DE3042295A1 - Compsn. contg. 2-amino-1,3,4-thiadiazine derivs. - useful as muscle relaxants for humans and animals - Google Patents

Abstract

Pharmaceutical compsns. contain at least one thiadiazine deriv. of formula (I) or their acid addn. salts. In (I) R is H or 1-7C opt. branched alkyl. R1 is H, phenyl, allyl or 1-7C opt. branched alkyl; R2 is phenyl opt. substd. by one fluoro, chloro, or 1-4C opt. branched alkyl, or 2,4-disubstd. by Cl or 1-4C opt. branched alkyl; R3 is H or 1-4C opt. branched alkyl, but if alkyl R2 must be unsubstd. phenyl. Pref. (I) are administered at 10-100 mg per kg per day and pref. cpds. have R3 H, R2 2,4-dichlorophenyl and NRR1 dimethylamino or 2-propenyl, both as their monohydrochlorides. Some (I) are already known as intermediates, antivirals, antiinflammatories and analgesics. They are now found to be useful as muscle relaxants for humans and animals, and can be used in the same way as chlordiazepoxide.

Description

SUBSTITUTED 6H-1,3,4-THIADIAZIN-2-AMINE,

METHOD OF MANUFACTURING IT AND USING IT The present invention relates to fluorophene compounds which are useful as muscle relaxants and which have the following general formula: wherein R is a straight or branched chain alkyl group having 1 to 7 carbon atoms, and their pharmaceutically acceptable acid addition salts. These compounds exhibit a particularly desirable separation of effects and produce muscle relaxation in doses that are not sedative.

The invention also relates to the use of compounds of the general formula wherein R represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 7 carbon atoms; R denotes a hydrogen atom, a straight-chain or branched alkyl group with 1 to 7 carbon atoms5, an allyl group or a phenyl radical; R2 is a phenyl radical, a phenyl radical monosubstituted by a fluorine or chlorine atom or by a straight-chain or branched-chain alkyl group with 1 to 4 carbon atoms or a phenyl radical disubstituted in 2- and 4-position by chlorine atoms or alkyl groups with 1 to 4 carbon atoms and R3 is a hydrogen atom or denotes a straight-chain or branched-chain alkyl group with 1 to 4 carbon atoms, with the proviso that when R3 represents a straight-chain or branched-chain alkyl group, R2 denotes an unsubstituted phenyl radical, as well as the pharmaceutically acceptable acid additin salts of these compounds in the treatment of t + muscle tension.

Examples of straight-chain or branched-chain alkyl groups with 1 to 7 carbon atoms that R and R1 can represent include the methyl, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, Isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl and the isoheptyl group. Examples of straight or branched chain alkyl groups having 1 to 5 carbon atoms or alkyl groups with 1 to Lt carbon atoms in the above radicals R2 and R can occur are included in the preceding examples.

To the pharmaceutically acceptable acid addition salts of the compounds of Formulas I and IV include those of any suitable inorganic or organic Acid. Suitable inorganic acids are e.g. hydrochloric acid, hydrobromic acid, Sulfuric acid or phosphoric acid. Suitable organic acids are e.g. carboxylic acids, such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, Succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, Maleic acid, hydroymaleic acid, Benzoic acid, hydroxybenzoic acid, Phenylacetic acid, cinnamic acid, salicylic acid and 2-phenoxybenzoic acid, or sulfonic acids, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.

Of the compounds of the formula IV, those in which R? is a substituted phenyl radical is preferred.

The 4-fluorophenyl compounds of the formula are particularly preferred I.

The compounds of the present invention include, for example those in which R and R1 represent a hydrogen atom, a methyl group, an ethyl group or a propyl group and especially those in which one of the R and R1 radicals represent a hydrogen atom. These compounds include, for example N-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine, N-ethyl-5- (4-fluoropbenyl) -6H-1,3,4-thiadiazin-2-amine, 5- (2,4-dichlorophenyl) -6H-1,3,4-thiadiazin-2-amine, 5- (2,4-dichlorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2- amine, 5- (2,4-dichloropheny N-ethy-6H-t, D, 4-thiadiazin-2-amine, 5- (2,4-dichlorophen! .L) -NßN-dimethyl-6H-1a3v4-thiadíazin-2 -amina 5- (2,4-dichlorophenyl) N-phenyl-6H-1,3,4-thiadiazin-2-amine, 5- (2,4-dichlorophenyl) -N- (methylethyl) -6H-1,3,4 -thiadiazin-2-amine, 5- (2,4-dichlorophenyl) -N-propyl-6H-1,3,4-thiadiazin-2-amine, 5- (2-fluorophenyl) -N-methyl-6H-1,3,4-thiadiazine- 2-amine, N-ethyl 6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine, 5-C2, -dichlorophenyl) -N-hexyl-6H-1,3,4-thiadiazin-2-amine and N-butyl-5- (2,4-dichlorophenyl) -6H-1,3,4-thiadiazin-2-amine, 5- (2,4-dichlorophenyl) -N-2-propenyl-6H-1,3 , 4-thiadiazin-2-amine, 5- (2,4-dichlorophenyl) -N-heptyl-6H-1,3,4-thiadiazin-2-amine and their acid addition salts.

The compounds of the invention are useful as muscle relaxants. These compounds can be transmitted to warm-blooded animals, mammals, rats, mice, dogs, cats, Horses, pigs, cows, sheep and humans can be administered. Unless the When the term "patient" is used, it should include the treated animal or the treated person can be understood.

The relaxing effectiveness of the compounds according to the invention due to its effectiveness in usual pharmacological selection tests, e.g. by demonstrating an antagonism of rigidity in rats after brain detachment, by inhibiting the polyrynaptic reflexes in the anesthetized cat and by the tail test in the mouse for dust, he will purify the inheritance Compounds can be administered orally or parenterally either alone or in the form of a pharmaceutical Preparations are administered. Pharmaceutical preparations, the usual pharmaceutical Carriers and containing a compound according to the invention as active ingredient can be used in Unit dosage forms, e.g.

as solid forms such as tablets, capsules and pills, or as liquid Solutions, suspensions or emulsions for oral and parental administration can be used. The administered dosage unit can be any muscle-relaxing-effective Be crowd. The amount of compound administered can vary over a wide range and about 10 to 100, preferably 10 to 30 mg / kg body weight of the patient per Day to achieve the desired effect. Unit doses can be about 5 to 500 mg of a compound of the formula I or IV and, for example to be administered 11 to 4 times a day.

The compounds of formulas I and IV can be prepared by lrlrmans a phenacyl halide of the formula wherein X is a chlorine or bromine atom, with a 4-substituted thiosemicarbazide of the formula converts, in which R, R1, R2 and R3 have the above meanings. The reaction is generally carried out in the presence of a solvent, for example a lower alkanol such as methanol, ethanol, isopropanol, n-propanol, n-butanol and the like, preferably methylanol. The reaction time can be from about 15 minutes to about 1 hour, preferably about 30 minutes, depending on the reactants, the solvent and the reaction temperature, which can be from about 60 to about 80.degree. C., preferably about 650.degree. The product is generally worked up by allowing the reaction mixture to cool and then concentrating in vacuo. The residue obtained is recrystallized from a suitable solvent, for example a mixture of a lower alkanol with, for example, acetone, butanone or ethyl acetate, for example a mixture of methanol / acetone or methanol / ethyl acetate, the compound of the formula I or IV in the form their hydrohalide salt is obtained.

Both the phenacyl halide and the 4-substituted thiosemicarbazide, used as starting materials for the preparation of the compounds of the formulas I. and IV are either commercially available or can be easily prepared by conventional chemical methods well known to those skilled in the art will. For example, the phenacyl halides can be prepared by halogenation of the corresponding (optionally substituted) methyl phenyl ketone using a sulfuryl halide, e.g., sulfuryl chloride, in e.g. acetic acid, where the corresponding phenacyl chloride is obtained, or by reacting the corresponding, optionally substituted benzene with a haloacetyl halide, .B. Chloroacetyl chloride, by a Friedel-Crafts conversion using a catalyst made of aluminum trichloride, for example the corresponding phenacyl chloride is produced. The 4-substituted Thiosemicarbazides can be prepared by adding an appropriately substituted Isothiocyanate in the usual way with hydrazine in the presence of e.g. diethyl ether.

The following examples illustrate the invention.

Example 1 N "Methyl-5-phenyl-6H 1,3,4-thiadiazin-2-amine hydrochloride 5, 255 g (0.05 moles) of 4-methyl-thiosemicarbazide and 7.73 g (0505 moles) of phenacyl chloride were refluxed in 200 ml of methanol for a period of 0 minutes with stirring (65 ° C) heated. At this point the solvent was removed in vacuo. The residue was dissolved in methanol, heated and then diluted with acetone. The mixture was then concentrated to about 200 ml. After the mixture 2 days 8.33 g of N-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrochloride were found obtained as a precipitate with a melting point of 176-1780c.

Example 2 2 N-Ethyl-5- (4-fluorophenyl) -6H-1,3,4-thiadiazin-2-amine hydrochloride 11.19 g of 4-ethyl-thiosemicarbazide and 17.6 g of 4-fluorophenacyl chloride were added in 400 ml of methanol in a full-size round bottom flask for 30 minutes of 1 1, the one with a magnetic stir bar and one through a CaCl2 drying tube protected X condenser, heated to reflux (65 ° C) with stirring. The solution was allowed to cool to room temperature and then concentrated into one yellow solid residue. The residue was made from a mixture of methanol and Butanone recrystallized, leaving 21.0 g (75.5%) of N-ethyl-5- (4-fluorophenyl) -GH-1,3,4-thiadiazin-2-amine hydrochloride with a melting point of 192-193 ° C.

The fluffy, yellowish-white solid was under a high vacuum dried at 65 ° C.

Example 3 5- (2,4-Dichlorophenyl) -6H-1 3 11 -thiadiazyn-2-amine hydrochloride 11.17 g (0.05 mol) 2,4-dichlorophenacyl chloride and 4.36 g (0.05 mol) thiosemicarbazide were heated to reflux (650 ° C.) with stirring for 30 minutes in 250 ml of methanol. The suspension obtained was cooled and filtered, with an initial yield obtained from 4.56 g of 5- (2,4-dichlorophenyl) -6H-1,3,4-thiadiazin-2-amine hydrochloride became. The reaction mixture was then diluted with ethyl acetate and increased concentrated on a steam bath to give 6.2 g of the same compound became. The two products were combined and made from a mixture of methanol and ethyl acetate recrystallized to give a product with a melting point of 170-172 0C was obtained.

Example 4 5- (2 4-Dichlorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 11.17 g of 2,4-dichlorophenacyl chloride and 5.755 g of 4-methyl-thiosemicarbazide were added reacted in 200 ml of methanol according to the procedure of Example 2. The initial one Crystallization was from a mixture. obtained from methanol and ethyl acetate. Of the Solid was then recrystallized from a mixture of methanol and ethyl acetate and dried under high vacuum at 650C, the 5- (2,4-dichlorophenyl) -N-methyl-6H-i, 3,4-thiadiazin-2-amine monohydrochloride with a melting point of 1950C.

Example 5 5- (2,4-Dichlorophenyl) -N-ethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride Using the procedure of Example 2, 9.3 grams were obtained (0.04 Mol) 2,4-dichlorophenacyl chloride and 4.77 g (0.04 mol) 4-ethyl-thiosemicarbazide in 200 ml of methanol reacted, with 6.5 g of 5 "(2 4-dichlorophenyl) -N-ethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride after recrystallization from a mixture of methanol and EthyJacetat with a Melting point of 197-1980C were obtained.

Example b 5- (2,4-Dichlorophenyl) -N, N-dimethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 4.16 g (0.035 mol) 4,4-dimethyl-thiosemicarbazide and 7.82 g (0.035 mol) 2,4-dichlorophenacyl chloride were implemented according to the procedure of Example 2. After concentration was the residue is mixed with ethyl acetate and concentrated again.

A yellow, needle-like solid was obtained. The solid was dried under high vacuum at 650C. Then everything became a mixture recrystallized from methanol and ethyl acetate and dried again under high vacuum 5 wherein the 5- (2,4-dichlorophenyl) -N, N-dimethyl-6H-1,3,4-thiadiazine-2-aminomonohydrochloride with a melting point of 219-2220c.

Example 7 5- (2,4-Dichlorophenyl) -N-phenyl-6H-1,3,4-thiadiazin-2-aminomial hydrochloride 4.54 grams (0.03 moles) of 4-phenyl thiosemicarbazide and 6.70 grams (0.03 moles) of 2,4-dichlorophenacyl chloride were after in 200 ml of methanol. the procedure of Example 2 implemented. To Recrystallization of the solid from a mixture of methanol and ethyl acetate G were 6.5 g of 5- (2,4-dichlorophenyl) -N-phenyl-6H-1,3,4-thiadiazin-2-ami-monohydrochloride obtained with a melting point of 1860C. The solid was then under High vacuum dried at 650C.

Example 8 5- (2,4-Dichlorophenyl) -N- (1-methylethyl) -6H-t, 3,4-thiadiazin-2-amine monohydrochloride 3.99 g (0.03 mol) 4-isopropylthiosemicarhazide and 6.70 g (0 (03 mol) 2,4-dichlorophenacyl chloride were reacted in 150 ml of methanol according to the procedure of Example 2. The product was concentrated and crystallized from a mixture of methanol and Recrystallized ethyl acetate. The product was then under high vacuum at 650c dried and recrystallized again from a mixture of methanol and ethyl acetate. Finally it was again dried under high vacuum at 65 ° C., the 5- (2,4-dichlorophenyl) -N- (1-methyllylethyl) -6H-1,3,4-thiadiazin-2-amine monohydrochloride with a melting point of 207-208 ° C.

Example 9 5- (2,4-dichlorophenyl) -N-propyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 6.70 g (0.03 mol) of 2-dichlorophenacyl chloride and 3.99 g (0.03 mol) of 4-n-propyl-thiosemicarbazide were reacted in 150 ml of methanol according to the procedure of Example 2. The product was after concentration and crystallization from a mixture of methanol and Recrystallized ethyl acetate, with 6.4 g of 5- (2,4-dichlorophenyl) N-propyl-6H-1, 3,4-thiadiazin-2-amine monohydrochloride with a melting point of 184-185 ° C. The product was subsequently dried under high vacuum at 650C.

Example 10 5- (2-Fluorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 8.62 g (0.05 mole) of 2-fluorophenacyl chloride and 5.22 g of 4-methylthiosemicarbazide were obtained reacted in 150 ml of methanol according to the procedure of Example 2. The product was recrystallized from a mixture of methanol and ethyl acetate, giving 6.7 g 5- (2-Pluophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride with a melting point of 183-1840c.

Example 11 5- (2,4-Dichlorophenyl) -N-hexyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 3.50 g of n-hexyl thiosemicarbazide and 4.47 g of 2,4-dichlorophenacyl chloride were added the procedure of Example 2 reacted in 200 ml of methanol. The solid obtained was recrystallized from a mixture of methanol and ethyl acetate, whereby 4.5 g 5- (2,4-dichlorophenyl) -N-hexyl-6H-1,3,4-thiadiazine-2amine-monohydro (chloride with a Melting point of 173-174 ° C were obtained.

Example 12 N-Butylw5- (2,4-dichlorophenyl) -6H-1,3,4-thiadiazin-2-amine monohydrochloride 4.47 g of 2,4-dichlorophenacyl chloride and 2.66 g of 4-n-butyl-thiosemicarbazide were added the procedure of Example 2 reacted in 150 ml of methanol. The solid obtained was recrystallized from a mixture of methanol and ethyl acetate to give 3.98 g of N-butyl-5- (2,4-dichlorophenyl) -6H-t, 3a4-thiadiazin-2-amine monohydrochloride with a melting point of 180-1820C.

Example 13 5- (2,4-dichlorophenyl) -N-2-propenyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 3.93 grams (0.03 moles) of 4-allyl thiosemicarbazide and 7.00 grams (0.03 moles) of 2,4-dichlorophenacyl chloride were implemented according to the procedure of Example 1. After recrystallization from a mixture of methanol and methyl acetate was 8 g of 5- (2,4-dichlorophenyl) -N-2-propenyl-6H-1,3,4-thiadiazin-2-amine obtained with a melting point of 188-1890C.

Example 14 5-t2,4-dichlorophenyl) -N-heptyl-6H-1n3,4-thiadiazin-2-amine monohydrochloride 3.78 g (0.02 mole) of 4 n-heptyl-thiesemicarbazide and 4.67 g (0.02 mole) of 2a4-dichlorophenacyl chloride were implemented according to the procedure of Example 1. After recrystallization from a mixture of methanol and methyl acetate was given 5.2 g of 5- (2,4-di-chlorophenyl) -N-heptyl-6H-1,3,4-thiadiazine-2-amine monohydrochloride obtained with a melting point of 175-177 ° C.

Example 15 N-Ethyl-6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine-hydrobromide 0.05 mol of i-methyl-phenacyl bromide and 0.05 mol of 4-ethyl-thiosemicarbazide were after implemented the procedure of Example 1, wherein 8.0 K N-ethyl-S-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrobromide with a melting point of 174-175 ° C. After recrystallization from a mixture of methanol and ethyl acetate was the product under high vacuum 65 ° C dried.

Example 16 5- (4-Fluorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride 8.63 g of 4-fluorophenacyl chloride and 4.66 g of 4-methyl-thiosemicarbazide were after Procedure of example 1 implemented. The product obtained became a mixture recrystallized from methanol and ethyl acetate, giving 5.6 g of 5- (4-fluorophenyl) -N-methyl-6H-1,3,4-thiadiazine-2-amine hydrochloride with a melting point of 139-141 ° C were obtained. The product was under vacuum dried at 650C.

Example 17 An exemplary pharmaceutical preparation in tablet form was made from the following ingredients: per tablet (a) 5- (2, II-dichlorophenyl) -N-methyl- 100.0 mg 6 [-1,3,4-thiadiazin-2-amine monohydrochloride (b) wheat starch 15.0 mg (c) lactose 33.5 mg (d) magnesium stearate 1.5 mg Part of wheat starch was used to make a granulated starch paste that together with the rest of the wheat starch and the lactose granulated, sieved and with the 'active ingredient (a) and the magnesium stearate. The mixture became tablets with each pressed with a weight of 150 mg.

Example 18 An exemplary pharmaceutical preparation for parenteral injections was produced from the following ingredients, the quantities being based on weight per volume: Quantity (a) 5- (2 5- (2,4-dichlorophenyl) -N-methyl-6H- 1,3,4-thiadiazin-2-amine monohydrochloride 100.0 mg (b) sodium chloride in § qs (c) water for injections 20.0 ml The preparation was prepared by dissolving the active ingredient (a) and sodium chloride so much in water for injections that the solution became isotonic. For multiple dosing, the preparation was filled into a single ampoule containing 100 mg of the active ingredient, or it was filled into 20 ampoules for single doses.

Example 19 An exemplary pharmaceutical preparation for hard gelatin capsules was made from the following ingredients: Amount (a) 5- (2? 4-dichlorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amine- -200.0 mg monohydrochloride (b) talc 35> 0 mg The preparation was made, by sieving the dry powders (a) and (b) through a fine-mesh sieve and then mixed well. The powder was then put into hard gelatine capsules No. 0 filled with a net filling weight of 235 mg per capsule I3example 20 An exemplary pharmaceutical preparation for pills was made from the following components: per pill (a) 5- (2,4-dichlorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 200 mg (b) corn starch 130 mg (c) liquid glucose 20 ml The pills were prepared by mixing the active ingredient (a) and the corn starch together and then added the liquid glucose with careful kneading, with a plastic mass was formed from which the pills were cut and shaped.

Example 21 The compounds of the preceding examples can each Administered to in a patient who is a muscle relaxant. effect is desirable, e.g., in a patient suffering from muscle spasm, one Effect muscle relaxation. In rats, muscle relaxation is through administration of chlordiazepoxide (Librium) parenterally (IV) inducible under the same conditions the compounds according to the invention also induce a comparable muscle relaxation For example, the compound of Example 6 has about three times the potency of chlordiazepoxide, while the compound of Example 10 is about half the potency of chlordiazepexide under the same conditions of parenteral administration It is therefore believed that the compounds of the present invention for the same indications and under the 3 corpse-i dosage conditions (discontinued on different efficacy) like those in rats for ghlordiazepoxide can be administered to humans.

For example, the compound of Example 6 can be used in doses of 1 - 50 mg can be administered 2 to 4 times daily for beneficial effects.

Example 22 Following the procedures of Examples 17-20 were pharmaceutical preparations produced, but instead of de-s used there Active ingredient 5- (2,4-dichlorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride 5- (4-fluorophenyl) -N-methyl-6H-1, 3,4-thiadiazin-2-amine hydrochloride or the N-ethyl-5- (4-fluorophenyl) -6H-1,3,4-thiadiazin-2-amine hydrochloride were used.

Claims (5)

Patent claims 1. Substituted SH-1ß3ß4-thiadiazin-2-amines of the general formula wherein R is a straight or branched chain alkyl group having 1 to 7 carbon atoms, and their pharmaceutically acceptable acid addition salts. 2. 5- (4-Fluorophenyl) -N-methyl-6H-1,3,4-thiadiazin-2-amin. 3. N-Ethyl-5- (4-fluorophenyl) -6H-1,3,4-thiadiazin-2-amine. 4. Process for the preparation of a compound according to one of claims 1-3, characterized in that (a) a phenacyl halide of the general formula wherein X is a chlorine or bromine atom, with a 4-substituted thiosemicarbazide of the general formula converts, wherein R has the meaning given in claim 1; (b) a halide salt obtained in accordance with xa) is reacted with a base to give the corresponding free amine, or (c) a free amine obtained in accordance with (a) or (b) is converted with a pharmaceutically acceptable salt to give the corresponding acid addition salt. 5. Use of the compounds according to any one of claims 1-3 for the treatment of muscle tension.