GB2086879A

GB2086879A - 5-Aryl-6H-1,3,4-thiadiazine-2- amines

Info

Publication number: GB2086879A
Application number: GB8035330A
Authority: GB
Original assignee: Richardson Merrell Inc
Current assignee: Richardson Vicks Inc
Priority date: 1980-11-04
Filing date: 1980-11-04
Publication date: 1982-05-19
Also published as: GB2086879B

Abstract

Compounds of the general formula <IMAGE> (wherein R is hydrogen or C1-7 alkyl; R1 is hydrogen, C1-7 alkyl, ally or phenyl; R2 is phenyl, phenyl carrying one F, Cl or C1-4 alkyl substituent or phenyl carrying 2-and 4-substituents selected from Cl and C1-4 alkyl; and R3 is hydrogen or C1-4 alkyl, provided that R2 is phenyl when R3 is alkyl) and their acid addition salts are muscle relaxants.

Description

SPECIFICATION 5-Aryl-6H-1 ,3,4-thiadiazine-2-a mines The present invention relates to compounds which can have utility as muscle relaxants and which have the formula

wnerein R is H, C17 straight or branched chain alkyl; R, is H, Cl-7 straight or branched chain alkyl, allyl or phenyl; R2 is phenyl, phenyl monosubstituted with F, Cl, C 1-4 straight or branched chain alkyl or phenyl disubstituted in the 2- and 4-positions with CI or C14 straight or branched chain alkyl; and R3 is H or C14 straight or branched chain alkyl, with the proviso that when R3 is straight or branched chain alkyl, R2 is unsubstituted phenyl; or a pharmaceutically acceptable acid addition salt thereof.

Illustrative examples of straight or branched chain C17 alkyl groups which R and R1 may represent as used herein include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tertbutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, iso-hexyl, n-heptyl, iso-heptyl, etc. Illustrative examples of straight or branched chain C15 alkyl and C14 alkyl groups mentioned in describing the groups R, and R2-R3, respectively, include, for example, the corresponding examples mentioned above.

Pharmaceutically acceptable acid addition salts of the compounds of Formula I include those of any suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, furmaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2phenoxybenzoic, or sulfonic acids such as, for example, methanesulfonic and 2-hydroxyethane sulfonic acid.

Of the compounds of Formula I, those wherein R2 is substituted phenyl are preferred, especially 4-fluorophenyl, and R3 is H.

Illustrative examples of compounds of this invention include those wherein R and R1 are H, CH, C2H5 or C3H7, especially those wherein one of R and R1 is H. These include, for example, N-methyl-S- phenyl-6H-1 ,3,4-thiadiazin-2-amine, N-ethyl-5-(44luorophenyl)-6K-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-thiadlazin-2- amine, 5-(2,4-dichlorophenyl)-N-ethyl-6H-1 ,3,4-thiadiazin-2-amine, 5-(2,4-dichlorophenyl)-N,N dimethyl-6H-1 ,3,4-thiadiazin-2-amine, 5-(2,4-dichlorophenyl)-N-phenyl-6H-1 ,3,4-thiadiazin-2-amine, 5-(2,4-dichlorophenyl)-N-( 1 -methylethyl)-6K-1 ,3,4-thiadiazin-2-amine, 5-(2,4-dichlorophenyl)-Npropyl-6H- 1 ,3 ,4-thiadiazin-2-a mine, 5-(2-fluorophenyl)-N-methyl-6K-1 ,3,4-thiadiazin-2-amine, Nethyl-6-methyl-5-phenyl-6H- 1 ,3,4-thiadiazin-2-a mine, 5-(2,4-dichlorophenyl)-N-hexyl-6H- 1 ,3,4thiadiazin-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 this invention are useful as muscle relaxants. These compounds can be administered to warm-blooded animals, mammals, rats, mice, dogs, cats, horses, pigs, cows, sheep and humans. As used herein, the term "patient" is intended to mean the animal or mammal being treated.

The muscle-relaxing activity of the compounds of this invention may be illustrated by their effectiveness in standard pharmacological screening tests, e.g., by demonstrating an antagonism of decerebrate rigidity in rats; by inhibition of polysynaptic reflexes in the anesthetized cat; and by the mouse Straub tail test.

The compounds of this invention can be administered orally or parenterally either alone or in the form of a pharmaceutical preparation. Pharmaceutical preparations containing conventional pharmaceutical carriers and as active ingredients compounds of this invention can be employed in unit dosage forms such as solids, for example, tablets, capsules and pills, or liquid solutions, suspensions or emulsions for oral and parenteral administration. The dosage unit adminstered can be any musclerelaxing effective amount. The quantity of compound adminstered can vary over a wide range to provide from about 10 to 100, preferably 10-30, mg/kg of body weight of the patient per day, to achieve the desired effect. Unit doses can contain about 5-500 mg of a compound of Formula I and may be administered, for example, from 1 to 4 times daily.

The compounds of Formula I are prepared by reacting a phenacyl halide of the formula

wherein X is Cl or Br, with a 4-substituted thiosemicarbazide of the formula

wherein R, R1, R2 and R3 are as hereinbefore defined. The reaction is generally conducted in the presence of a solvent, e.g., a lower alkanol, such as, methanol, ethanol, isopropanol, n-propanol, nbutanol, and the like, preferably methanol. The reaction time may vary from about 1 5 minutes to about 1 hour, preferably about 30 minutes, depending upon the reactants, the solvent and the reaction temperature which may vary from about 600C to about 800C, preferably about 650 C. The product is generally worked-up by permitting the reaction mixture to cool and then concentrating it in vacuo.The resultant residue is recrystallized from an appropriate solvent, e.g., a mixture of a lower alkanol with, e.g., acetone, butanone or ethyl acetate, e.g. methanol/acetone or methanol/ethyl acetate, producing the compound of Formula I as its hydrohalide salt.

Both the phenacyl halide and the 4-substituted thiosemicarbazide which are employed as starting materials in the preparation of the compounds of Formula I are either commercially available or, when unavailable, are very readily preparable by standard chemical reaction which are well-known to those of ordinary skill in the art. For example, the phenacyl halides may be prepared by halogenating the corresponding methyl (optiona lly-substituted)phenyl ketone using a sulfuryl halide, e.g., sulfuryl chloride, in e.g., acetic acid, to prepare the corresponding phenacyl chloride; or by reacting the corresponding optionally substituted benzene with a haloacetyl halide, e.g., chloroacetyl chloride via a Friedel Crafts reaction using an aluminum trichloride catalyst, e.g., to prepare the corresponding phenacyl chloride.The 4-substituted thiosemicarbazides may be prepared by conventionally reacting the appropriate substituted isothiocyanate with hydrazine in the presence, e.g., of diethyl ether.

Examples The following examples are illustrative of the invention.

Example 1 N-Methyl-5-phenyl-6H -1 ,3,4thiadiazin-2-amine hydrochloride 5.255 g (.05 mole) of 4-methyl-thiosemicarbazide and 7.73 g (.05 mole) of phenacyl chloride are heated and stirred at reflux (650C) in 200 ml of methanol for 30 minutes. At this time, the solvent is removed in vacuo. The residue is dissolved in methanol, warmed and then diluted with acetone.

Thereafter, it is concentrated to approximately 200 ml. After standing for 2 days, 8.33 g of N-methyl-S- phenyl-6H-1 ,3,4-thiadiazin-2-amine hydrochloride are deposited. m.p. 176--1780C.

Example 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 are heated and stirred under reflux (650C) in 400 ml of methanol for 30 minutes in a one liter round bottom flask equipped with a magnetic stirring bar and a condenser protected by a CaCI2 drying tube. The solution is allowed to cool to room temperature and is then concentrated to a yellow solid residue. The residue is recrystallized from methanol/butanone yielding 21.0 g (75.5%) of N-ethyl-5-(4-fluorophenyl)-6H1 ,3,4-thiadiazin-2-amine hydrochloride. m.p. 192--1930C. The fluffy, yellowish white solid is dried under high vacuum at 650C.

Example 3 5-(2,4-Dichlorophenyl)-6H-1 ,3,4thiadiazin-2-amine hydrochloride 11.17 g (.05 mole) of 2,4-dichlorophenacyl chloride and 4.36 g (.05 mole) of thiosemicarbazide are stirred and heated in 250 ml of methanol at reflux (650C) for 30 minutes. The resultant suspension is allowed to cool and is filtered to yield a first crop of 4.56 g of 5-(2,4-dichlorophenyl)-6H-1 ,3,4- thiadiazin-2-amine hydrochloride. The reaction mixture is then diluted with ethyl acetate and concentrated on a steam bath further yielding 6.2 g of the same compound. The two products are added together and recrystallized from methanol/ethyl acetate. m.p. 170--1720C.

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 are reacted in 200 ml of methanol using the procedure of Example 2. The initial crystallization is made from methanol/ethyl acetate. The solid is then recrystallized from methanol/ethyl acetate and dried at 650C under high vacuum to produce 5-(2,4-dichlorophenyl)-N-methyl-6H-1 ,3,4-thiadiazin-2-amine monohydrochloride. m.p. 1 950C.

Example 5 5-(2,4-Dichlorophenyl)-N-ethyl-6H-1 ,3,4thiadiazin-2-amine monohydrochloride Utilizing the reaction conditions of Example 2, 9.3 g (.04 mole) of 2,4-dichlorophenacyl chloride and 4.77 g (.04 mole) of 4-ethylthiosemicarbazide are reacted in 200 ml of methanol to produce 6.5 g of 5-(2,4-dichlorophenyl)-N-ethyl-6H-1 ,3,4-thiadiazin-2-amine monohydrochloride after recrystallization which, in this case, was from methanol/ethyl acetate. m.p. 1 97-1 980C.

Example 6 5-(2,4-Dichlorophenyl)-N,N-dimethyl-6H-1 ,3,4thiadiazin-2-amine monohydrochloride 4.16 g (.035 mole) of 4,4-dimethyl-thiosemicarbazide and 7.82 g (.035 mole) of 2,4dichlorophenacyl chloride are reacted under the conditions of Example 2. After concentration, ethyl acetate is added to the residue and further concentration is employed. A yellow, needle-like solid is produced. The solid is dried under high vacuum at 650C. Subsequently, it is recrystallized from methanol/ethyl acetate and again dried under high vacuum to produce 5-(2,4-dichlorophenyl)-N,N dimethyl-6H-1 ,3,4-thiadiazin-2-amine monohydrochloride. m.p. 21 9-2220C.

Example 7 5-(2,4-Dichlorophenyl)-N-phenyl-6H-1 ,3,4thiadiazin-2-amine monohydrochloride 4.54 g (.03 mole) of 4-phenyl-thiosemicarbazide and 6.70 g (.03 mole) of 2,4-dichlorophenacyl chloride are reacted in 200 ml of methanol using the conditions of Example 2. Recrystallization of the solid is from methanol/ethyl acetate, yielding 6.5 g of 5-(2,4-dichlorophenyl)-N-phenyl-6H-1 ,3,4- thiadiazin-2-amine monohydrochloride. m.p. 1860C. The solid was subsequently dried under high vacuum at 650C.

Example 8 5-(2,4-Dichlorophenyl)-N-(1 -methylethyl)-6H-1 ,3,4-thiadiazin-2-amine monohydrochloride 3.99 g (.03 mole) of 4-isopropyl-thiosemicarbazide and 6.70 g (.03 mole) of 2,4dichlorophenacyl chloride are reacted in 1 50 ml of methanol under the conditions of Example 2. The concentrated product is crystallized and recrystallized from methanol/ethyl acetate. The product is dried under high vacuum at 650C and recrystallized again from methanol/ethyl acetate. It is finally dried again at 650C under high vacuum producing 5-(2,4-dichlorophenyl)-N-( 1 -methylethyl)-6H-1 ,3,4- thiadiazin-2-amine monohydrochloride. m.p. 207--2080C.

Example 9 5-(2,4-Dichlorophenyl)-N-propyl-6H-1,3,4-thiadiazin2-amine monohydrochloride 6.70 g (.03 mole) of 2,4-dichlorophenacyl chloride and 3.99 g (.03 mole) of 4-n-propylthiosemicarbazide are reacted in 1 50 ml of methanol under the conditions of Example 2. The concentrated product is crystallized and then recrystallized from methanol/ethyl acetate, to produce 6.4 g of 5-(2,4-dichiorophenyl)-N-propyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 184- 1 850C. The product is then dried at 650C under high vacuum.

Example 10 5-(2-Fluorophenyl)-N-methyl-6H-1 ,3,4-thiadiazin-2-amine monohydrochloride 8.62 g (.05 mole) of 2-fluorophenacyl chloride and 5.22 g of 4-methyl-thiosemicarbazide are reacted in 1 50 ml of methanol under the conditions of Example 2. The product is recrystallized from methanol/ethyl acetate, yielding 6.7 g of 5-(2-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 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 are reacted under the conditions of Example 2 in 200 ml of methanol. The resultant solid is recrystallized from methanol/ethyl acetate producing 4.5 g of 5-(2,4-dichlorophenyl)-N-hexyl-6H-1 ,3,4-thiadiazin-2- amine monohydrochloride. m.p. 173-1 740 C Example 12 N-Butyl-5-(2,4-dichlorophenyl)-6H-1 ,3,4thiadiazin-2-amine monohydrochloride 4.47 g of 2,4-dichlorophenacyl chloride and 2.66 g of 4-n-butyl-thiosemicarbazide are reacted under the conditions of Example 2 in 1 50 ml of methanol.The solid obtained is recrystallized from methanol/ethyl acetate, producing 3.98 g of N-butyl-5-(2,4-dichlorophenyl)-6K-1 ,3,4-thiadiazin-2- amine monohydrochloride. m.p. 180-1 820C.

Example 13 5-(2,4-Dichlorophenyl)-N-2-propenyl-6H-1 3,4-thiadiazin-2-amine monohydrochloride 3.93 g (.03 mole) of 4-allyl-thiosemicarbazide and 7.00 g (.03 mole) of 2,4-dichlorophenacyl chloride are reacted in accordance with the conditions of Example 1. Recrystallization from methanol/methyl acetate produces 8 g of 5-(2,4-dichlorophenyl)-N-2-propenyl-6K-1 ,3,4-thiadiazin-2- amine. m.p. 188-1890C.

Example 14 5-(2,4-Dichlorophenyl)-N-heptyl-6H-1,3,Sthiadiazin-2-amine monohydrochloride 3.78 g (.02 mole) of 4-n-heptyl-thiosemicarbazide and 4.67 g (.02 mole) of 2,4-dichlorophenacyl chloride are reacted analogously to Example 1. After recrystallization from methanol/methyl acetate, 5.2 g of 5-(2,4-dichlorophenyl)-N-neptyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride are produced.

m.p. 175-1770C.

Example 15 N-Ethyl-6-methyl-5-phenyl-6H-1 ,3,4thiadiazin-2-amine hydrnbromide .05 Mole of -methyl-penacyl bromide and .05 mole of 4-ethyl-thiosemicarbazide are reacted using the procedure of Example 1 to prepare 8.0 g of N-ethyl-6-methyl-5-phenyl-6H-1,3,4-thiadiazin- 2-amine hydrobromide. m.p. 1 74-1 750C. After recrystallization from methanol/ethyl acetate, the product is dried at 650C under high vacuum.

Example 16 5-(4-Fluorophenyl)-N-methyl-6H-1 ,3,4thiadiazin-2-amine hydrochloride 8.63 g of 4-fluorophenacyl chloride and 4.66 g of 4-methyl-thiosemicarbazide are reacted by using the conditions of Example 1. The resultant product is recrystallized from methanol/ethyl acetate yielding 5.6 g of 5-(4-fluorophenyl)-N-methyl-6H-1 ,3,4-thiadiazin-2-amine hydrochloride. M.p. 139- 141 0C. The product compound is dried under high vacuum at 650 C.

Example 17 An illustrative composition for tablets is as follows: Per Tablet (a) 5-(2,4-Dichlorophenyl)-N-methyl-6H-1 ,3,4-thiadiazin-2-amine mono hydrochloride 100.0 mg (b) Wheat starch 15.0 mg (c) Lactose 33.5 mg (d) magnesium stearate 1.5 mg A portion of the wheat starch is used to make a granulated starch paste which together with the remainder of the wheat starch and the lactose is granulated, screened and mixed with the active ingredient (a), and the magnesium stearate. The mixture is compressed into tablets weighing 1 50 mg each.

Example 18 An illustrative composition for a parenteral injection is the following wherein the quantities are on a weight to volume basis.

Amount (a) 5-(2A-Dichlornphenyl)-N-methyl-6H1 1 ,3,4-thiadiazin-2-amine mono- hydrochloride 100.0 mg (b) Sodium chloride q.s.

(c) Water for injection to make 20.0 ml The composition is prepared by dissolving the active ingredient (a) and sufficient sodium chloride in water for injection to render the solution isotonic. The composition may be dispensed in a single ampoule containing 1 00 mg of the active ingredient for multiple dosage or in 20 ampoules for single dosage.

Example 19 An illustrative composition for hard gelatin capsules is as follows: Amount (a) 5-(2,4-Dichlorophenyl)-N-methyl-6H-1 ,3,4-thiadiazin-2-amine mono hydrochloride 200.0 mg (b) Talc 35.0 mg The composition is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg per capsule.

I Example 20 An illustrative composition for pills is the following: Per Pill (a) 5-(2,4-Dichlorophenyl)-N-methyl-6H-1 ,3,4-thiadiazin-2-amine mono hydrochloride 200 mg (b) Corn Starch 130 mg (c) Liquid glucose 20 ml The pills are prepared by blending the active ingredient (a) and the corn starch; then adding the liquid glucose with thorough kneading to form a plastic mass from which the pills are cut and formed.

Example 21 The compounds of the preceding examples each can be administered to achieve muscle relaxation in a patient in which a muscle-relaxing effect is desired e.g. in a patient suffering from a muscle spasm. Muscle relaxation is inducible in rats by admisitration of chiordiazepoxide (Librium- Registered Trade Mark) parenterally (i.v.) So also, the compounds of this invention induce comparable muscle relaxation under similar conditions. For example, the compound of Example 6 has about 3 times the potency of chlordiazepoxide while the compound of Example 10 has about 1/2 the potency of chlordiazepoxide, under similar conditions of parenteral administration. It is, therefore, anticipated that the compound under consideration will be administered to humans for the same indications and under the same dosage conditions (adjusted for differential potency) as those seen in rats for chlordiazepoxide. For example, the compound of Example 6 could be administered in doses of 1-50 mg, 2 to 4 times daily, to achieve beneficial effects.

Example 22 Compositions similar to those described in Examples 1 7-20 are prepared except that 5-(4 fluorophenyl)-N-methyl-6K-1 ,3,4-thiadiazin-2-amine hydrochloride or N-ethyl-5-(4-fluorophenyl)-6H 1 ,3,4-thiadiazin-2-amine hydrochloride are used in place of the 5-(2,4-dichlorophenyl)-N-methyl-6H- 1,3,4-thiadiazin-2-amine hydrochloride.

Claims

1. A compound of the formula

wherein R is hydrogen or C17 alkyl; R is hydrogen, C17 alkyl, allyl or phenyl; R2 is phenyl, phenyl carrying one F, Cl or C14 alkyl substituent or phenyl carrying 2- and 4substituents selected from Cl and C14 alkyl; and R3 is hydrogen or C14 alkyl, provided that R2 is phenyl when R3 is alkyl; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound as claimed in claim 1 wherein R2 is 4-fluorophenyl.

3. A compound as claimed in claim 1 or claim 2 wherein R3 is hydrogen.

4. A compound as claimed in any preceding claim wherein R is hydrogen.

5. A compound as claimed in any preceding claim wherein R1 is C17 alkyl.

6. A compound as named herein.

7, 5-(4-Fluorophenyl)-N-methyl-6K-1 ,3,4-thiadiazin-2-amine.

8. N-Ethyl-5-(4-fluorophenyl)-6H-f,3,4-thiadiazin-2-amine.

9. A compound as claimed in any preceding claim for pharmaceutical use.

10. A compound as claimed in any preceding claim for use as a muscle relaxant.

11. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.