IE50432B1 - 5-aryl-6h-1,3,4-thiadiazine-2-amines - Google Patents

Description

The present invention relates to novel compounds having the formula wherein R is C^_7 alkyl; and the pharmaceutically 5 acceptable salts thereof.

R may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, isohexyl, n-heptyl or isoheptyl. 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 and phosphoric acid. Suitable organic acids are, for example, carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-phenoxyben2oic acids, or sulfonic acids such as methanesulfonic and 2-hydroxysulfonic acids.

Preferred compounds of the invention are 5-(4fluorophenyl)-N-methyl-6H-l,3,4-thiadiazin-2-amine and - (4-fluorophenyl)-N-ethyl-6H-l,3,4-thiadiazin-2-aiaine, and the pharmaceutically acceptable acid addition salts thereof.

' The compounds of this invention can have utility as muscle-relaxants. A pharmaceutical composition according to the invention comprises a compound of the invention in association with a physiologically 80432 - 3 acceptable excipient.

Compounds of the invention can be administered to warm-blooded animals, mammals, rats, mice, dogs, cats, horses, pigs, cows, sheep and humans. 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 anesthetised 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 administered can be any muscle-relaxing effective amount. The quantity of compound administered to a subject can vary over a wide range to provide from 10 to 100, preferably 10 to 30, mg/kg of subject body weight per day, to achieve the desired effect. Unit doses can contain about 5 to 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 may be prepared by reacting a 4-fluorophenacyl chloride or bromide with a 4-substituted thiosemicarbazide of the formula HjN-NH-CS-NHR wherein R is 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 or n-butanol, preferably methanol. The '50432 - 4 reaction time may vary from 15 minutes to 1 hour and is preferably about 30 minutes, depending upon the reactants, the solvent and the reaction temperature which may vary from 60 to 80°C, preferably about 65°C.

The product is generally worked up by permitting the reaction mixture to cool and then concentrating it in vacuo. The resultant residue is recrystallised 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, to give 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 reactions which are well known to those of ordinary skill in the art. For example, the phenacyl halide may be prepared by halogenating the corresponding methyl 4-fluorophenyl ketone using a sulfuryl halide, e.g. sulfuryl chloride, in, say, acetic acid, to prepare the corresponding phenacyl chloride; or by reacting fluorobenzene with a haloacetyl halide, e.g. chloroacetyl chloride, via a Friedel drafts reaction using, say, an aluminium trichloride catalyst. The 4-substituted thiosemicarbazide may be prepared conventionally by reacting the appropriate substituted isothiocyanate with hydrazine in the presence of, say, diethyl ether.

The following Examples 1 and 2 illustrate the preparation of the compounds of the invention.

EXAMPLE 1 -(4-Fluorophenyl)-N-raethyl-6£-l,3,4,-thiadiazin-2amlne hydrochloride 4.66 g of 4-methyl-thiosemic5rbazide and 8.63 g of 4-fluorophenacyl chloride are heated and stirred at reflux in 200 ml of methanol for 30 minutes. The - 5 solvent is then removed in vacuo. The residue is recrystallised from methanol/ethyl acetate; 5.6 g of title product, m.p, 139-141°C, are obtained and o dried under high vacuum at 65 C.

EXAMPLE 2 N-Ethyl-5-(4-fluorophenyl)-6fl-l,3,4-thladiazin-2-amine hydrochloride 11.19 g of 4-ethyl-thiosemicarbazide and 17.6 g of 4-fluorophenacyl chloride are heated and stirred under reflux (65°C) in 400 ml of methanol for 30 minutes in a one litre round-bottom flask equipped with a magnetic stirring bar and a condenser protected by a CaCl2 drying tube. The solution is allowed to cool to room temperature and is then concentrated to a yellow solid residue. The residue is recrystallised from methanol/butanone to yield 21.0 g (75.5%) of the title product, m.p. 192-193°C. The fluffy, yellowish-white solid is dried under high vacuum at 65°C.

The following Examples 3 to 6 illustrate compositions of'the invention. In each case, the active ingredient may be the product of either Example 1 or Example 2.

EXAMPLE 3 A portion of a 15 mg amount of wheat starch is used to make a granulated starch paste which is then granulated with the remainder of the wheat starch and 33.5 mg lactose, screened and mixed with 100 mg of the active ingredient and 1.5 mg magnesium stearate. The mixture is compressed into tablets weighing 150 mg each.

EXAMPLE 4 100 mg of the active ingredient is dissolved in 20 ml water for injection, with sufficient sodium chloride to render the solution isotonic. The composition may be administered parenterally, and dispensed in a single ampoule containing 100 mg of the active - 6 ingredient, for multiple dosage, or in 20 ampoules for single dosages.

EXAMPLE 5 200 mg of powdered active ingredient and 35 mg powdered talc are passed through a fine mesh screen and mixed well. The powder is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg per capsule.

EXAMPLE 6 Pills are prepared by blending, per pill, 200 mg of the active ingredient and 130 mg corn starch, and then adding 20 ml liquid glucose,with thorough kneading, to form a plastic mass from which the pills are cut and formed.

Claims (11)

1. wherein R is Cj_ 7 alkyl; or a pharmaceutically acceptable acid addition salt thereof.

2. 5-(4-Fluorophenyl)-N-methyl-6H-l,3,4-thiadiazin-2amine hydrochloride.

3. N-Ethyl-5-(

4. -fluorophenyl)-6fl-l,3,4-thiadiazin-2amine hydrochloride. 10 4. A process for preparing a compound of the formula wherein R is C^_ ? alkyl; or a pharmaceutically acceptable acid addition salt thereof; 15 which comprises: (a) reacting a phenacyl halide of the formula Ο II F wherein X is Cl or Br with a 4-substituted thiosemicarbazide of the formula II HgN-NH-C-KH-R 5. Wherein R is defined as above; (b) reacting a halide salt produced by (a) with a base to produce the corresponding free amine; or (c) reacting a free amine produced by (a) or (b) with a pharmaceutically acceptable salt to produce the corres10 ponding acid addition salt.

5. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 3 or a pharma ceutically acceptable acid addition salt thereof in associa tion with a physiologically acceptable excipient. 15

6. A composition as claimed in claim 5, which is in the form of a tablet, capsule, lozenge, pill, powder, suppository, solution, suspension, syrup, or emulsion.

7. A composition as claimed in claim 5 which is in unit dosage form. - 9

8. A method of achieving a muscle-relaxing effect in a non-human animal which comprises administering to the animal in which a muscle relaxing effect is desired an amount effective to achieve a muscle-relaxing effect of 5 a compound as claimed in any one of claims 1 to 3.

9. A process for preparing a compound of the formula given and defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to Examples 1 10. And 2 of the accompanying Examples.

10. A compound of the formula given and defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by a process claimed in a preceding claim.

11. 15 11. a pharmaceutical composition according to claim 5 substantially as hereinbefore described with particular reference to Examples 3-6 of the accompanying Examples.