IL46860A - 2-amino-5-(trifluoromethylphenyl) alkyl-1,3,4-thiadiazole derivatives their production and pharmaceutical compositions containing them - Google Patents

Description

4C860/2 • 46860/2 This invention relates to 2-amino- 5- ( trifluoromethyl phenyl) -alkyl-1 , 3 , 4-thiadiazoles , to their preparation and to pharmaceutical compositions containing them.

The invention provides compounds of formula I, and acid addition salts thereof in which is hydrogen, fluorine, chlorine or trifluorometh 1, lorine, in which R3 is an alkyl group having from 1 to 4 carbon atoms, n is 1,2,3 or 4 and m is 1,2 or 3, provided that (a) when R^^ is trifluoromethyl , the two trifluoromethyl groups are not attached . to adjacent carbon atoms, and - 2 - 600-6422/C (b) when is trifluoromethyl , R2 is hydrogen .

The invention also provides a process for the production of compounds of formula I, characterised by subject in which R^, R^, Z and the proviso are as defined above , to strong Lewis acid conditions.

The strong Lev/is acid conditions may be provided by employing a medium comprising a strong mineral acid, for example phospho 0r/ic, hydrochloric or sulphuric acids, or a phosphorus halide or oxyhalide, for example phosphorvus tribromide. Suitable reaction times vary, for example from 0.5 to 20 hours, preferably from 2 to 6 hours, and temperatures of from 40° to 100°C, preferably from 50° to 65°C may suitably be employed.

The reactions may be carried out in the absence of a solvent, or in the presence of an inert solvent, - 3 - 600-6422/C preferably an inert aromatic solvent, for example benzene,^ toluene, xylene or chlorobenzene.

The compounds of formula I may be isolated and purified using conventional techniques. Where required, free base forms of the compounds may be converted into acid addition salt forms in conventional manner, and vice versa.

The compounds of formula II may be obtained by ting a compound of formula III, in which R^, R^, Z and the proviso are as defined above, and X is chlorine or bromine, with thiosemicarbazide of formula IV, The process is suitably carried out in an inert solvent, suitably a dialkylformamide , for example dimethyl-formamide. A convenient reaction temperature is from 0° to 80°C, preferably from 15° to 50°C. A suitable reaction time is from 1 to 24 hours, preferably from 2 to 6 hours.

- - The compounds of formula II may be isolated. and ^ purified using conventional techniques. Alternatively, by carrying out the above process under strong Lewis acid conditions, the compound of formula II may undergo ring closure iri situ to give the compound of formula I.

. The compounds of formula III are known or may be obtained in known manner from available starting materials.

The compounds of formula I , possess pharmacological activity. In particular, they possess sedative- hypnotic and minor tranquilizer activity as indicated by 1) their ability to produce docility in behaviour tests in mice given 25 to 200 mg/kg of animal body weight, i.p. t of the test compound according to the 30-word adjective check sheet system basically as described in "Pharmacologic techniques in drug evaluation" ed. Nodine and SieglerN, Yearbook Medical Publishers, Chicago, 1964, pp 36-54; 2) by their ability to antagonize chronic convulsions and death in mice given 50 to 250 mg/kg i.p. of -sulfamoylazepine ; 3) by the hexobarbital reinduction method of Winter, (J. Pharmacol and Exp.

Therap. , 94, 7-11 1948) in which the reinduction of anesthesia after recovery from hexobarbital induced - 5 - 600-6422/C anesthesia is used to determine sedative-hypnotic activity--' in mice given 70 mg/kg of animal body weight, i.p. of hexobarbital followed immediately after, the mice regain their righting reflexes by 25 to 200 mg/kg of animal body weight, i.p., of the test compound; 4) as indicated in Cebus monkeys ^ implanted electrodes .

Brain readings are obtained via a ten or sixteen channel electroencephalograph. For the recording sessions, the monkeys are restrained by neck and waist plates in chairs in full side observation cages at the same time every night for thirteen and one half hours from Monday to Thursday.

Gross behaviour is monitored via closed circuit television and video tape recordings. The compounds of formula (I) are administered p.o. at a dosage of from about 1.8 to 60, about 30 mg/kg immediately on placing the monkey in 'the* -observation cages with at least seven days intervening between drug administrations. Physiological saline is administered via a similar route and at the same times/ on all control runs. Control data are collected at least three days per week and accumulated to give control data for fifteen sessions per monkey. Data from each session are statistically compared via computer analysis with the previous 5-15 control sessions for the particular animal, with particular emphasis given to the following phases of - 6 - 600-6422/C the sleep-wakefulness cycle: resting awake, light sleep, deep sleep, paradoxical (REM) sleep, "pseudo-" paradoxical sleep, latency to onset of deep sleep, and latency to onset of first epoch of paradoxical sleep; and 5) as indicated in the cat given typically 5 to 30 mg/kg of animal body weight of the active material and tested in sleep studies permanent using /chzonlG. cortical and subcortical electrode placements, with eye movement measured via electro-oculogram. Brain readings are obtained via Gross Model 6 electroencephalo¬ graphs, and the gross behaviour of the animal is monitored via closed circuit television and video tape recordings.

The compounds of formula I are accordingly indicated for use as minor tranquillisers and sedative-hypnotic agents .

An indicated suitable daily dosage for both uses is from 75 to 1500 milligrams. For minor tranquilliser use the dosage is preferably administered in divided doses of from 18 to 750 milligrams two to four times daily, or in retard form. For sedative-hypnotic use the dosage is preferably administered in a single dose at bedtime.

The compounds may be used in free base form or in the form of pharmaceutically acceptable acid addition salts, which salt forms have the same order of activity as the free base forms. Suitable acids for salt formation in^ elude inorganic acids, for example hydrochloric acid, and organic acids, for example succinic acid.

For such usage, the compounds of formula I may be admixed with conventional pharmaceutically acceptable diluents or carriers, and, optionally, other excipients, and administered in such forms as tablets or capsules.

A preferred group of compounds of formula I are those in which and R2 are hydrogen, the CF^ group is in the meta-position, and Z is ^CE^ where n= 1,2,3 or 4.

A particularly preferred compound is 2-amino-5- ( 3-trifluoro- methylbenzyl) -1 , 3 , 4-thiadi azole . (Compound A).

Compounds of a structure similar to that of the compounds of the present invention but which do not bear at least one trifluoromethyl substituent in the phenyl ring are known from DOS 2,212,245.

The biological activity of 2-amino-5-(2~phenethyl)-1 ,3,4-thiadiazole (Compound B), which is the most active from among the known compounds, was compared with the activity of the above-mentioned preferred Compound A.

Although in the docility test in mice (test method 1-)-on page 4) there was no significant difference between the activities of the compounds, Compound A having an ED^Q of 118.2 mg/kg and Compound B having 125.9 mg/kg, in the more important sedative-hypnotic test on Cebus monkeys (test method A- on page 5),. it was found that whereas Compound B was inactive at a dosage of 30 mg/kg p.o. and actually increased waking time at 15 mg/kg, Compound A had an ED^ of 15 mg/kg and was thus 46860/2 EXAMPLE 1 1- ( 3 ' -Tri fluoromethylphenylacetyl ) -thiosemicar- i bazide (II) Λ mixture of- 60.0 g (0.3 mole) of ( 3-trifluorome- thylphenyl) acetic acid and 80 ml of thionyl chloride in the presence of 10 drops of dimethylfor amide is heated on a water bath for 3 hours. The excess thionyl chloride is evaporated under reduced pressure, and any remaining traces of thionyl. chloride are removed by addition of dry benzene followed by evaporation. To the resulting acid chloride dissolved in 100 ml of absolute dimethylformamide is added with cooling 29.3 g (0.32 mole)- of thiosemicarbazide. 'The mixture is maintained at room temperature overnight and the excess solvent is removed under reduced pressure. On addition of ice water to the residue, a solid is precipi¬ tated which is then recrystallized from acetone/hexane to give 1- ( 31 trifluoromethylphenylacetyl) -thiosemicarbazide m.p. 1970-199°C.

EXAMPLE 2 (Compounds of formula II) Following the procedure of Example 1 and using appropriate starting materials in approximately equivalent amounts, the following compounds may be obtained :- a) 1- (4 ' -tri fluoromethylphenylacetyl) thiosemicarbazide, ■■ . · .· b) 1- (3* jS'-biSCtrifluoroniethyDphenylacetyD thiosemi- carbazide, c) 1- (5'-chloro-3 ' -trifluoromethylphenylacetyl)^thiosemicarbazide , d) 1- (2' , 5 ' -dichloro-3 ' -trifluoromethylphenylacety1) / thiosemicarbazide, e) 1- (3-/3"' -"trifluoromethylphenyl7-propionyl) ^thiosemicarbazide, f) 1- (4-/3 '-trifluoromethylphenyl7-butyryl) 7'thiosemi- carbazide, g) 1- (5-/3*' -trifluoromethylphenyl7-pentanoyl) 7;thiosemicarbazid h) 1- ( 2-/T'-trifluoromethylphenyl/-propionyl) thiosemicarbazide, i) 1- (3-/3* -trifluoromethylphenyl7-butyryl) /thiosemicarbazide, j) 1- (4-/3 ' -trifluoromethylphenyi -pentanoylJrthiosemi- carbazide, or k) 1- (2-methyl-3-/T' -trifluoromethylphenyl7-propionyl)^ thiosemicarbazide . 1) 1 —( 3- 2 ' ,6 '-dichloro-3' -trifluoromethylphenyl7-propionyl) thiosemicarbazide EXAMPLE 3 2-Amino- 5- ( 3-trifluoromethylbenzyl) -1 , 3 , -thia- diazole (I) A mixture of 32.0 g (0.115 mole) of 1- (3 '-trifluoro-methylphenylacetyl) -thiosemicarbazide and 48.0 g of phosphorous tribromide is heated in a water bath to a temperature of 60°-65°C and maintained at that temperature for 4 hours. The resulting mixture is cooled and poured into a 50% weight/volume - 10 - 46860/2 solution of sodium hydroxide in ice water. The resulting ^ product is extracted with methylene chloride, washed with water and dried over anhydrous potassium carbonate. The solvent is evaporated and the residue recrystallized from methanol and water to give 2-amino-5~ ( 3-trifluoromethyl-benzyl) -1, 3 , 4-thiadiazole , m.p. 174°-176°C.

EXAMPLE 4 (Compounds of formula I) a Following the procedure of Example 3 and using 1-in place of/(3 ' -trifluoromethylphenylacetyl -thiosemi- j carbazide, an approximately equivalent amount of the compounds of Example 2 a) to k), the following compounds may be obtained :- a) 2-amino-5-(4-trifluoromethylbenzyl)-1 ,3,4-thiadiazole, m.p. 194-195°C, b) 2-ramino-5-(3»5-bis/trifluoromethyl7benzyl)-1 ,3,4-thiadiazole, c) 2-amino-5-(5-chloro-3-trifluoromethylbenzyl)-1 ,3,4- thiadiazole, d ) 2-amino-5-( , 5-d ichloro-3-trifluorometh lbenzyl)- 1 ,3,4-thiadiazole, e) 2-amino-5-/2- (3-tr fluoromethylpheneth 1^7-1 ,3,4- thiadiazole, m.p. 151-152°C, f ) 2-amino-5- 3-(3-trifluoromethylphenyl)propyl7-1 ,3,4- thiadiazole, m.p. l6l°-l62°Cf 46860/3 - 11 - g) 2-amino-5- [4- ( 3-trifluorornethylphenyl) butyl ] -1 , 3 , 4- thiadiazole, m.p. 135°-137CC, h) 2-amino-5- (1- [3-trifluorornethylphenyl] -ethyl) -1 , 3 , 4- thiadiazole, m.p. 163°-164.5°C, i) 2-amino-5- (2 - [3 -trifluorornethylphenyl] -propyl) -1,3,4- thiadiazole , m.p. 138-1 0°C, < j) 2-amino-5- (3 - [ 3-trifluorornethylphenyl] -butyl) -1,3,4- thiadiazole, or k) 2-amino-5- (l-methyl-2- [3-trifluorornethylphenyl] -ethyl) - 1, 3 , 4-thiadiazole, m.p. 131-133°C. 1) 2-amino-5-/2-(2,6-dichloro-3-trifluoromethylr phenethylj,7-1 »3»4-thiadiazole , m.p. 167-168.5°C 46860/2 - 12 -

Claims (15)

1. A process for the production of 2-amino-5- ( trifluoromethylphenyl) alkyl-1 , 3 , 4-thiadiazoles of the formula and of acid addition salts thereof in which is hydrogen, fluorine, chlorine or trifluoromethyl , R2 is hydrogen, fluorine or chlorine, ,3 or . -fCH, —CH-, 2 m in which R^ is an alkyl group having from 1 to 4 carbon atoms, n is 1,2,3 or 4 and m is 1,2 or 3 , provided that (a) when R is trifluoromethyl , the two trifluoromethyl groups are not attached ^ to adjacent carbon atoms, and 46860/2 -13 - (b) when is trifluoromethyl , R2 is hydrogen^ characterised subjecting a compound of formula II, in which R^, R^, Z and the proviso are as defined above , trong Lewis acid conditions.'

2. A process for the production of a compound of formula I, stated in claim 1, substantially as described in Example 3 or Example 4.

3. A compound of formula I, stated in claim 1, and its acid addition salts whenever prepared by a process as claimed in claim 1 or claim 2.

4. A compound of formula Γ7~ stated in claim 1 and its acid addition salts.

5. A compound as claimed in claim 3 or claim 4 , in which and R2 are hydrogen, the CF3 group is in the meta-position and Z is iCH where n is 1,2,3 or 4. 46860/3

6. 2-Amino 5-( 3~trifluoromethylbenzyl)~1 , 3 , 4-thiadi

7. 2-Amino-5-(3-trifluoroinethylphenethyl)-1 , 3»4-thiadiazo¾*,

8. · 2-Amino 5-/3- ( 3-trifluoromethylphenyl)propy2-7-1 ,3,4-thiadiazole.

9. 2-Amino-5- 4-(3-trifluoromethylphenyl) utyl7-1 »3,4-thiadiazole.

10. 0. 2-Amino 5_( 1 -/3-trifluoromethylphenyl)-ethyl7-1 ,3,4-thiadiazole.

11. · 2-Amino-5-i4-trifluoromethylbenzyl)-1 , 3, 4-thiadiazole,

12. 2-Amino-5-(2- 3-trifluoromethylphenyl7-propyl)-.1 ,3*4-thiadiazole.

13. 2-Amino-5-( 1 -methyl-2- 3-trifluoromethylphenyl7-ethyl)- 1 ,3,4-thiadiazole.

14. A compound according to any one of Claims 3-13 in the form of an acid addition salt.

15. A pharmaceutical composition comprising a compound according to any one of Claims 3-13» in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutically acceptable diluent or carrier. PC:mz