyanide, 1,2-dehydropiperidine of general formula XVI is converted into the corresponding 2-cyanoanalogues of general formula

XVII. Hydrolysis of 2-cyanopiperidines of general formula XVII to 2-piperidinecarboxylic acids of general formula XVIII is carried out by reacting 2-cyanopiperidines of general formula XVIII with an inorganic acid, such as hydrochloric or sulfuric acid.

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

In practice, 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 pentachloride, at a temperature of -10 to 200°C for 5 minutes to 5 hours. After the reaction is complete, 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.

It is well known from the literature that the ester derivative of N ² -arylsulfonyl-L-argininamide (I), where R 2 , R 3 , R 4 , R 5 , R 6 or R 7 is alkyl, aralkyl or aryl, can be prepared from the carboxylic acid derivative of N ² -arylsulfonyl-L-argininamide, where R 2 , R 5 , R 6 , R 7 , R 8 or R 9 is hydrogen, by conventional esterification methods well known from the literature. It is also well known that the carboxylic acid derivative can be prepared from the ester by conventional hydrolysis or acid hydrolysis. The conditions under which the esterification, hydrolysis or acid hydrolysis would be carried out are given in the literature.

The N ² -Arylsulfonyl-L-argininamide of formula I according to the invention forms addition salts with various inorganic or organic acids. Certain N ² -arylsulfonyl-L-argininamides containing a free carboxyl group, where R 2 , R 5 , R 6 , R 7 , R 8 , 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 the form of salts. Furthermore, 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, ethanesulfonic, benzenesulfonic, p-toluenesulfonic or the like.

In the same manner, the product can be obtained as a pharmaceutically acceptable salt by reacting the free carboxylic acid with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, N,N'-dibenzylethyldiamine, N-ethylpiperidine or the like.

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

As previously mentioned, the N ² -arylsulfonyl-L-arginamides of formula I and their salts are characterized by a highly specific inhibitory effect on thrombin in mammals and a significantly lower toxicity, and therefore these compounds are useful as diagnostic reagents for the determination of thrombin in blood and/or as pharmaceuticals for the treatment or prevention of thrombosis.

The compounds of the invention are also useful as platelet aggregation inhibitors.

The antithrombotic effect of the N ² -arylsulfonyl-L-argininamide according to the invention was compared with the effect of the known antithrombotic preparation N ² -(p-tolylsulfonyl)-L-arginine methyl ester by determining the coagulation time of fibrinogen. The measurement of the coagulation time of fibrinogen was carried out in the following manner:

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

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

The concentration required to prolong the coagulation time by a factor of 2, which is necessary for the known antithrombotic preparation N ² -(p-tolylsulfonyl)-L-arginine methyl ester, is 1.100 µM. Thrombin inhibitors are listed in Table I by indicating R and Ar in formula I and the acid residue.

When a solution containing the N ² -arylsulfonyl-L-arginineamide of the invention is administered intravenously to animals, a high antithrombotic effect is maintained in the bloodstream for 1 to 3 hours. The half-life for the breakdown of the antithrombotic compounds of the invention in the bloodstream has been shown to be approximately 60 minutes; the physiological conditions of the hosts (rats, rabbits, dogs and chimpanzees) are well maintained. The experimental decrease in fibrinogen in animals caused by thrombin infusion is satisfactorily controlled by the simultaneous infusion of the compounds of the invention.

The acute toxicity values (LD50) determined by intravenous administration of compounds of formula I in mice (male/20 g) range from 150 to 600 milligrams per kilogram of body weight.

Selected LD50 values for some compounds obtained by the method of the invention are given in the following Table I.

Table 1

Compound

HN

C—NH—(CH2J3CHCOR

_CHSCOOH

Compound

HN

C—NH—(CH2JsCHCOR / I

CH ,-O

N

260

CH^COOH

In contrast, the LD50 values for ^N2- dansyl-N-butyl-L-argininamide and ^N2- dansyl-N-methyl-N-butyl-L-argininamide 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 parenterally, i.e., intramuscularly, intravenously, or subcutaneously, by injection. For parenteral administration, the compounds may be used in the form of sterile solutions containing additional solutes, for example, sufficient saline or glucose to render the solution isotonic.

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 sublingually in the form of lozenges in which the active ingredient is mixed with sugar or corn syrup, flavorings and coloring agents and then 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 therapeutic dose per day is 10 to 50 milligrams/kg for parenteral administration, 10 to 500 mg/kg for oral administration.

The invention is illustrated by the following examples.

Example 1

A. N ² -(2-dibenzothienylsulfonyl jL-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 800 ml of benzene. The reaction mixture was stirred for 5 hours at 60 °C, during which time the product precipitated. After one hour at room temperature, the precipitate was filtered and washed successively with benzene and water to give 127 g (76%) of N ² -( 2-dibenzothienylsulfonyl)-L-arginine.

B. N ² -(2-dlbenzothienylsulfonyl]-L-arginyl chloride:

A suspension of 4.21 g of N ² -(2-dibenzothienylsulfonyl)-L-arginine in 20 ml of thionyl chloride is stirred for 2 hours at room temperature. Addition of cold dry diethyl ether produces 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)-L-arginyl-N-(2-methoxyethyl j-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 g of N ² -(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained as described above. The reaction mixture was stirred overnight at room temperature. Then 50 ml of chloroform was added, the chloroform solution was washed with 2X 25 ml of saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ester to give 5.5 g of powdered N ² -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)-glycine ethyl ester.

Analysis: C25H23O6N5S2. V2 H2SO3 calculated:

50.49% C, 4.07% H, 11.78% N;

n q 1070 ηη·

50.22 _% C, 4.18% H, 11.51% N.

D. N ² -(dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine

A solution of 5.5 g of N ² -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)-glycine ethyl ester in 15 ml of methanol and 15 ml of 2N sodium hydroxide solution is heated to 40 °C and this temperature is maintained for 10 hours. Then the reaction mixture is concentrated and chromatographed on 200 ml of ion exchanger (Daiaion

SK 102, with a grain size of 0.045 to 0.074 millimeters (200 to 300 mesh) in H ⁺ form, supplied by Mitsubishi Chemical Industries Limited, Japan), which resin is filled with water, washed with a mixture of ethanol/water (1/4) and eluted with a solution of ethanol/water/ammonium hydroxide (10/9/1),

The main fraction is concentrated to dryness, washed with ethyl ether, and 3.05 g (yield = 62%) of N ² (2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)-glycine is obtained in the form of an amorphous substance.

Infrared spectrum (KBr):

3,400, 1,630, 1,280 cm-1.

Analysis: C23H29O6N5S2 calculated:

51.57% C, 5.46% H, 13.08% N;

J 0,*

51.35 'O/o C, 5.63% H, 12.36% N. Example 2 1-Methyl-1-[N ² -(3-n-propoxybenzenesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid

To a well-stirred solution of 3.27 g (0.01 mol) of 1-(L-arginyl)-4-methyl-2-piperidinecarboxylic acid dihydrochloride and 2.7 grams of potassium carbonate in 100 ml of 0.1 N-NaOH solution is added dropwise with stirring and cooling over 30 minutes 2.35 grams (0.01 mol) of 3-n-propoxybenzenesulfonyl chloride in 80 ml of benzene, after which the mixture is reacted for 15 hours at room temperature.

After the reaction was completed, the benzene layer was separated and the remaining aqueous layer was adjusted to pH 9 with 1N-HCl solution to obtain an oily product. The oily product was extracted with 50 ml of n-butanol, which was repeated 5X. After extraction, the n-butanol solution was washed with 50 ml of water, distilled under vacuum to remove the solvent, and 3.50 g of 4-methyl-1-[N ² - (3-n-propoxybenzenesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid was obtained as an amorphous powder.

Elemental analysis for: C22H55N5O6S calculated:

53.10% C, 7.09% H, 14.08% N; you £i ] c women o ·

52.98% C, 7.05 θ/ο H, 13.79% N.

Infrared spectrum (KBr, cm ⁴ ):

3.300 (wide), 1.630, 1.160.

Example 3

A. Ethyl 1-[N ² -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-N ^G -nitro/-L-arginyl]-4-methyl-2-piperidinecarboxylate

To a well-stirred solution of 4.08 g of ethyl 1-(N ^G -nitroL-arginyl)-4-methyl-2-piperidinecarboxylate hydrochloride and 3.03 g of triethylamine in 200 ml of chloroform was added portionwise 3.69 g of 3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride while maintaining the temperature at 5°C. The reaction mixture was stirred for 5 hours at room temperature. At the end of this time, the reaction mixture was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.

The chloroform 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 3.61 g (62%) of ethyl 1-[N ² -(3 methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-N ^G -nitroL-arginyl]-4-methyl-2-piperidinecarboxylate as an amorphous solid.

Infrared spectrum (KBrj:

3400, 1730,16'35 cm'i..

Nuclear magnetic resonance spectrum, (CDsOD) <5 (ppm):

6.5 (1H, t), 7.1 (1H, d), 7.4 (1H, d).

ΝΟ,ΝΚ H ^í N (CHjLCHCOK Z“ NH I

B. Ethyl 1-{N 2 -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl l -L-arginyl|-4-methyl-2-piperidinecarboxylate-acetate).

To a solution of 3.00 g of ethyl 1-[N ² -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl j N ^G -nitro-L-arginyl] -4-methyl-2-piperidinecarboxylate in 100 ml of ethanol and 20 ml of acetic acid was added 0.9 g of palladium black, and then the mixture was shaken for 15 hours under a hydrogen atmosphere at room temperature. The solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation from ethanol/diethyl ether gave 2.38 g (78%) of ethyl 1-[N ² -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl j -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate.

C. 1-[N ² -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid

A solution of 2.00 g of ethyl 1-[N ² -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate acetate in 20 ml of ethanol and 10 ml of N NaOH solution was stirred overnight at room temperature. The reaction mixture was then neutralized with 2N HCl and concentrated in vacuo to give a gummy precipitate which was extracted with 3X 150 ml of chloroform. The chloroform solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.45 g (85%) of 1-[N ² -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid.

Infrared spectrum (KBr):

3.400, 1.620, 1.460, 1.380 cm ^-1 .

Analysis for: C23H36O5N6S calculated:

54.31% C, 7.13% H, 16.52% N; found:

54.09% C, 7.00 0/0 H, 16.80% N.

Various other N ^z -arylsulfonyl-L-argininamides or their acid addition salts were synthesized according to the method set forth in the preceding examples and the results are shown in the following table.

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The compounds listed in the following table refer to the method of preparation of the compound listed in III were prepared in the same manner. In the second column, the ternary references listed in this table are

Number ArSOaCl or ArSOsH Starting substance Product or salt Amino acid ester HN (literary reference) \

C—NH— (CH ₂ 1 oCHCOR

Ber. 84, 1254 (1956)

Number ArSOzCl or ArSOsH Starting material Product or salt Amino acid ester HN (literary reference) V

C—NH— (CH2JsCHCOR

Ber., SB, 951 (1953)

Number ArSOzCl or; ArSO3H Starting substance Product or salt Amino acid ester HN (literary reference) \

C—NH—(CH2jsCHCOR

©

AND

CA, 22, 413

Number ArSOzCl or ArSOsH Starting material Product or salt Amino acid ester HN (literary reference) \

C—NH—(CH2)sCHCOR

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

Number ArSOzCl or ArSCbH Starting material Product or salt Amino acid ester HN (literary reference) V

C—NH—(CH2)3CHCOR

J-Ex. (2) 118, 75

Number ArSO4Cl or ArSO3H Starting material Product or salt Amino acid ester HN or salt

C—NH—(CH2)3CHCOR

Zhur Obschei Khim, 30, 1218 (1960)

Pure ArSO4Cl or ArSO4H Starting material Product or salt Amino acid ester HN (literary reference) \

C—NH—(CH ₂ ) sCHCOR

Number ArSOzCl or ArSOsH Starting material Product or salt Amino acid ester HN (literary reference)

C—NH—(CH2)3CHCOR

Tablets suitable for oral administration:

Tablets containing the following ingredients can be prepared in a known manner. Folder Quantity per tablet (mg) N ² - (3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine lactose corn starch talc magnesium stearate 250 140 35 20 5 total 450 Oral capsules: Capsules consisting of the following ingredients are obtained by thoroughly mixing the ingredients and filling the resulting mixture into hard gelatin capsules. Ingredient Amount per capsule (mg) N ² -(3-cyclohexyl-4-methoxyphenylsulfonyl j -L-arginyl-N-butylglycine lactose 250 250 total 500 Sterile infusion solution: The following components are dissolved in water suitable for intravenous perfusion and the resulting solution is sterilized. Components Quantity (g) N ² - (3-cyclohexyl-4-methoxyphenylsulfonyl j -L-arginyl-N-butylglycine buffer system glucose distilled water 25 upon request 25 500

Arylsulfonyl chlorides:

A. 3-Butoxy-2,4-dimethoxybenzenes ^! sodium phonate

To a well-stirred solution of 50.8 g of 2-butoxy-1,3-dimethoxybenzene in 160 ml of carbon tetrachloride was added dropwise 16.1 ml of chlorosulfonic acid at 0 to 4° C. The reaction mixture was stirred for 1 hour at room temperature, 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 to give 63.3 g (85.1 percent) of sodium 3-butoxy-2,4-dimethoxybenzenesulfonate.

B. 3-Butoxy-2,4-dimethoxybenzenesulfonyl chloride

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

The reaction mixture was stirred for 15 minutes and gradually poured into 1,000 ml of ice water and stirred thoroughly. After 1 hour, the aqueous layer was decanted and the remaining oil was extracted with benzene, washed with water, dried over anhydrous sodium sulfate, distilled to remove the solvent and then distilled again in vacuo to give 47.5 g (80.1%) of 3-butoxy-2,4-dimethoxybenzenesulfonyl chloride (b.p. 154-155°C/133 Pa).

Analysis for: C12H1SCIO5S calculated:

46.68% C, 5.56% H;

found:

46.71% C, 5.60% H.

The following Table IV lists arylsulfonyl chlorides that have not been previously described in the chemical literature and were prepared by the above method.

Ar—SO2Cl

Ar

Number

/ ^C 'Z

OCH,CH _? CH * ^{2 X} CH

OÍCH^CH^ ^0,CH /3 ^CH i

CH, ch ₃ oích^ch^ and IV

Boiling point (melting point)

165 to 166 °C/133 Pa (57.5 to 58.5 °C)

112 to 115 °C/133 Pa (33 to 35 °C)

127 to 129°C/66.5 Pa

148 to 150 ^Q C/133 Pa

143 to 145 °C/133 Pa (48 to 51 °C) (41 to 42 °C)

139 to 140 °C/133 Pa

129.5 to 132 °C/133 Pa

145 to 148 °C/133 Pa

151.5 to 153.5 °C/199.5 Pa

155 to 156 ^/266 Pa

-ch ₃

0ř^), ^CH 3

Boiling point (melting point)

Ar—SOzčl

Ar

Number (44 to 45 °C) .CH*

TT

About CH^CH^CH^OGH,

187°C/133Pa

OCH3

198 to 200 °C/266 Pa

210 to 220 °C/133 Pa

160 to 162 °C/266 Pa

154 to 155 °C/133 Pa

170 to 172 “C/266 Pa

OCH ₃

183 to 185 °C/133 Pa (46 to 47 °C)

131 °C/133 Pa (65 to 66 °C)

Ar—SO2Cl

Ar

Boiling point (melting point)

^OřC % ^CH á O

OtCHjiCHs o(ch ₂ ) ₅ ch ₃ (30 to 32 °C)

208 to 210 °C/133 Pa

178 to 179 °C/266 Pa oily substance

165 to 168 °C/133 Pa oily substance

χ

OC.H5

109 to 110 °C/199.5 Pa

111 to 116 °C/133 Pa

CH

/ ^CH * ^OCHCH^CH^ oily substance

OCH^CH

From ^CH 3 CH, oily substance

148 to 150 °C/33 Pa

00¾¾

23B773

Number

Ar—SO2Cl Ar

Boiling point (melting point)

152 to 153 ⁰ C/266 Pa

133 to 134 °C/133 Pa

142 to 143 °C/133 Pa

oc^ ₅

CHt,

0((¾% ch ₃

CH, / ³

(CH _í ) _í CH _i

OfCH^CH^

121 to 122 °C/133 Pa

133 to 135 °C/133 Pa

136 to 139 °C/133 Pa (95 to 96 °C) (101 to 103 °C)

142 to 144 °C/133 Pa

Boiling point (melting point)

Ar—SO2Cl

Ar

Number

0CH ₂

CH, _from CH ₃

(50 to 51°C)

158 to 160 °C/133 Pa

159 to 160 °C/133 Pa

151 to 152 °C/133 Pa

158 to 159 “0/133 Pa

Claims (9)

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, C 9 -C 16 -cycloalkylphenyl, fluorenyl , thioxanthenyl, or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10alkyl, C1-C10alkoxy, C2-C10alkoxycarbonyl and oxo, and X is halogen and optionally converting the reaction product obtained above by reaction with an inorganic or organic acid into an acid addition salt or liberating it by reaction of a salt with a base or an acid amide. 1,2,3,4-tetrahydro-tin-1-yl 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 C 9 -C 16 -cycloalkylphenyl carbon, fluorenyl, thioxanthenyl or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkoxycarbonyl and oxo group and X is halogen, and optionally converting the product obtained above by reaction with an inorganic or organic acid into an acid addition salt thereof is liberated by reaction of the salt with a base or an acid amide. 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-bromo-phenyl , any of which is unsubstituted or substituted with at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkoxycarbonyl and oxo group, and X is halogen, and optionally the reaction obtained above the product is converted by reaction with an inorganic or organic acid into an acid addition salt or is liberated by reaction of a salt with a base or an acid amide. A process for the preparation of N ² -arylsulfonyl-L-argininamides of the general formula I HN C — N — CH ₂ Cl ₂ C H ₂ C HC OR! AND HZN H HNSO2 (I) Ar where R is a group (1) Ri / —N \ I will invent CH (CH 2) ⁿ COOR 3 ^r 2 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 of 3 to 10 carbon atoms, (C 4 -C 10) cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-4-pyranylmethyl, 2- or 3-pyrldylmethyl and phenyl, R2 is hydrogen or alkyl of 1 to 10 carbon atoms, R 3 is hydrogen or alkyl of 1 to 10 carbon atoms, and n is an integer of 0 or 1, (2) wherein wherein R a is -COOR e, where R g is hydrogen or C 1 -C 10 alkyl, R 5 is hydrogen or C 1 -C 10 alkyl, and m is an integer of 0 or 2, Rd is in the 2 or 3 position, and R g can be in the position 2, 3, 4, 5 or 6, (3) where p is an integer of 1 or 2, (4) 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 and C 1 -C 10 alkoxy and at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, 9, 9-dioxobenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted with at least one hydroxy group of 10, C 1 -C 10 alkoxy, C 9 -C 16 cycloalkylphenyl fluorenyl, thioxantenyl or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkoxycarbonyl and oxo, 3- cyclohexyl-4-ethoxycarbonyloxyphenyl, or a phenyl group 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 further optionally substituted with at least one methyl, ethyl, methoxyl ethoxy, hydroxy and halogen, and pharmaceutically acceptable salts thereof, characterized in that L-argininamide II is reacted HN G - N - CH 2 CH 2 CH 2 - CHCOR (II) / III H2N Η NH2 where R is as defined above, with an arylsulfonyl halide of formula III ArSOzX (III) where Ar is as defined above and X is halogen, 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. 2. Process according to claim 1, characterized in that the L-argininylide of the formula II is reacted HN \ C - N - CH 3 CH 2 CH 2 - CHCOR (II) / III H2N H NHz where R is R1 / '—N \ CH (CH 2) n COOR 3 Rz kde 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 and 3 to 10 carbon atoms and (C 4 -C 10) cycloalkylalkyl, R 2 is hydrogen or C 1 -C 5 alkyl, R 3 is hydrogen or C 1 -C 10 alkyl, n is 0 or 1, 238773 with an arylsulfonylbalogenide of formula III ArSOzX (III) where 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 5 alkyl, and C 1 -C 10 -alkoxy and at least one C 7 -C 12 aralkyl, C 2 -C 6 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl 3. A process according to claim 1, wherein L-argininamide of formula II is reacted HN \ C — N —- CH2CH2CH2 — CHCOR (II) H2N H NHz where R is a group (1) COOH with an arylsulfonyl halide of formula III ArSChX (III) where Ar is phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, phenazinyl, quinoxalinyl, phthalazinyl, or acridinyl, any of which is unsubstituted or substituted by at least one hydroxy, C1-C10alkoxy, C1-C10alkoxy and X is halogen, and optionally the reaction product obtained above is converted by reaction with an inorganic or organic acid into an acid addition salt or is liberated by reaction of a salt with a base or an acid amide. 4. A process according to claim 1, wherein L-argininamide of formula II is reacted HN \ C - N - CH 2 CH 2 CH 2 - CHCOR (II) / I! HzN Η NHz where R is ( where Rd is - COORe wherein R e is hydrogen or C 1 -C 10 alkyl, R 5 is hydrogen or C 1 -C 10 alkyl, and m is 1 or 2, R 4 is at the 2 or 3 position and R 5 can be at the 2 position , 3, 4, 5 or 6, with an arylsulfonyl halide of formula III ArSOžX (III) where Ar is phenoxyphenyl, dibenzothienyl, phenoxathiinyloic, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl, phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or substituted with at least 1, alkoxy, or substituted with at least one C 1 -C 10 alkyl or C 1 -C 10 alkyl, or fluorenyl, thioxantenyl or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxycarbonyl and X is halogen, and optionally the reaction product obtained above is converted by treatment with an inorganic or organic acid into an acid addition salt or liberated by reaction of a salt with a base or an acid amide. 5. A process according to claim 1, wherein L-argininamide of formula II is reacted HN \ C — N — C 1 CH 2 Cl 2 k — CHCOR (II) / I I Hž'N Η NHz where R is a group (1) Ri / —N \ CHjCHzjnCOORS Rz kde R 1 is tetrahydrofurfuryl or tetrahydro-4-pyranylmethyl, R2 is alkyl of 1 to 10 carbon atoms, R 3 is hydrogen or C 1 -C 10 alkyl, n is 0 or 1, and (2) wherein p is 1 or 2, with an arylsulfonyl halide of formula III ArSOzX (III) where Ar is a phenyl group substituted with at least one amino group, an alkylamino group having 1 to 10 carbon atoms, an acylamino group having 1 to 10 carbon atoms, a hydroxyalkyl having 1 to 10 carbon atoms and phenyl, a phenyl group substituted with at least one hydroxy group, an alkyl of 1 C 1 -C 10 alkoxy having at least one C 7 -C 12 aralkyl, C 2 -C 4 alkylcarbonyl, phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, phenazinyl , phthalazinyl, 1,2,3,4-tetrahydroquinolyl or acridinyl, any of which is unsubstituted or: substituted by at least one hydroxy, C1-C10 alkoxy and C1-C10 alkyl or fluorenyl, thioxanthenyl or 2H- a chromenyl group, any of which is unsubstituted and substituted with at least one hydroxy group , alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkoxycarbonyl of 2 to 10 carbon atoms and oxo, and X is halogen, and optionally the reaction product obtained above is converted by reaction with an inorganic or organic acid into addition salts. with an acid or liberated by reaction of the salt with a base or acid amide. 6. A process according to claim 1, wherein L-argininamide of formula II is reacted HN C — N — CH2CH2CH2 — CHCOR (II) HsN H NHz where R is Ri / —N \ CH (CH ₂ ) _n COOR 3 R2 where R1 is alkyl of 2 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthloalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms C 4 -C 10 cycloalkylalkyl and phenyl Ra is alkyl of 1 to 5 carbon atoms, R 5 is hydrogen or C 1 -C 10 alkyl and n is a number, 0 or 1 with an arylsulfonyl halide of formula III ArSO2X (III) where Ar is phenyl substituted with at least one amino group, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxy and phenyl, phenyl substituted with at least one hydroxy, C 1 -C 5 alkyl, and (C až-C a alko my) alkoxy group with at least one C až 12-C ar ar aralkyl (C až alkyl alkyl alkyl alkyl), phenylcarbonyl (C a 6 6 a), phenyl, phenoxyphenyl, dibanzothienyl, phenoxathiinyl, 1H-indazolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl 7. A process according to claim 1, wherein L-argininamide of formula II is reacted HN \ C — N — CH 2 CH 3 CH 2 - CHCOR (II) HžN H NH2 where R is a group (1) Ri / —N \ CH (CH 2) _n COOR 3 R? where R 1 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 with an arylsulfonyl halide of formula III ArSOzX (III) where Ar is phenyl substituted with at least one amino group, C 1 -C 10 alkylamino, C 1 -C 10 acylamino, C 1 -C 10 hydroxyalkyl and phenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-indazolyl, quinolinyl, phenoxalnynyl , phthalazinyl, 8. A process according to claim 1, wherein L-argininamide of formula II is reacted HN \ C—N—UIHCH.CH. ~ CHCOR (II) HžN Η NH2 where R is ( where R 4 is -COOR 6 wherein R 6 is hydrogen or alkyl of 1 to 10 carbon atoms, R 8 is hydrogen or alkyl; having 1 to 10 carbon atoms and m is 1 or 2, R 4 is at the 2 or 3 position and R 8 can be at the 2, 3, 4, 5 or 6 position, with an arylsulfonyl halide of formula III ArSOzX (III) where Ar is phenoxyphenyl, dibenzothienyl, phenoxathiinyl, 1H-inida, zolyl, quinolyl, indolinyl, phenazinyl, quinoxalinyl, phthalazinyl or acridinyl; up to 10 carbon atoms, or a cycloalkylphenyl group of 9 to 16 carbon atoms, fluorenyl, thioxanthenyl or 2H-chromenyl, any of which is unsubstituted or substituted by at least one hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms , C 2 -C 10 alkoxycarbonyl and oxo, and X is halogen, and optionally the reaction product obtained above is converted by reaction with an inorganic or organic acid into an acid addition salt, or is liberated by reaction of a salt with a base or an acid amide. 9. The method of claim 1, wherein L-argininamide of formula II is reacted HN \ C — N — CH2Cl-12CH2 — CHCOR (II) Z I I H21N Η NH2 where R is a group (1) Ri Z —N \ CH (CH 2) n COOR 3 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, alkylsulfinylalkyl of 2 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, C 4 -C 10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl and tetrahyidro-4-pyranylmethyl wherein: R 6 is -COOR 6 wherein R 6 is hydrogen or C 1 -C 10 alkyl, R 5 is hydrogen or C 1 -C 10 alkyl, and m is 1 or 2, R 4 is substituted at the 2 or 3 position, and R 5 can be substituted at position 2, 3, 4, 5 or 6 (3) where p is the number 1 or 2, (4) COOH -NO with an arylsulfonyl halide of formula III ArSOzX (III) where 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, halo, ethoxy, hydroxy, ethoxy, X is halogen, and optionally the reaction product obtained above is converted by treatment with an inorganic or organic acid into an acid addition salt or liberated by reaction of a salt with a base or an acid amide.