CA1152991A - 5-(optionally substituted phenyl)-6h-1,3,4- thiadiazine-2-amines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE A method of achieving a muscle-relaxing effect in a patient comprises administering to a patient in which a muscle relaxing effect is desired an amount effective to achieve a muscle-relaxing effect of a compound of the formula wherein R is H, or , or C1-7 straight or branched chain alkyl; R1 is H, Cl-7 straight or branched chain alkyl, allyl or phenyl; R2 is phenyl, phenyl monosubstituted with F, Cl, C1-4 straight or branched chain alkyl or phenyl disubstituted in the 2- and 4-positions with Cl or C1-4 straight or branched chain alkyl; and R3 is H or C1-4 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.

Description

1~ 52~91 M-1049 Foreign 5-(OPTIONALLY SUBSTITUTED PHENYL)-6H-1,3,4-THIADIAZINE-2-AMINES
SUMMARY OF THE INVENTION
The present invention relates to fluorophenyl com-pounds which are useful as muscle relaxants and which have the following general formula S.~ NH-alkyl ~ ~ ~N
wherein the alkyl group contains 1-7 carbon atoms and is straight or branched chain. Such compounds show a parti-~: 10 cularly desirable separation of effects producing a muscle rel:axant effect at doses which are not sedative.
The present application also relates to a method of ~ : achieving a muscle-relaxing effect in a patient comprises :~: :administering to a patient in which a muscle relaxing effect is desired an amount effective to achieve a mus-~; cle-relaxing efect of a compound of the formula ~: : R
R3~ S ~ N-R

: :wherein R i5 H, Cl 7 straight or branched chain alkyl;
:Rl is H, Cl_7 straight or branched chain alkyl, allyl ~or phenyl;

:. : . , M-1049 Foreign R2 is phenyl, phenyl monosubstituted with F, Cl, Cl_4 straight or branched chain alkyl or phenyl disubstituted in the 2- and 4-positions with Cl or Cl_4 straight or branched chain alkyl; and R3 is H or Cl_4 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.
DETAILED DESCRIPTION OF THE INVENTION
Illustrative examples of straight or branched chain Cl_7 alkyl groups which R and Rl may represent as used herein include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pen-tyl, isopentyl, neopentyl, n-hexyl, iso-hexyl, n-heptyl, iso-heptyl, etc. Illustrative examples of straight or branched chain Cl_s alkyl and Cl_4 alkyl groups mentioned in describing the groups Rl and R2-R3, respectively, in-clude, 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 phos-phoric acid. Suitable organic acids are, for example,carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tar-taric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and

2-phenoxybenzoic, 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-fluoro-phenyl, and R3 is H.
Illustrative examples of compounds of this invention include those wherein R and Rl ~re H, CH3, C2Hs or C3H7, ' ::

~1~2$91 M-1049 Foreign especially those wherein one of R and Rl is H. These include, for example, N-methyl-5-phenyl-6H-1,3,4-thiadia-zin-2-amine, N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadia-zin-2-amine, 5-(2,4-dichlorophenyl)-6H-1,3,4-thiadiazin-s 2-amine, 5-(2,4-dichlorophenyl)-N-methyl-6H-1,3,4-thia-diazin-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-dichlorophe-nyl)-N-(l-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-thiadiazin-2-amine, N-ethyl-6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine, 5-(2,4-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-thia-diazin-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 demon-strating 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, suspen-sions or emulsions for oral and parenteral administration.

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~i52~91 M-1049 Foreign The dosage unit administered can be any muscle-relaxing effective amount. The quantity of compound administered c:an vary over a wide range to provide from about 10 to ~.00, 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 .. .
~2--C-C-x wherein X is Cl or Br, with a 4-substituted thiosemicarbazide of the formula S

Rl wherein R, Rl, R2 and R3 are as hereinbefore defined. The reaction is generally conducted in the presence of a sol-vent, e.g., a lower alkanol, such as, methanol, ethanol, isopropanol, n-propanol, n-butanol and the like, pre-ferably methanol. ~he reaction time may vary from about 15 minutes to about 1 hour, preferably about 30 minutes, depending upon the reactants, the solvent and the reaction temperature which may vary from about 60C to about 80C, preferably about 65C. The product is generally worked-up by permitting the reaction mixture to cool and then con-centrating it in vacuo. The resultant residue is recrys-tallized from an appropriate solvent, e.g., a mixture of a lower alkanol with, e.g., acetone, butanone or ethyl ace-tate, 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 thio-semicarbazide which are employed as starting materials in the preparation of the compounds of Formula I are either commercially available or, when unavailable, are very ~1~2991 M-1049 Foreign readily preparable by standard chemical reactions which are well-known to those of ordinary skill in the art. For example, the phenacyl halides may be prepared by halo-yenating the corresponding methyl (optionally-substi-tuted)phenyl ketone using a sulfuryl halide, e.g., sul-furyl chloride, in e.g., acetic acid, to prepare the cor-responding phenacyl chloride or by reacting the corres-ponding 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-sub-stituted thiosemicarbazides may be prepared by conven-tionally reacting the appropriate substituted isothio-cyanate with hydrazine in the presence, e.g., of diethyl ether.
EXAMPLES
The following examples are illustrative of the inven-tion.

N-Methyl-5-phenyl-6H-1,3,4-thiadiazin-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 t65C) 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-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydro-chloride are deposited. m.p. 176-178C.

N-Ethyl-5-(4-fluorophenyl)-6 -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 (65C) 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 CaC12 drying ~ iS~g 9 1 M-1049 Foreign 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)-6H-1,3,4-thiadiazin-2-amine hydrochloride. m.p. 192-193C. The fluffy, yellowish white solid is dried under high vacuum at 65C.

5-(2,4-Dichlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydro-chloride 11.17 g (.05 mole) of 2,4-dichlorophenacyl chloride and 4.36 g (.05 mole) of thiosemicarbazide are stirred and heated in 2S0 ml of methanol at reflux (65C) for 30 minu-tes. The resultant suspension is allowed to cool and is filtered to yield a first crop of 4.S6 g of 5-(2,4-di-chlorophenyl)-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.
170-172C.

5-(2~4-DichloroPhenyl)-N-methyl-6H-l~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 65C under high vacuum to produce 5-(2,4-di-chlorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine mono-hydrochloride. m.p. 195C.
EXAMPLE S
5-(2v4-Dichlorophenyl)-N-ethyl-6H-1,3,4-thiadiazin-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 ~5;~:!39~
M-1049 Foreign ml of methanol to produce 6.5 g of 5-(2,4-dichlorophe-nyl)-N-ethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride after recrystallization which, in this case, was from methanol/ethyl acetate. m.p. 197-198C.

';-(2,4-Dichlorophen~l)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 4.16 g (.035 mole) of 4,4-dimethyl-thiosemicarbazide and 7.82 g (.035 mole) of 2,4-dichlorophenacyl chloride are reacted under the conditions of Example 2. After con-centration, ethyl acetate is added to the residue and fur-ther concentration is employed. A yellow, needle-like solid is produced. The solid is dried under high vacuum at 65C. Subsequently, it is recrystallized from metha-nol/ethyl acetate and again dried under high vacuum toproduce 5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thia-diazin-2-amine monohydrochloride. m.p. 219-222C.

5-(2,4-Dichlorophenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-amine monohYdrochloride 4.54 9 (.03 mole) of 4-phenyl-thiosemicarbazide and 6.70 9 (.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 metha-nol/ethyl acetate, yielding 6.5 g of 5-(2,4-dichloro-phenyl)- N-phenyl-6H-1,3,4-thiadiazin-2-amine monohydro-chloride. m.p. 186C. The solid was subsequently dried under high vacuum at 65C.

5-(2J4-Dichloro~henyl)-N-(l-methylethYl)-6~-1 L3 ~ 4-thiadia-zin-2-amine monohydrochloride

3.99 g (.03 mole) of 4-isopropyl-thiosemicarbazide and 6.70 g l.03 mole) of 2,4-dichlorophenacyl chloride are reacted in 150 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 65C and recrystallized again from methanol/ethyl acetate. It is finally dried ' ! ~ : . ' ' :

' 1152~91 M-1049 Foreign again at 65C under high vacuum producing 5-(2,4-dichlo-rophenyl)-N-(l-methylethyl)-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 207-208C.

5-(2,4-Dichlorophenyl)-N-propyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 6.70 g ~.03 mole) of 2,4-dichlorophenacyl chloride and 3.99 g (.03 mole) of 4-n-propyl-thiosemicarbazide are reacted in 150 ml of methanol under the conditions of Example 2. The concentrated product is crystallized and then recrystallized from methanol/ethyl acetate, to pro-duce 6.4 g of 5-(2,4-dichlorophenyl)-N-propyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 184-185C.
The product is then dried at 65C under high vacuum.

5-(2-FluorophenYl)-~-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride 8.62 9 (.05 mole) of 2-fluorophenacyl chloride and 5.22 g of 4-methyl-thiosemicarbazide are reacted in 150 ml of methanol under the conditions of Example 2. The pro-duct is recrystallized from methanol/ethyl acetate, yield-ing 6.7 g of 5-(2-fluorophenyl)-N-methyl-6H~1,3,4-thia-diazin-2-amine monohydrochloride. m.p. 183-184C.

5-(2,4-~ichloroPhenYl)-N-hexyl-6H-l~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 con-ditions of Example 2 in 200 ml of methanol. The resultant solid is recrystallized from methanol/ethyl acetate pro-ducing 4.5 9 of 5-(2,4-dichlorophenyl)-N-hexyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 173-174C.

~-ButYl-s-l2~4-dichlorophe-nyl)-6H-l~3~4-thiadiazin-2 amine monohYdrochloride

4.47 g of 2,4-dichlorophenacyl chloride and 2.66 9 of 4-n-butyl-thiosemicarbazide are reacted under the con-ditions of Example 2 in 150 ml of methanol. The solid ,, ' M-1049 Foregin llSZ9~
g obtained is recrystallized from methanol/ethyl acetate, producing 3.98 g of N-butyl-5-(2,4-dichlorophenyl)-6H
:L,3,4-thiadiazin-2-amine monohydrochloride. m.p. 180-182C.

S-(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-6H-1,3,4-thia-diazin-2-amine. m.p. 188-189C.

5-(2,4-Dichlorophenyl)-N-hePtyl-6H-1,3,4-thiadiazin-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 recrystal~lzation from methanol/methyl acetate, 5.2 g of 5-(2,4-dichloro-phenyl)-N-heptyl-6H-1,3,4-thiadiazin-2-amine monohydro-chloride are produced. m.p. 175-177C.

N-Ethyl-6-methyl-5-Phenyl-6H-l~3~4-thiadiazin-2-amine hydrobromide .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-phe-nyl-6H-1,3,4-thiadiazin-2-amine hydrobromide. m.p. 174--175C. After recrystallization from methanol/ethyl ace-tate, the product is dried at 65C under high vacuum.

5-(4-FluoroPhenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride ~.63 g of 4-fluorophenacyl chloride and 4.66 g of 4-methyl-thiosemicarbazide are reacted by using the con-ditions of Example 1. The resultant product is recrystal-lized from methanol/ethyl acetate yielding 5.6 g of ~ . .
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1~52991 M-1049 Foreign 5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride. M.p. 139-141C. The product compound is dried under high vacuum at 65C.

An illustrative composition for tablets is as fol-lows:
Per Tablet ta) 5-(2,4-Dichlorophenyl)-N-methyl- 100.0 mg 6H-1,3,4-thiadiazin-2-amine monohydrochloride (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 150 mg each.

An illustrative composition for a parenteral injec-tion is the following wherein the quantities are on a weight to volume basis.
Amount (a) 5-(2,4-Dichlorophenyl)-N-methyl- 100.0 mg 6H-1,3,4-thiadiazin-2-amine monohydrochloride (b) Sodium chloride q.s.
(c) Water for injection to make 20.0 ml -The composition is prepared by dissolving the active in-gredient (a) and sufficient sodium chloride in water for injectioh to render the solution isotonic. The composi-tion may be dispensed in a single ampoule containing 100 mg of the active ingredient for multiple dosage or in 20 ampoules for single dosage.

1~ 5 ~ ~ 1 M-1049 Foreign An illustrative composition for hard gelatin capsules is as follows:
Amount (a) 5-(2,4-Dichlorophenyl~-N-methyl- 200.0 mg 6H-1,3,4 thiadiazin-2-amine monohydrochloride (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.

An illustrative composition for pills is the fol-lowing:
-Per Pill (a) 5-(2,4-Dichlorophenyl)-N-methyl- 200 mg 6H-1,3,4-thiadiazin-2-amine monohydrochloride (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 glu~ose with thorough kneading to form a plastic mass from which the pills are cut and formed.

The compounds of the preceding examples each can be administered to achieve muscle relaxation in a patient in which a mu5cle-relaxing effect is desired, e.g., in a patient suffering from a muscle spasm. Muscle relaxation is inducible in rats by adminlstration o chlordiazepoxide (Librium) paenterally (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 tha potency of chlordiazepoxide while the compound of Example 10 has about 1/2 the po~ency of .

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~, 1~91 M-104~ Foreign chlordia7epoxide, 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 S conditions (adjusted for differential potency) as those seen in rats for chlordiazepoxide. For example~ the com-pound of Example 6 could be administered in doses of 1-50 mg, 2 to 4 times daily, to achieve beneficial effects.

Compositions similar to those described in Examples 17-20 are prepared except that 5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride or N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine hy-drochloride are used in place of the 5-(2,4-dichloro-phenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochlo-ride.

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Claims (6)

1. The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:
   l. A process for preparing a compound of the formula wherein alkyl contains 1-7 carbon atoms and is straight or branched;
   and the pharmaceutically acceptable acid addition salts thereof;
   which comprises:
   (a) reacting a phenacyl halide of the formula wherein X is C1 or Br with a 4-substituted thiosemicarbazide of the formula wherein alkyl 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 corres-ponding acid addition salt.
2. 2. A process according to claim l for preparing 5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine which comprises reacting 4-fluorophenacyl chloride with 4-methylthiosemicarbazide.
3. 3. A process according to claim 1 for preparing N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine which comprises reacting 4-fluorophenacyl chloride with 4-ethylthiosemicarbazide.
4. 4. A compound of the formula wherein alkyl contains 1-7 carbon atoms and is straight or branched whenever prepared by the process of claim 1.
5. 5. 5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadia-zin-2-amine whenever prepared by the process of claim 2.
6. 6. N-Ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadia-zin-2-amine whenever prepared by the process of claim 3.