GB1565885A – Phenyl thiazolyl ketone derivatives
– Google Patents
GB1565885A – Phenyl thiazolyl ketone derivatives
– Google Patents
Phenyl thiazolyl ketone derivatives
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Publication number
GB1565885A
GB1565885A
GB2541877A
GB2541877A
GB1565885A
GB 1565885 A
GB1565885 A
GB 1565885A
GB 2541877 A
GB2541877 A
GB 2541877A
GB 2541877 A
GB2541877 A
GB 2541877A
GB 1565885 A
GB1565885 A
GB 1565885A
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GB
United Kingdom
Prior art keywords
compound
ketone
process according
compound according
acid
Prior art date
1978-05-31
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
Application number
GB2541877A
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CHERQUI J
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CHERQUI J
Priority date (The priority date 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 date listed.)
1978-05-31
Filing date
1978-05-31
Publication date
1980-04-23
1978-05-31
Application filed by CHERQUI J
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CHERQUI J
1978-05-31
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patent/GB1565885A/en
1980-04-23
Publication of GB1565885A
publication
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patent/GB1565885A/en
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Classifications
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
C07D277/28—Radicals substituted by nitrogen atoms
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
C07D277/24—Radicals substituted by oxygen atoms
Description
(54) PHENYL THIAZOLYL KETONE DERIVATIVES
(71) I, JEAN CHERQUI, a French citizen, of 55 Rue Pergolese, 75016 Paris,
France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to he performed, to be particularly described in and by the following statement: This invention relates to phenyl thiazolyl-2 ketone oximes, to a process for their preparation and to pharmaceutical compositions continting them.
The present invention provides compounds of the general formula
in which X is oxygen, sulphur or a direct bond and R is a hydrogen atom or an alkyl group, having from 1 to 4 carbon atoms.
Those compounds in which X is a direct bond are oximes derived from m-trifluoro- methylphenyl thiazolyl-2 ketones, those in which X is oxygen are oximes derived from m-triíluoromethoxyphenyl thiazolyl-2 ketones, and those in which X is sulphur are derived from m-uiíluoromethylthiophenyl thiazolyl-2 ketones.
The substituent R on the thiazole nucleus may be a hydrogen atom but is preferably an alkyl group having from 1 to 4 carbon atoms, especially an ethyl, propyl, isopropyl or butyl group.
The compounds of the general formula I are bases and may be converted into addition salts with organic or mineral acids, preferably physiologically tolerable organic or mineral acids, for example hydrochloric acid, sulphuric acid, acetic acid, lactic acid, pyruvic acid, tartaric acid, citric acid, keto-glutaric acid, benzoic acid, pamoic acid, glucose -1 phosphoric acid, carbamoylaspartic acid and maleic acid.
The aminalcohol chain attached to the oxime group contains an asymmetric carbon atom and the compounds of the general formula I may be resolved into their optical isomers, for example with an optically-active organic acid (for example a-tartaric acid or a-camphosulphuric acid).
In addition, the compounds of the general formula I may be resolved in a conventional manner, into their syn- and anti-isomers.
The compounds of the general formula I can be prepared in accordance with the present invention by condensing a phenyl thiazolyl-2 ketone of the general formula
in which
R and X have the meanings given above, with an O-substituted hydroxylamine of the general formula
The resulting oxime of the general formula
I may be converted into a salt by the addition of an acid, resolved into its optical isomers, and/or resolved into its syn- and anti-isomers.
Althernatively, there can be used a hydroxylamine of the general formula III which has already been resolved into its optical isomers, to form an optically-active compound of the general formula I.
The process of the present invention is preferably carried out using a hydroxylamine salt, for example a dihydrochioride or a diacetate salt, and the condensation is advantageously carried out by heating the starting materials in a solvent having a boiling point of from 600 to 1500C in the presence of a base. Polar aprotic solvents, for example dimethylformamide, acetonitrile, dimethylsulphoxide and dimethylacetamide are preferred.
The base is suitably the salt of a weak add, for example sodium acetate or sodium carbonate; an alkali metal hydroxide may also be used, especially in an accurately calculated amount.
The compounds of the general formula I have interesting pharmacological properties.
More especially they are effective vasodilators and may therefore be used in the treatment of peripheral angiopathy and arteritis, and for the treatment of conditions involving problems of cardiac irrigation and in coronaritis.
They also exhibit an improving effect on arterial pressure.
The present invention therefore also provides pharmaceutical compositions comprising as active ingredient compounds of the general formula I or physiologically tolerable acid addition salts thereof, in admixture or conjunction with pharmaceutically suitable carriers.
These pharmaceutical compositions may be in a form suitable for oral, parenteral, sublingual or rectal administration, for example in the form of tablets, coated tablets, sugarcoated tablets, capsules, sub-lingual tablets, oral solutions or suspensions, solutions or suspensions for injection, and suppositories.
They suitably contain the active ingredient in an amount of from 5 to 250 mg per unit dosage, and may also contain one or more other active ingredients having a similar or complementary action.
The therapeutic dosage will vary depending on the therapeutic indication and may be from 10 to 50 mg of active ingredient per day by a single dose, or repeated doses of 10 mg of active ingredient.
The ketones of the general formula II used as starting materials may be obtained from thiazole – 2 – carboxylic acids using the
Friedel-Craft reaction, and the corresponding aromatic compound.
The following Examples illustrate the ia- vention.
Example I (5 n-propylthiazolyl-2) (m-trifiuoromethyl- phenyl) ketone O-(diethylaminopropyl-2) oxime
14 g of 5 – n – propylthiazole – 2 carboxylic acid are dissolved in 75 ml of dichloroethane, 5 ml of thionyl chloride are added and the whole is refluxed for 30 minutes. The mixture is then allowed to cool to room temperature and the hydrogen chloride formed is removed under vacuum. To the remaining mixture are added 10 g of aluminium chloride and then 13 g of rr,ru,tr trifluorotoluene. The mixture is stirred overnight and then poured onto an ice-water mixture and stirred again for one hour. The organic phase is decanted off, washed with water, dried over sodium sulphate, filtered, and evaporated to dryness. The residue is purified by distillation in vacuo. The (5-ns propylthiazolyl-2) (m – trifluoromethylpheny1) ketone fraction is collected in the form of a pale fawn liquid. The yield is about 60%. The (5 – n – propylthiazolyl – 2) (m – trifluoromethylphenyl) ketone is dissolved in 40 ml of pyridine and 22 g of O – (diethylaminopropyl – 2) – hydroxylamine dihydrochloride previously dissolved in a mixture of 20 ml of water and 20 ml of pyridine.
The mixture is heated to 1000C for 2 hours and then allowed to cool to room temperature.
100 ml of iced water are added while stirring vigorously. The oxime gradually precipitates;
After 4 hours the crystals are separated, drained then washed with water until the washings are neutral. The crystals are dried in vaciw.
(5 – n – propylthiazolyl – 2) (m – trifluoro- methylphenyl) ketone 0 – (diethylaminopropyl – 2) – oxime is obtained in the form of colourless crystals, insoluble in water and soluble in pyridine, methanol and methylene chloride. This compound can be purified by dissolving it in a solution of methane sulphonic acid to form the methane sulphone which has a melting point of 192–1950C.
Example II (5-ethylthiazolyl-2) (m-trifluoromethoxyphenyl)
ketone O-(dimethylaminopropyl-2)-oxime
Using the method described in Example I but using 5 – ethylthiazolyl – 2 – carboxylic acid and trifluoromethoxybenzene, the title compound is obtained in a yield of about 44%, and has a melting point of 158–1600C.
Example III (5thylthiazoly1-2) (m-trifluoromethylthio- phenyl) ketone O-(diethylaminopropyl-2)
oxime
Using the method described in Example I but using 5 – ethylthiazolyl – 2 – carboxylic acid and trifluoromethylthiobenzene, (5 ethylthiazolyl – 2) (m – trifluoromethylthio phenyl) 0 – (diethylaminopropyl – 2) – oxime is obtained in an overall yield of 31%. Its hydrochloride has a melting point of 186 1870C.
Example IV
Tablets containing 25 mg of (5-n-propyl
thiazolyl-2) (m-trifluoromethylphenyl) ketone (diethylaminopropyl-2)-oxime, methane
sulphonate
(5-n-propylthiazolyl-2) (m
trifluoromethylphenyl) ketone
(O-diethylaminopropyl-2)
oxime, methane sulphonate 250 g
wheat starch 450 g
corn starch 300 g
carboxymethylcellulose 40 g
calcium carbonate 1200 g
magnesium stearate 50 g
talc 50 g
Aerosil (‘Aerosil’ is a registered
Trade Mark) 20 g for 10,000 tablets.
Example V
Pharmacological Tests
The vasomotor effects of the compounds of the invention were demonstrated using the rabbit ear test. Groups of 10 rabbits received increasing doses (5 to 50 mg/kg intravenously) of the compound to be tested and a polygraph was used to measure the rate of flow of blood in the external ear vein. Papaverine was used as a comparative test substance. At a dosage of mg/kg for both the test compound and Papaverine, the test compound exhibits vasomotor effects identical to those of
Papaverine.
The acute toxicity was determined in mice.
The compounds to be tested were injected intravenously in increasing doses. After an observation period of 7 days (constant temperature 370) the number of mortalities was recorded and the lethal dose (LD 50) was calculated using the Bliss statistical method.
The LD 50 ranged from 80 to 150 mg/kg according to the compound administered.
WHAT I CLAIM IS:
1. A compound of the general formula
in which X is oxygen, sulphur or a direct bond and R is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.
2. An optically active isomer of a compound according to claim 1.
3. The syn-isomer of a compound according to claim 1 or claim 2.
4. The anti-isomer of a compound according to claim 1 or claim 2.
5. An addition salt of a compound according to any one of claims 1 to 4, with an organic or mineral acid.
6. An addition salt according to claim 5 which is physiologically tolerable.
7. A process for preparing a compound according to claim 1, which comprises condensing a ketone of the formula
in which X and R have the meanings specified in claim 1, with a substituted hydroxylamine of the formula
8. A process according to claim 7 wherein the substituted hydroxylamine is optically acuve.
9. A process according to claim 7, wherein the product is resolved into its optically active isomers.
10. A process according to any one of claims 7 to 9, wherein the product is resolved into its syn- and anti-isomers.
11. A process according to any one of claims 7 to 10, wherein the product is salified with an organic or mineral acid.
12. A process according to claim 7 carried out substantially as described in any one of
Examples I to III herein.
13. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 or a physiologically tolerable acid addition salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier.
14. A composition according to claim 13 in a form suitable for oral, parenteral, sublingual or rectal administration.
15. A composition according to claim 13 or claim 14 which is in unit dosage form and contains from 5 to 250 mg of active ingredient.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (15)
**WARNING** start of CLMS field may overlap end of DESC **. Example IV Tablets containing 25 mg of (5-n-propyl thiazolyl-2) (m-trifluoromethylphenyl) ketone (diethylaminopropyl-2)-oxime, methane sulphonate (5-n-propylthiazolyl-2) (m trifluoromethylphenyl) ketone (O-diethylaminopropyl-2) oxime, methane sulphonate 250 g wheat starch 450 g corn starch 300 g carboxymethylcellulose 40 g calcium carbonate 1200 g magnesium stearate 50 g talc 50 g Aerosil (‘Aerosil’ is a registered Trade Mark) 20 g for 10,000 tablets. Example V Pharmacological Tests The vasomotor effects of the compounds of the invention were demonstrated using the rabbit ear test. Groups of 10 rabbits received increasing doses (5 to 50 mg/kg intravenously) of the compound to be tested and a polygraph was used to measure the rate of flow of blood in the external ear vein. Papaverine was used as a comparative test substance. At a dosage of mg/kg for both the test compound and Papaverine, the test compound exhibits vasomotor effects identical to those of Papaverine. The acute toxicity was determined in mice. The compounds to be tested were injected intravenously in increasing doses. After an observation period of 7 days (constant temperature 370) the number of mortalities was recorded and the lethal dose (LD 50) was calculated using the Bliss statistical method. The LD 50 ranged from 80 to 150 mg/kg according to the compound administered. WHAT I CLAIM IS:
1. A compound of the general formula
in which X is oxygen, sulphur or a direct bond and R is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.
2. An optically active isomer of a compound according to claim 1.
3. The syn-isomer of a compound according to claim 1 or claim 2.
4. The anti-isomer of a compound according to claim 1 or claim 2.
5. An addition salt of a compound according to any one of claims 1 to 4, with an organic or mineral acid.
6. An addition salt according to claim 5 which is physiologically tolerable.
7. A process for preparing a compound according to claim 1, which comprises condensing a ketone of the formula
in which X and R have the meanings specified in claim 1, with a substituted hydroxylamine of the formula
8. A process according to claim 7 wherein the substituted hydroxylamine is optically acuve.
9. A process according to claim 7, wherein the product is resolved into its optically active isomers.
10. A process according to any one of claims 7 to 9, wherein the product is resolved into its syn- and anti-isomers.
11. A process according to any one of claims 7 to 10, wherein the product is salified with an organic or mineral acid.
12. A process according to claim 7 carried out substantially as described in any one of
Examples I to III herein.
13. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 or a physiologically tolerable acid addition salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier.
14. A composition according to claim 13 in a form suitable for oral, parenteral, sublingual or rectal administration.
15. A composition according to claim 13 or claim 14 which is in unit dosage form and contains from 5 to 250 mg of active ingredient.
GB2541877A
1978-05-31
1978-05-31
Phenyl thiazolyl ketone derivatives
Expired
GB1565885A
(en)
Priority Applications (1)
Application Number
Priority Date
Filing Date
Title
GB2541877A
GB1565885A
(en)
1978-05-31
1978-05-31
Phenyl thiazolyl ketone derivatives
Applications Claiming Priority (1)
Application Number
Priority Date
Filing Date
Title
GB2541877A
GB1565885A
(en)
1978-05-31
1978-05-31
Phenyl thiazolyl ketone derivatives
Publications (1)
Publication Number
Publication Date
GB1565885A
true
GB1565885A
(en)
1980-04-23
Family
ID=10227358
Family Applications (1)
Application Number
Title
Priority Date
Filing Date
GB2541877A
Expired
GB1565885A
(en)
1978-05-31
1978-05-31
Phenyl thiazolyl ketone derivatives
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GB
(1)
GB1565885A
(en)
1978
1978-05-31
GB
GB2541877A
patent/GB1565885A/en
not_active
Expired
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Legal Events
Date
Code
Title
Description
1980-07-09
PS
Patent sealed
1982-12-30
PCNP
Patent ceased through non-payment of renewal fee
