CA1050031A - 2,5-substituted thiadiazoles - Google Patents
2,5-substituted thiadiazolesInfo
- Publication number
- CA1050031A CA1050031A CA222,445A CA222445A CA1050031A CA 1050031 A CA1050031 A CA 1050031A CA 222445 A CA222445 A CA 222445A CA 1050031 A CA1050031 A CA 1050031A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- amino
- hydrogen
- trifluoromethyl
- thiadiazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
2,5-SUBSTITUTED THIADIAZOLES
Abstract of the Disclosure Novel 2,5-substituted thiadiazoles are described which are useful as minor tranquilisers/sedative-hypnotics. These compounds have the following structure:
Abstract of the Disclosure Novel 2,5-substituted thiadiazoles are described which are useful as minor tranquilisers/sedative-hypnotics. These compounds have the following structure:
Description
Thi.s invention relates to 2,5-substituted thiadia--zoles.
The invention provides cornpcunds of formula I, Rl ~ N-N
R2 Z~S~NH2 in which Rl is hydrogen, fluorine, chlorine or trifluoromethyl, R2 is hydrogen, fluorine or chlorin~, and Z is 13 2tn ' HtCH2t(n-~- 13 or tCH~ ~ C~-, ~ in which R3 is an alkyl sroup having from 1 to 4 carbon atoms, n is 112,3 or 4 .: and m is 1,2 or ~, pro~ided that laj when R~ is trifluoromethyl, the two . trifluoromethyl groups are not attached lS to ad~acent carbon atoms, and i ~ 2 - 600-6422/~
3~L
(b) when Rl is trifluoromethyl, R2 is hydrogen.
The invention also provides a process for the production of compounds of formula I, characterised by subjecting a compound of formula II t z~ ~NH/ ~C~ 2 II
in which Rl, ~2' Z and the proviso are as defined above, to strong Lewis acid c~nditions.
: The strong Le~7is acid conditions may be provided by employing a medium comprisins a strong mineral acid, for example phosphoric, hydrochloric or sulphuric acids, or a phosphorus halide or o~yhalide, for ~xample phosphorus 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 100C, preferably : from 50 to 65C 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 - ~00-6~22/C
3~
preferably an inert aromatic solvent, for example b~nzene, 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 con~entional manner, and vice versa.
The compounds of formula II may be obtained by reacting a compound of formula III, ~ 3 III
in which Rl, R2, Z and the proviso are as defined above, and X is chlorine or bromine, with thiosemicarbazide of formula IV, NH2-NH-~-NH2 - 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 80C, preferably from 15 to 50C. A suitable reaction t~me 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 Le~is acid con-ditions, the compound of formula II may undergo ring closure ln situ to give the compo~nd of formula I.
The compounds of formula III are known or may be obtained in kno~m manner from available starting materials.
The compounds of formula I , possess pharmacolo-gical activity. In par.icular, they pocsess 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 OL animal body ~eight, i.p.
of the test compound accordir.g to the 30-~Jord adjective check sheet system basically as described by Ir~in, S.
(Gordon Research Conference, Medicinal Chemistry, 1959~ and Chen (Symposium on Sedative and Hypnotic Drugs, Williams and l~lilkins, 1954): 2) by their ability to antagonize clonic convulsions and death in mice aiven 50 to 250 mg/kg i.p. of the test substance prior to administration of 50 mg/kg i.p. of N-sulfamoylazepine; 3) by the hexobarbital reinduction method of Winter, (J. Pharmacol and Exp.
Therapc, 94, 7-11 1946) in ~hich th~ reinduction of ancsthesia after recovery from hexobarbital induced i ~,~
~05~(~31 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 using chronically implanted electrcdes.
Brain readings are obtained via a ten or sixteen channel elec~ncephalograph. 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 about 30 mg/kg immediately on placing the monkey in the observation cages with at least seven days intervening between drug administration~. 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 ~eek and accumulated to give control data for fifteen sessions per monkey. Data from each session are statistically compared via computer analysis ~ith the previous 5-15 control sessions for the particular ani~al, w1th part cu1ar emphasls given to the fo11owing phases of , - 6 ~ 600-6422/C
the sleep-wakefulness cycle: resting awake, light sleep, deep sleep, paradoxical (R~M) 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 using chronic 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 ~;
vla closed circult television and video tape recordings.
The compounds of formula I are accordingly ;~ indicated for use as minor tranquillisers and sedative-hypnotic agents.
lS An indicated suitable daily dosage for both uses is from 75 to 1500 milligrams. FQr minor tranquilliser use the dosage is preferably administere 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.
-T~e compounds may be used in free base form or in the form of pharmaceutically acceptable acid addition ,.. . .
. ~ .
~ 7 - ~00-6~22/C
3~
salts, which salt forms have the same order of activity as the free base orms. Suitable acids for salt formation in-clude 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 Rl and R2 are hydrogen, the CF3 group is in the meta-position, and Z is tCH2~ where n= 1,2,3 or 4.
n A particularly preferred compound is 2-amino-5-(3-t~ifluoro-methylbenzyl)-1,3,4-thiadiazole.
The iollowing Examples i.lustrate the in.ention:-, .
- .. . . .
~()50(~3~ 600-6 ~22~c ) 1-(3'-Trifluoromethylphenylacetyl)-thiosemicarbazide (II) A mixture of 60.0 g (0.3 mole) of 3-trifluorome-thylphenylacetic acid and 80 ml of thionyl chloride in the S presence of 10 drops of dimethylformamide is heated on a water bath for 3 hours. The e~cess thionyl chloride is evaporated ur.der reduced pressure, and any rem2ining traces of thionyl chloride are removed by addition of dry benzene followed by evaporation. To the resultins acid chloride dissolved in 100 ml of absolute di~.ethylfor~a~ide is added with cooling 29.3 g (0.32 mole~ of thiosemica~bazide. The mixture is maintained at room temperature overnight and the excess solvent is removed under reduced pressure. On addition of lce ~tater to the residue, a solid is precipi-tated ~Ihich is then recrystallized from acetone/hexane to give 1-(3'-trifluoromethylphenylacetyl)-thiosemicarbazide, m.p. 197 - 199C.
EX~SPLE ? ~Compounds of formula II) Follo~ing the procedure of Example 1 and using appropriate starting materials in approximately equivalent amounts, the fol1ow~ng compounds may be obtained:-.. , ~' ' .
.. . .
~5~33l a) 1-(4'-trifluoromethylrhenylacetyl.) thiosemicarbazide~
b) 1-(3',5'-di(trifluoromethyl)phenylacetyl)~thiosemi~
car~azide, c) 1-(5'-chloro-3'~trifluoromethylphenylacetyl~-thio-se~icarbazide, d) 1-(2',5'-dlchloro-3'-trifluoromethylphenylacetyl)-~hiose~icarbazide, . .
e) 1-(3-/3'-trifluoromethylphenyl7-propionyl)-thiosemi-carbazide, : . f) 1-(4-/3'-trifluoromethylphenyl7-butyryl) ~thiosemi-carbazide, g) 1-(5-/3'-trifluoromethylphenyl7 pentanoyl)-thiosemi~arbazide h) 1-(2-/3'-trifluoromethylphenyl7-propionyl)-thiosemi-carbazide, i) 1-(3-/3'-trifluoromethylphenyl7-butyryl)-thiosemicarbazide, (4-/3'-trifluoromethylphenyl7-pentanoyl)-thiosemi-carbazide, or ~ k) 1-(2-methyl-3~/3'-trifluoromethylphenyl7-propionyl)-: thiosemicarbazide.
: EX~PLE 3 2-Amino-5-~3-trifluoromethylbenzyl)-1,3,4-thia _ diazole (I) I
A mixture of 32.0 g ~0.115 mole) of 1-~3'-trifluoro-methylphenylacetyl)-thiosemicarbazide and 48.0 g of phosphorus tribromide is heated in a waterbath to a temperatur~ of 60-65C and mai~tained at that temperature for 4 hours. The resulting mixture is cooled and poured into a 50% weight/volume ., .
~ ' ~1 ~ 10 - 600-6422/C
3~
-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-~enzyl)-1,3,4-thiadiazole, m.p. 174-176C.
EXA~PLE 4 (Compounds of formula I) Follo~ling the procedure of Example 3 and using . in place of 3'-trifluoromethylphenylacetyl-3-thiosemi-carbazide, an approximately equivalent amount of the comPounds of Example 2 a)to k), the follo~ing compounds may be obtained:-a) 2-amino-5-(4-trifluoromethylbenzyl)-1,3,4-thiadiazole, m.p. 194 - 195C.
b) 2-amino-5-(3,5-di[trifluoromethyl]benzyl)-1,3,4-thia-diazole, c) 2-amino-5-(5-chloro-3-trifluoromethylbenzyl)-1,3,4-thiadiazole, d) 2-amino-5-(2,5-dichloro-3-trifluoromethylbenzyl)-1,3,4-thiadiazole, e) 2-amino-5-(3-trifluoromethylphenethyl)-1,3,4-thiadiazole, m.p. 151-152C, f) 2-amino-5-(3-trifluorcmethylphenylpropyl)-1,3,4-thia-diazole, m.p. 161-162C, .
,~
~ 600-6422/C
~J g) 2-amino-5-(4-[3-trifluoromethylphenyl]butyl)-1,3,4-thiadiazole, m.p. 135 - 137C., h) 2-amino-5~ [3-trifluoromethylphenyl3-ethyl) 1,3,4-thiadiazole, m.p. 163 - 164.5C., i) 2-amino-5-(2-[3-trifluoromethylphenyl3-propyl)-1,3,4-thiadiazole, m.p. 138 - 140C., j) 2-amino-5-(3-[3-trifluororethylphenyl]-butyl)-1, 3, A -thiadiazole, or - k) 2-amino-5~ methyl-2-r3-trifluoromethylphenyl]-ethyl)-1,3,4-thiadiazole, m.p, 131-133C.
A~
.. . .. .
~ . .
The invention provides cornpcunds of formula I, Rl ~ N-N
R2 Z~S~NH2 in which Rl is hydrogen, fluorine, chlorine or trifluoromethyl, R2 is hydrogen, fluorine or chlorin~, and Z is 13 2tn ' HtCH2t(n-~- 13 or tCH~ ~ C~-, ~ in which R3 is an alkyl sroup having from 1 to 4 carbon atoms, n is 112,3 or 4 .: and m is 1,2 or ~, pro~ided that laj when R~ is trifluoromethyl, the two . trifluoromethyl groups are not attached lS to ad~acent carbon atoms, and i ~ 2 - 600-6422/~
3~L
(b) when Rl is trifluoromethyl, R2 is hydrogen.
The invention also provides a process for the production of compounds of formula I, characterised by subjecting a compound of formula II t z~ ~NH/ ~C~ 2 II
in which Rl, ~2' Z and the proviso are as defined above, to strong Lewis acid c~nditions.
: The strong Le~7is acid conditions may be provided by employing a medium comprisins a strong mineral acid, for example phosphoric, hydrochloric or sulphuric acids, or a phosphorus halide or o~yhalide, for ~xample phosphorus 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 100C, preferably : from 50 to 65C 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 - ~00-6~22/C
3~
preferably an inert aromatic solvent, for example b~nzene, 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 con~entional manner, and vice versa.
The compounds of formula II may be obtained by reacting a compound of formula III, ~ 3 III
in which Rl, R2, Z and the proviso are as defined above, and X is chlorine or bromine, with thiosemicarbazide of formula IV, NH2-NH-~-NH2 - 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 80C, preferably from 15 to 50C. A suitable reaction t~me 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 Le~is acid con-ditions, the compound of formula II may undergo ring closure ln situ to give the compo~nd of formula I.
The compounds of formula III are known or may be obtained in kno~m manner from available starting materials.
The compounds of formula I , possess pharmacolo-gical activity. In par.icular, they pocsess 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 OL animal body ~eight, i.p.
of the test compound accordir.g to the 30-~Jord adjective check sheet system basically as described by Ir~in, S.
(Gordon Research Conference, Medicinal Chemistry, 1959~ and Chen (Symposium on Sedative and Hypnotic Drugs, Williams and l~lilkins, 1954): 2) by their ability to antagonize clonic convulsions and death in mice aiven 50 to 250 mg/kg i.p. of the test substance prior to administration of 50 mg/kg i.p. of N-sulfamoylazepine; 3) by the hexobarbital reinduction method of Winter, (J. Pharmacol and Exp.
Therapc, 94, 7-11 1946) in ~hich th~ reinduction of ancsthesia after recovery from hexobarbital induced i ~,~
~05~(~31 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 using chronically implanted electrcdes.
Brain readings are obtained via a ten or sixteen channel elec~ncephalograph. 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 about 30 mg/kg immediately on placing the monkey in the observation cages with at least seven days intervening between drug administration~. 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 ~eek and accumulated to give control data for fifteen sessions per monkey. Data from each session are statistically compared via computer analysis ~ith the previous 5-15 control sessions for the particular ani~al, w1th part cu1ar emphasls given to the fo11owing phases of , - 6 ~ 600-6422/C
the sleep-wakefulness cycle: resting awake, light sleep, deep sleep, paradoxical (R~M) 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 using chronic 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 ~;
vla closed circult television and video tape recordings.
The compounds of formula I are accordingly ;~ indicated for use as minor tranquillisers and sedative-hypnotic agents.
lS An indicated suitable daily dosage for both uses is from 75 to 1500 milligrams. FQr minor tranquilliser use the dosage is preferably administere 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.
-T~e compounds may be used in free base form or in the form of pharmaceutically acceptable acid addition ,.. . .
. ~ .
~ 7 - ~00-6~22/C
3~
salts, which salt forms have the same order of activity as the free base orms. Suitable acids for salt formation in-clude 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 Rl and R2 are hydrogen, the CF3 group is in the meta-position, and Z is tCH2~ where n= 1,2,3 or 4.
n A particularly preferred compound is 2-amino-5-(3-t~ifluoro-methylbenzyl)-1,3,4-thiadiazole.
The iollowing Examples i.lustrate the in.ention:-, .
- .. . . .
~()50(~3~ 600-6 ~22~c ) 1-(3'-Trifluoromethylphenylacetyl)-thiosemicarbazide (II) A mixture of 60.0 g (0.3 mole) of 3-trifluorome-thylphenylacetic acid and 80 ml of thionyl chloride in the S presence of 10 drops of dimethylformamide is heated on a water bath for 3 hours. The e~cess thionyl chloride is evaporated ur.der reduced pressure, and any rem2ining traces of thionyl chloride are removed by addition of dry benzene followed by evaporation. To the resultins acid chloride dissolved in 100 ml of absolute di~.ethylfor~a~ide is added with cooling 29.3 g (0.32 mole~ of thiosemica~bazide. The mixture is maintained at room temperature overnight and the excess solvent is removed under reduced pressure. On addition of lce ~tater to the residue, a solid is precipi-tated ~Ihich is then recrystallized from acetone/hexane to give 1-(3'-trifluoromethylphenylacetyl)-thiosemicarbazide, m.p. 197 - 199C.
EX~SPLE ? ~Compounds of formula II) Follo~ing the procedure of Example 1 and using appropriate starting materials in approximately equivalent amounts, the fol1ow~ng compounds may be obtained:-.. , ~' ' .
.. . .
~5~33l a) 1-(4'-trifluoromethylrhenylacetyl.) thiosemicarbazide~
b) 1-(3',5'-di(trifluoromethyl)phenylacetyl)~thiosemi~
car~azide, c) 1-(5'-chloro-3'~trifluoromethylphenylacetyl~-thio-se~icarbazide, d) 1-(2',5'-dlchloro-3'-trifluoromethylphenylacetyl)-~hiose~icarbazide, . .
e) 1-(3-/3'-trifluoromethylphenyl7-propionyl)-thiosemi-carbazide, : . f) 1-(4-/3'-trifluoromethylphenyl7-butyryl) ~thiosemi-carbazide, g) 1-(5-/3'-trifluoromethylphenyl7 pentanoyl)-thiosemi~arbazide h) 1-(2-/3'-trifluoromethylphenyl7-propionyl)-thiosemi-carbazide, i) 1-(3-/3'-trifluoromethylphenyl7-butyryl)-thiosemicarbazide, (4-/3'-trifluoromethylphenyl7-pentanoyl)-thiosemi-carbazide, or ~ k) 1-(2-methyl-3~/3'-trifluoromethylphenyl7-propionyl)-: thiosemicarbazide.
: EX~PLE 3 2-Amino-5-~3-trifluoromethylbenzyl)-1,3,4-thia _ diazole (I) I
A mixture of 32.0 g ~0.115 mole) of 1-~3'-trifluoro-methylphenylacetyl)-thiosemicarbazide and 48.0 g of phosphorus tribromide is heated in a waterbath to a temperatur~ of 60-65C and mai~tained at that temperature for 4 hours. The resulting mixture is cooled and poured into a 50% weight/volume ., .
~ ' ~1 ~ 10 - 600-6422/C
3~
-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-~enzyl)-1,3,4-thiadiazole, m.p. 174-176C.
EXA~PLE 4 (Compounds of formula I) Follo~ling the procedure of Example 3 and using . in place of 3'-trifluoromethylphenylacetyl-3-thiosemi-carbazide, an approximately equivalent amount of the comPounds of Example 2 a)to k), the follo~ing compounds may be obtained:-a) 2-amino-5-(4-trifluoromethylbenzyl)-1,3,4-thiadiazole, m.p. 194 - 195C.
b) 2-amino-5-(3,5-di[trifluoromethyl]benzyl)-1,3,4-thia-diazole, c) 2-amino-5-(5-chloro-3-trifluoromethylbenzyl)-1,3,4-thiadiazole, d) 2-amino-5-(2,5-dichloro-3-trifluoromethylbenzyl)-1,3,4-thiadiazole, e) 2-amino-5-(3-trifluoromethylphenethyl)-1,3,4-thiadiazole, m.p. 151-152C, f) 2-amino-5-(3-trifluorcmethylphenylpropyl)-1,3,4-thia-diazole, m.p. 161-162C, .
,~
~ 600-6422/C
~J g) 2-amino-5-(4-[3-trifluoromethylphenyl]butyl)-1,3,4-thiadiazole, m.p. 135 - 137C., h) 2-amino-5~ [3-trifluoromethylphenyl3-ethyl) 1,3,4-thiadiazole, m.p. 163 - 164.5C., i) 2-amino-5-(2-[3-trifluoromethylphenyl3-propyl)-1,3,4-thiadiazole, m.p. 138 - 140C., j) 2-amino-5-(3-[3-trifluororethylphenyl]-butyl)-1, 3, A -thiadiazole, or - k) 2-amino-5~ methyl-2-r3-trifluoromethylphenyl]-ethyl)-1,3,4-thiadiazole, m.p, 131-133C.
A~
.. . .. .
~ . .
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound of formula I, I
in which R1 is hydrogen, fluorine, chlorine or trifluoromethyl, R2 is hydrogen, fluorine or chlorine, and Z is , or , 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 R1 is trifluoromethyl, the two trifluoromethyl groups are not attached to adjacent carbon atoms, and (b) when R1 is trif1uoromethyl, R2 is hydrogen, characterised by subjecting a compound of formula II, II
in which R1, R2, Z and the proviso are as defined above, to strong Lewis acid conditions.
in which R1 is hydrogen, fluorine, chlorine or trifluoromethyl, R2 is hydrogen, fluorine or chlorine, and Z is , or , 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 R1 is trifluoromethyl, the two trifluoromethyl groups are not attached to adjacent carbon atoms, and (b) when R1 is trif1uoromethyl, R2 is hydrogen, characterised by subjecting a compound of formula II, II
in which R1, R2, Z and the proviso are as defined above, to strong Lewis acid conditions.
2. A process according to Claim 1 in which the Lewis acid conditions are provided by employing a medium comprising a phosphorus halide or oxyhalide.
3. A process according to Claim 1 in which the reaction temperature is from 50 to 65°C.
4. A compound of formula I, stated ln Claim 1, or a salt form thereof, whenever produced by a process according to Claims 1, 2 or 3, or an obvious chemical equivalent.
5. A process for the production of 2-amino-5-(3-trifluoromethylbenzyl)-1,3,4-thiadiazole by heating a mixture of 1-(3'-trifluoromethylphenylacetyl)-thiosemi-carbazide and phosphorus tribromide to a temperature of 60-65°C for approximately 4 hours.
6. 2-Amino-5-(3 trifluoromethylbenzyl)-1,3,4-thiadiazole, or a salt form thereof, whenever produced by a process according to Claim 5, or an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45267874A | 1974-03-20 | 1974-03-20 | |
| US05/528,477 US3965110A (en) | 1974-07-05 | 1974-11-29 | 2-Amino-5-(trifluoromethyl phenylalkyl)-1,3,4-thiadiazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050031A true CA1050031A (en) | 1979-03-06 |
Family
ID=27036857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA222,445A Expired CA1050031A (en) | 1974-03-20 | 1975-03-18 | 2,5-substituted thiadiazoles |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS50154251A (en) |
| CA (1) | CA1050031A (en) |
| CH (1) | CH593957A5 (en) |
| DD (1) | DD117463A5 (en) |
| DE (1) | DE2510439A1 (en) |
| DK (1) | DK136248B (en) |
| ES (1) | ES435777A1 (en) |
| FI (1) | FI750696A (en) |
| FR (1) | FR2264532B2 (en) |
| GB (1) | GB1482371A (en) |
| HU (1) | HU169267B (en) |
| IE (1) | IE40948B1 (en) |
| IL (2) | IL46860A (en) |
| NL (1) | NL7503058A (en) |
| NO (1) | NO750829L (en) |
| SE (1) | SE404695B (en) |
| SU (1) | SU645574A3 (en) |
-
1975
- 1975-03-10 CH CH299775A patent/CH593957A5/xx not_active IP Right Cessation
- 1975-03-11 DK DK98275AA patent/DK136248B/en unknown
- 1975-03-11 SE SE7502708A patent/SE404695B/en unknown
- 1975-03-11 DE DE19752510439 patent/DE2510439A1/en active Pending
- 1975-03-11 FI FI750696A patent/FI750696A/fi not_active Application Discontinuation
- 1975-03-12 NO NO750829A patent/NO750829L/no unknown
- 1975-03-14 NL NL7503058A patent/NL7503058A/en not_active Application Discontinuation
- 1975-03-17 GB GB10987/75A patent/GB1482371A/en not_active Expired
- 1975-03-18 FR FR7508350A patent/FR2264532B2/fr not_active Expired
- 1975-03-18 IE IE576/75A patent/IE40948B1/en unknown
- 1975-03-18 CA CA222,445A patent/CA1050031A/en not_active Expired
- 1975-03-18 JP JP50031907A patent/JPS50154251A/ja active Pending
- 1975-03-18 HU HUSA2761A patent/HU169267B/hu unknown
- 1975-03-18 IL IL46860A patent/IL46860A/en unknown
- 1975-03-18 ES ES435777A patent/ES435777A1/en not_active Expired
- 1975-03-18 DD DD184853A patent/DD117463A5/xx unknown
- 1975-03-19 SU SU752115292A patent/SU645574A3/en active
-
1976
- 1976-03-18 IL IL46860*TA patent/IL46860A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU169267B (en) | 1976-10-28 |
| SU645574A3 (en) | 1979-01-30 |
| FR2264532B2 (en) | 1978-08-04 |
| IL46860A (en) | 1977-12-30 |
| IL46860A0 (en) | 1975-05-22 |
| IE40948L (en) | 1975-09-20 |
| JPS50154251A (en) | 1975-12-12 |
| ES435777A1 (en) | 1977-07-01 |
| DD117463A5 (en) | 1976-01-12 |
| CH593957A5 (en) | 1977-12-30 |
| DK136248C (en) | 1978-03-13 |
| DK136248B (en) | 1977-09-12 |
| NO750829L (en) | 1975-09-23 |
| IE40948B1 (en) | 1979-09-12 |
| SE404695B (en) | 1978-10-23 |
| GB1482371A (en) | 1977-08-10 |
| NL7503058A (en) | 1975-09-23 |
| DE2510439A1 (en) | 1975-09-25 |
| FI750696A (en) | 1975-09-21 |
| DK98275A (en) | 1975-09-21 |
| FR2264532A2 (en) | 1975-10-17 |
| SE7502708L (en) | 1975-09-22 |
| AU7928975A (en) | 1976-09-23 |
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