FR2480752A1 - O-Substd. thiazolyl tri:fluoromethyl ketone oxime(s) - having vasodilating, coronary dilating and hypotensive properties - Google Patents

Abstract

O-Alkylamino alkyl oximes of formula (I), their optically active and racemic mixtures, and their salts with acids, are new. X is O, S, or a bond; R is H or lower alkyl; R1 and R2 are each H or CH3; R3 is H, lower alkyl, benzyl, or lower alkenyl; R4 is lower alkyl, lower alkenyl, or lower aralkyl; or R3 and R4 together form a 4-6 membered alkylene chain which may be interrupted by one or two hetero atoms selected from O, S and -NR5; R5 is H, lower alkyl, hydroxyalkyl, acyloxyalkyl, or alkoxyalkyl; n is 0 or 1. (I) are vasodilators, coronary dilators and hypotensives. (I) may be given orally, parenterally, sublingually, percutaneously or rectally at an adult daily dosage of 10-200 mg. It may be given alone or with a substance having a complementary or synergistic action such as a nitro cpd., papaverine, or a diuretic.

Description

NOVEL COMPOUNDS DERIVED FROM PHENYLIHIAZOLYLCETOXE, THEIR PROCESS FOR OBTAINING
TION AND PHARMACEUTICAL COMPOSITIONS IN CONTENTS.

 The subject of the present invention is novel phenylthiazolylketone derivatives and a process for the preparation of these compounds.

 It relates more particularly to oximes of phenylthiazolylketone, substituted for oxygen by an alkylaminoalkylated chain.

It specifically has for oDjet the O-alkylaminoalcoyloximes of phenylthiazolylketone corresponding to the general formula (I).

wherein X is sulfur oxygen or a carbon-carbon direct bond.

R is hydrogen or a lower alkyl radical
R1 and R2 distinctly from each other, represent hydrogen
or a methyl radical.

dans lequel R est l'hydrogène. un radical alcoyle inférieur, un radical hydroxyalcoyle, acyloxyalcoyle ou alcoxyalcoyle et n représente zéro ou un. R3 represents hydrogen, a lower alkyl radical, a
benzyl radical or lower alkenyl radical
R4 represents a lower alkyl radical, an ar.ylalkyl radical
lower, or a lower alkenyl radical.
or R3 and R4 together form an alkylene chain having 4
has 6 carbon atoms which can be interrupted by either one or two
heteroatoms selected from the group consisting of oxygen and sulfur, or by a radical

where R is hydrogen. a lower alkyl radical, a hydroxyalkyl, acyloxyalkyl or alkoxyalkyl radical and n represents zero or one.

A subject of the invention is also the salts of the compounds of general formula I with a mineral or organic acid, preferably a therapeutically acid
The invention also extends to the active optical forms of compounds of general formula I when the molecule contains at least one asymmetric carbon atom.

 The invention also extends to syn and anti geometric isomers or to mixtures in any proportions of these isomers.

dans laquelle les substituants R, R1, R2, R3 et R4 sont définis comme précédement.Among the compounds of general formula I, it is possible to distinguish 3 currently preferred subgroups a) the trifluoromethylated derivatives of general formula 1A

wherein the substituents R, R1, R2, R3 and R4 are defined as above.

dans laquelle les substituants R, R1, R2 > R3 et R4 sont définis comme précédemment. b) trifluoromethoxylated derivatives of general formula IB

in which the substituents R, R1, R2> R3 and R4 are defined as above.

dans laquelle les substituants R, R1, R2, R3 et R4 sont définis comme précédemment, ainsi que les sels de chacun des composés de ces sous-groupes. and C) the trifluoromethylthio derivatives of general formula I

in which the substituents R, R1, R2, R3 and R4 are defined as above, as well as the salts of each of the compounds of these subgroups.

 As far as the invention is concerned, the term lower alkyl denotes a hydrocarbon radical having from one to five carbon atoms such as, for example, ethyl, propyl, butyl or isopropyl.

 The term "lower alkenyl" denotes an unsaturated hydrocarbon chain having from 2 to 6 carbon atoms such as, for example, an allyl, methylallyl, dimethylallyl or 2-enyl but radical.

dans laquelle R est un hydrogene ou un radical alcoyle inférieur, ou un de ses dérives fonctionnels avec un trifluorobenzàr.e de formule généraleîll

dans laquelle X est un oxygenen un soufre ou une liaison directe pour former une (m.phényl thiazolyl-2) cétone de formule générale IV.

The term lower arylalkyl denotes a phenyl or (substituted phenyl) lower alkyl radical. The phenyl ring can, for example, be substituted by one, two or three substituents chosen from the group consisting of a halogen, a lower alkoxy radical, a lower alkyl radical, an alkylthio radical, a trifluoromethyl redical and a methylenedioxy radical.
Among the acids suitable for the salification of the compounds of general formula I, mention may be made in particular of hydrochloric acid, sulfuric acid, acetic acid, lactic acid, pyruvic acid, tartaric acid. , citric acid, ketoglutaric acid, beuzoic acid, dichlorobenzolic acid, pazolic acid, B-phosphoric glucose acid, N / carbamoylaspartic acid or malic acid
The invention also relates to a process for obtaining the compounds of general formula I which consists in subjecting to a reaction of
Friedel Craft, a thiazole carboxylic acid of general formula II

in which R is a hydrogen or a lower alkyl radical, or one of its functional derivatives with a trifluorobenzar with the general formula

in which X is an oxygen or a sulfur or a direct bond to form a (m.phenyl thiazolyl-2) ketone of general formula IV.

in which the definition of the substituents R and X remains unchanged.

which is reacted with an O-substituted hydroxylamine of general formula
V.

in which R1 and R2 are distinctly from each other, hydrogen or a methyl radical, and R3 and R4 have the meanings provided previously
to form the corresponding oxime of general formula I which can be optionally salified by adding an acid or split into its optical or geometric isomers
It is also possible to use a hydroxylamine 0 substituted beforehand split so as to form an oxime of general formula I optically active.

The Friedel-Craf t reaction is carried out using preferably a functional derivative of thiazole carboxylic acid such as, for example, an acid chloride, an acid anhydride or a lower alkyl ester.
This reaction is carried out in an inert solvent, in particular in an aromatic hydrocarbon solvent such as benzene, toluene, xylene, c-ymene or durene,
The oxidation reaction is preferably carried out using a hydroxylamine salt such as for example a hydrochloride, an acetate or a formate; the condensation is preferably carried out by heating between 50 and 100 in an inert solvent with a boiling point between 60 and 1500.

The reaction is further carried out in the presence of a basic substance such as, for example, sodium, calcium or lithium carbonate, a pyridic base such as pyridine, collidine or lutidine, triethylamine, dimethylaniline, dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide,
It is preferred to use for this condensation an aprotic polar solvent and acetonitrile, divinylsulfone, dimethylsulfoxide, tetrahydrofuran or tetramethylurea coavent more particularly.

The subject of the invention is also another process for obtaining the compounds of general formula (I) in optically active or racemic form which consists in condensing a thiazolyl 2-carboxaldehyde of general formula (VI) with a trifluorobenzene of general formula (III) in which X is an oxygen, a sulfur or a direct bond, in the presence of a metallic agent to force a benzhydrol of general formula (VII).

which is oxidized to phenyltnlazolylcetong of general formula (IV).

The phenylthiazolyl ketones of general formula CIV) can also be obtained by analogy with the method described by C. VAN DER
STELT et al. ArzneimittelForechung Tome I4, 1964, p. 804 in which a thiazolylcarboxaldehyde of general formula (VI) is reacted with a trifluoromethyl-X phenyl magnesium salt
The thiazolylcarboxaldehydes of general formula (VI) can themselves be obtained from a thiazolylcarboxylic acid of foc either mule (II) by means of an alkali metal borohydride complex or by passing through the acid chloride by catalytic hydrogenation in the presence of platinum, or alternatively by transforming the thiazolcarboxylic acid of general formula (II) into dimethylamide which is reduced by means of an aluminohydride to the corresponding aldehyde.

 The invention also extends to the therapeutic use of the compounds of general formula I in optically inactive or split form, as well as their salts with a mineral or organic acid.

 The compounds of general formula I are endowed with interesting pharmacological properties. More particularly, they manifest vasodilator, coronarodilator and hypotensive properties. They therefore find use as a drug for peripheral angiopathies, disorders of the arterial or venous circulation, angina pectoris, coronary artery disease and disorders caused by insufficient cardiac irrigation. They are also suitable for improving or normalizing blood pressure.

For the purpose of therapeutic use, the compounds of general formula
I will be used in the form of pharmaceutical compositions, containing, in addition to the active principle, one or more inert, non-toxic, pharmaceutically acceptable excipients.

These pharmaceutical compositions may also contain another active principle of similar, complementary or synergistic action, such as for example a diuretic, a nitro derivative or papaverine.
The pharmaceutical compositions according to the invention are in one of the forms suitable for administration by the oral, parenteral, sublingual, percutaneous or rectal route, such as, for example, tablets, dragees, coated tablets, enteric coating, tablets with disintegration or release of the delayed active ingredient, capsules, capsules, microcapsules, sublingual tablets, oral solutions or suspensions, injectable solutions, solutions in polar solvent for percutaneous application, suppositories.

The unit dosage can vary widely. It ranges from 10 to 100 mg of active ingredient. The daily dosage in adults ranges from 10 to 200 mg.

The following examples illustrate the invention without limiting it
Example I O-diethylaminopropyl-2 (5-n propylthiazolyl-2) m.trifluoromethyl phenyl ketoxime
Stage A
14 g of 5-n propylthiazole 2-carboxylic acid are dissolved in 75 ml of thionyl chloride and the mixture is brought to reflux of the solvent for 30 minutes. The mixture is then allowed to return to ordinary temperature, and the hydrochloric acid formed is removed by vacuum.

 The remaining solution is added with 10 g of aluminum chloride, then after 10 minutes of contact, 13 g of α α α trifluorotoluene. Stirring is continued for 12 hours, then the mixture is poured into a mixture of water and ice. The suspension formed is stirred for one hour. The organic phase is then decanted, washed with water, then. it is dried over sodium sulfate, the filter and it is dried to dryness. The dry residue is purified by distillation under vacuum. The (5-n propylthiazolyl-2) (m.trifluoromethyl phenyl) ketone is thus collected with a yield of 60% in the form of a pale yellow oil.

Stage B
The whole of (5-n-propylthiazolyl-2) (m.trifluoromethyl phenyl) ketone obtained in the preceding stage is dissolved in 40 ml of pyridine and a solution of 22 g of (0-diethylaminopropyl) dihydrochloride is added thereto. 2) hydroxylamine in a mixture of 50 nl of water and 50 ml of pyridine
The mixture is brought to 1000 and maintained at this temperature for two hours. The solution is then allowed to return to room temperature, and 100 nl are then added. of ice water and crystallization is started by scraping the substituted oxime gradually precipitates. The crystals are separated after four hours of contact, they are washed with water until the washing waters are neutral and they are dried under vacuum.
The (0-diethylaminopropyl -2) [(5-n propylthiazolyl-2) (m.trifluoromethylphenyl)] ketoxime is thus obtained in the form of crystals
colorless, insoluble in water and soluble in pydidine, nethanol and methylene chloride,
This compound can be purified by conversion to methane sulfonate by dissolving in the stoichiometric amount of methane sulfonic acid in solution in water.

 (0-Diethylaminopropyl-2) [(5-n propylthiazolyl-20 (m.trifluoromethyl phenyl)] methane sulfonate ketoxime melts at 192-195.

Example II
(0-diethylaminopropyl -2) [(5-ethylthiazolyl-2) (m.trifluoromethoxy
phenyl)] ketoxime.

 Using the procedure of Example I, starting from (5-ethylthiazoly-2) carboxylic acid and trifluoromethoxybenzene, the (0-diethylaminopropyl -2) [(5-ethylthiazolyl-2) (m. trifluoromethoxyphenyl)] ketoxime with an overall yield of 44%.

After recrystallization from methanol, the pure product melts at 158,160.

Example III
(0-diethylaminopropyl -2) [(m.trifluoromethylthio). (5-ethylthiazolyl
-2)] ketoxime.

By operating as 2 Example I starting from (5-ethylthiazolyl-2) carboxylic acid and trifluoromethylthio. benzene, (O-diethylaminopropyl -2) [(m. trifluoromethylthio) (5-ethylthiazolyl-2)] ketoxime is obtained with an overall yield of 31 Z.

 The hydrochloride can be formed by dissolving in an aqueous solution of hydrochloric acid in a stoichiometric amount. By evaporation, the hydrochloride crystallizes and is separated by filtration. The hydrochloride melts at 186 -187.

Example IV
Ô- (terbutylaminopropyl-i) [(5-ethylthiazolyl-2) Cm. trifluoroethoxy-
phenyl)] ketoxime
Starting from 6 g of [(5-ethylthiazolyl-2) (m. Trifluoromethoxyphenyl)] ketone obtained according to the method of Example II and hydroxylamine hydrochloride, 4.36 g of [(5- ethylthazolyl-2) (m.trifluoromethoxyphenyl)] ketoxime scus form colorless crystals insoluble in 1 Skin, sparingly soluble in methanol and ethanol, soluble in dimethylformamide.

The [(5-ethylthiaolyl-2) (m.trifluoromethyoxyphenyl)] ketoxi is taken up in 50 ml of isopropyl ether. A solution of 4.7 g of 3-terbutylaminopropyl bromide in 40 ml of isopropyl ether and 0.5 ml of triethylamine is very gradually added. After addition, the mixture is brought to reflux of the solvent for six hours and then after cooling, the mixture is added with 20 ml of normal sodium hydroxide. The organic phase is stirred vigorously and then decanted. The organic phase is washed with water several times, with dilute acetic acid and then again with water, dried over sodium sulfate, filtered and evaporated to dryness.

The dry residue, consisting essentially of 0- (terbutylaminopropyl-1) [(5-ethylthiazolyl-2) (m. Trifluoromethoxyphenyl)] ketoxime, is recrystallized from acetonitrile twice.

produces you pure bottom at 144-145. It forms colorless crystals soluble in polar solvents and sparingly soluble in alcohols, ether and chlorinated halides. It is soluble in aqueous hydrochloric acid, dilute sulfuric acid and aqueous methane sulfonic acid.

Example V
0 - [(3-morpholyl-2) 2-methylpropyl-1] [(5-ethylthiazolyl-2) m.trifluo
tomethoxyphenyl)] ketoxime.

 Using the procedure of Example IV starting from [(5-ethylthiazolyl-2) (m.trifluoromethoxyphenyl)] ketoxime and 1-bromeo 2methyl 3- (norpholyl-1) propane, 0- [3 - (2-morpholyl) 2-methyl-propyl-1] [(5-ethylthiazolyl-20 (m.trifluoromethoxyphenyl)] ketoxime in the form of hydrochloride melting at 189-190.

The hydrochloride is soluble in water, methanol and methanol
L-bromo 2-methyl 3- (morpholyl-l) propane is obtained by the addition, under Michael's reaction conditions, of morpholine to l-bromo 2-methylprop 2-ene.

Example VI 25 mg Tablets
0- (2-diethylaminopropyl) [(5-n-propylthiazolyl-2) (m.trifluoromethyl
phenyl)] ketoxime as methane sulfonate.

Active ingredient 250 g
Wheat starch 480 g
Mals starch 330 g
Carboxymethylcellulose 40 g
Calcium carbonate 1,200 g
Magnesium stearate 50 g
Talc 50 g
Colloidal silica (Aerosil) 20 g
per 10,000 finished tablets at an average weight of about 0.240 g.

Example VII
Pharmacological study of the compounds according to the invention a) - Determination of the acute toxicity
Acute toxicity was determined on batches
of ten Swiss mice of 22 g average weight.

 The compounds according to the invention were administered in increasing doses to batches of mice intraperitoneally 2n suspension in gummed water. A batch of control mice receives only the solvent. The animals are kept under observation overnight at constant temperature; the dead are counted and the average lethal dose is evaluated graphically according to the Miller and Tainter method. For all compounds, the average lethal dose ranges from 80 to 150 mg / kg. The compounds according to the invention are therefore less toxic than papaverine.

b) - Demonstration of the vasomotor effect
The vasomotor activity of the compounds according to the invention was determined by the test of the isolated ear of the rabbit according to a technique derived from that described by SN Rasmussen Acta Physiol. Scand. 1972, 84, 472,
Batches of rabbits of approximately 2 to 3 kg are anesthetized with urethane intraperitoneally, then the two ears of each rabbit are prepared. The central artery is dissected as close as possible to the birth of the ear and a catheter is placed there. The blood is then expelled from the artery by massive injection of isotonic saline The rabbits are then sacrificed and the ears are cut out at their base. the blood which may have remained there is expelled by physiological saline. The ear is immediately screwed up in a gutter, one end of which collects the venous tributary.

 The infusion pressure is kept constant. The infusion fluid is Klebs fluid at pH 7. It is maintained at a temperature of 37 - 0.5. The flow rate is measured using a calibrated dropper provided with a counter. The return to zero takes place every dlx seconds. Debits are recorded using a polygraph. The higher the flow, the higher the height of the line.

The compounds according to the invention are injected at doses of 100, 200 and 500 pg in a volume of 0.1 ml.

 100 and 200 p of papaverine hydrochloride and 500 g of sodium nicotinate are then administered. Papaverine hydrochloride, at doses of 100 and 200 g induces a significant increase in flow rate due to vasodilation It is less than that caused by 100 and 200 g of the compounds according to the invention. Sodium nicotinate at a dose of 500 μg causes an increase in flow rate comparable to that caused by administration of 100 μg of compound according to the invention.

 The vasomotor action of the compounds according to the invention is therefore greater than that of papaverine hydrochloride and that of sodium nicotinate.

Claims (5)

CLAIMS The subject of the invention is 1) the O-alkylaminoalkyloximes of general formula I in which X is oxygen, sulfur or a direct carbon-carbon bond. R 1 is hydrogen or a lower alkyl radical R 1 and R 2 distinctly from each other represent hydrogen or a methyl radical. R3 represents hydrogen2, a lower alkyl radical, a benzyl radical or a lower alkenyl radical. R4 represents a lower alkyl radical, a lower alkenyl radical or a lower aralkyl radical or else R3 and R4 together form an alkyl chain having from 4 to 6 atoms which can be interrupted by one or two hetercatomes chosen from the group consisting of oxygen and sulfur, and by a radical in which R5 is hydrogen, a lower alkyl radical, a hydroxyalkyl, acyloxyalkyl or alkoxyalkyl radical and n represents zero or one. 20) the salts of the compounds of claim 1 with a mineral or organic acid, preferably a therapeutically compatible acid. 30) the optically active forms of the compounds of general formula I when the molecule contains at least one asymmetric carbon atom. 4) the compounds according to one of claims I to 30 of formula 1A

wherein the substituents n, R, R1, R2, R3, and R4 are defined as above. 5) The trifluoromethoxylated derivatives according to one of claims I to 30 of general formula 1B

in which the substituents n, R, R1, R2, R3 and R4 are defined as above.  6) The trifluoromethylthio derivatives according to one of claims 10 to 30 -of general formula IC

 in which the substituents n, R, R1, R2, R3 and R4 are defined as above. 7) The pharmaceutical compositions containing as active principle at least one compound according to one of claims 10 to 60 in association with an excipient or an inert, non-toxic, pharmaceutically acceptable vehicle. 8) A composition according to claim 70 in which the vehicles or  the inert excipients are those suitable for administration by the oral, parenteral, sublingual, percutaneous or rectal route. 90) A composition according to one of claims 7 "or 80 in which the content of active principle ranges from 10 to 100 mg. 10) A pharmaceutical composition according to claim 70 in which is added to the active ingredient according to claim 1 "another active ingredient of similar, synergistic or complementary action.