IL44845A - 2-amino-5-(2-aminoethyl)-thiazole derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

1456257 2 - Aminothiazole derivatives CENTRE D'ETUDES POUR L'INDUSTRIE PHARMACEUTIQUE 15 May 1974 [16 May 1973] 21614/74 Heading C2C Novel 2-aminothiazole derivatives of the general formula wherein R is a group of formula or linked with the sulphur atom by its central carbon atom: R 1 and R 2 , which may be the same or different, are hydrogen atoms or alkenyl, alkyl, cycloalkyl, aryl or aralkyl groups (which groups may optionally be substituted by halogen atoms or hydroxy groups), or form, together with the nitrogen atom to which they are linked, a saturated heterocyclic ring having 4 to 8 ring members and optionally containing a nitrogen, oxygen, or sulphur atom as a second heteroatom and being optionally substituted by an alkyl group; and R 3 and R 4 , which may be the same or different, are hydrogen atoms or alkyl or cycloalkyl groups, or form, together with the nitrogen atom to which they are linked, a saturated heterocyclic ring having 5 or 6 ring members and optionally containing oxygen, nitrogen, or sulphur as a second hetero-atom which (in the case of nitrogen) is optionally substituted by an aryl, haloaryl, alkoxyaryl, alkyl, hydroxyalkyl, haloalkyl, alkoxy, trifluoromethyl or halohydroxyalkyl group; and the mineral and organic acid addition and quaternary ammonium salts thereof are prepared by reacting AH with BNCS. (A being -NR 1 R 2 when B is -CH 2 -R 0 -CH 2 -NR 3 R 4 and, when R 2 is H, being when B is R 1 , R 0 being -CH = CH- or -C # C-) and cyclizing the resulting thiourea of the general formula by heating in an acid medium to form a thiazoline of the general formula wherein R is (b) above, when R 0 is -CH = CH-, or (a) above linked to the N atom by the C atom which is not adjacent to its double bond, when R 0 is -C # C-, and optionally isomerizing the thiazoline obtained in which R is (a) above by heating in solution at above 100‹ C. or treating with concentrated acid to form a thiazole of the first general formula above wherein R is linked to the N atom by the C atom adjacent to its double bond; followed optionally by salification. Isothiocyanates of the general formula are prepared by treating with CS 2 in the presence of cyclohexylcarbodiimide at a low temperature in a solvent. Pharmaceutical compositions having antiinflammatory and hypocholesterolemic activity comprise, as active ingredient, a 2-aminothiazole derivative of the first general formula above a mineral or organic acid addition or quaternary ammonium salt thereof, together with a physiologically acceptable carrier or excipient. [GB1456257A]

Description

?nis o' 'aian mnpti ' wsm Tnaan 2-»Ajnino-5-(2-aminoethyl)-thiazoletderivativee, their preparation and pharmaceutical compositions containing them Centre d*Etudes pour &· Industrie fharinaceutique C: 42985 The present invention relates to new of 2-amino-5- (2-aminoethyl)-thiazole , to a process for preparation thereof and to the use thereof in human and veterinary medicine.

The compounds according to the invention are of the formula : wherein E, F and G are hydrogen or E and G taken together or F and G taken together represent a carbon to carbon bond, and 21 which may be the same or different, are hydrogen atoms or alkenyl', alkyl, cycloalkyl, phenyl, phenyl loweralkyl groups (which groups may be substituted by halogen or hydroxy) or form, together with the nitrogen atom to which they are linked, a saturated heterocyclic ring having 4 to 8 ring members and optionally containing a nitrogen or oxygen atom as a second heteroatom and being optionally substituted by an alkyl group; and R^ and R^ , which may be the same or different, are hydrogen atoms, alkyl or cycloalkyl groups, or form, together with the nitrogen atom to which they are linked, a saturated heterocyclic ring having 5 or 6 ring members and optionally containing oxygenor nitrogen as a second heteroatom which (in the case of nitrogen) is optionally substituted by a phenyl group which may be substituted by a halogen atom or a trifluoromethyl or lower alkoxy group.

The alkyl and alkenyl groups and the alkyl portions of the aralkyl groups in the compounds of the formula I advant¬ ageously are straight or branched and have 1 to 12 carbon atoms and preferably 1 to 4 carbon atoms in their straight chain.

The cycloalkyl groups of and R2 in the derivatives of formula (I) generally have 4 to 12 carbon atoms, and •particularly 5 to 8 carbon atoms, in the ring.

The derivatives (I) possess valuable anti- inflamrnatorv and hypocholesterolemic properties.

These properties, associated with a low toxicity, are particularly marked in the case of the compounds of formula (I) comprising two heterocyclic rings and especially a heterocyclic ring containing two nitrogen atoms one of which carries an alkyl group. Compounds wherein is cycloalkyl are also important.

Compounds of the formula I may be prepared by reacting an amine, of the formula AH with an isothiocyanate of the formula B - N = C = S (A being -N(R. when B is -CH--R -CH -N(R_R.) 1 2 2 o z J 4 or when R2 is hydrogen, being (R3R4)'-CH2-R -CH2- H- and B is R^ -, Rq being a vinylene group (-CH=CH-) or ethynylene (-C=C-) group) to form an intermedia e of formula: then cyclising this intermediate, by heating in acid medium, to form a thiazoline derivative of formula: wherein E, F and G are hydrogen when RQ is vinylene, or G and E are a carbon to carbon bond, when RQ is ethynylene; and, when a thiazole of formula I above is required wherein F and G are carbon to carbon bond, isomerising a thiazoline as just defined wherein E and F are a carbon to carbon bond.

The starting amines N(R_R. ) - CH -R -CH -NH are known 3 4 2 o 2 2 compounds and may be prepared by the process described by R. Dahlbom, B,Karlen, A.Lindquist, R. George and D.J. Jenden in Acta Fharm. Suedica, 4, (4) , 247 , (1967) or in Chem.Abst. 68,21805 k (1968) when R is. ethynylene. When R is vinylene, o o they may be prepared by the process of T. Singh, R. Stiel and J. Biel in J. Med. Chem., 1969,12,368.

The preparation of the new starting isothiocyanates N(R_R. )-CH„-R -CK -N=C=S may be effected in conventional 3 4 2 o 2 manner by treating an amine of the formula N(R R. ) -CH--R -CH - J 4 L o 2 with carbon disulphide in the presence of cyclohexylcarbodi- imide, at a low temperature (e.g. -20 to -10 °C) in a solvent such as ether .

The reaction of the amine AH with the isothiocyanate P-N=C S is generally performed by admixing solutions containing stoichiometric quantities of the two reagents , the solvent being the same for each solution ( eg. hydrocarbon), for example under reflux for 15 minutes to three hours according to the nature of A and of B, evaporating of the solvent under vacuum, dissolving the residue, which is generally oily, in an aqueous acid solution, heating this solution to 100°C for at least abrut one hour, cooling and separating the precipitate or the oily phase which is formed by adding alkali.

The precipitate can be isomerised by heating it to reflux in a solvent with high boiling point, for example higher than 100 °C, or by treating it with a concentrated acid, such as concentrated sulphuric acid, at about 80 °C for period of time varying from a few minutes to a few hours.

The compound/ of the formulji I may be prepared in the form of their simple or multiple acid addicion salts with mineral or organic acids, such as their hydrohalides , for example their hydrochlorides, hydrobromides , sulphates, oxalates, methanesul- phonates, maleates, lactates, or tartrates, or in the form of quaternary ammonium salts . These salts are prepared by dissolving the free base in etherified solutions containing a stoichiometric quantity of the chosen acid.

The following examples illustrate the invention.

EXAMPLE 1 Preparation of 2-cyclohexylamirio 5-p-diethylamino- 2 < ethylidene Δ -thiazoline (derivative No.l) and of its hydrochloric ethyl. . a) Into a solution of 21g (0.15 mole) of 1-amino 4- diethylamino 2-butyne in 50 ml of benzene is introduced, drop- wise, a solution of 21g (0.15 mole) of cyclohexyl isothiocyanate in 50 ml of benzene.

The mixture is heated to reflu for 40 minutes, then the benzene is evaporated under vacuum. The residual oil is taken- up in 150 ml of 2N UCfi arid the mixture is heated for 1 hour at 100 °C. After cooling, the reaction medium is neutralised by addition of a solution of 2N NaOH. The precipitate formed is filtered'and dried. Thus there is obtained 38.2 g of the crude product (yield, 90%), which, after purification, by - - recrystallisation in an ether mixture of petroleum/cyclohexane , provides 29g of crystals (yield 70%) whose melting point, determined by Koefier block, is 125°-126°C. b) In a flask containing 8.25g (0.14 mole) of dicyclohexylcarbodiimide , 30ml of carbon disulphide and 100 ml of ether is introduced, dropwise, solution of 5.6g (0.04 mole) of 1-amino 4-diethyl-amino 2-butyne in 5 ml of the same solvent.

The temperature of the mixture is kept between -10° and -12 °C during the introduction of the amine, then the mixture is left at ambient temperature for 18 hours. After filtering, the etherified solution is evaporated under vacuum. The oily residue constituted by 4-diethylamino 1- isothiocyanato 2-butyne, is dissolved in 25 ml of benezene, then introduced into a mixture of 3.96g (0.04 mole) of cyclohexylamine dissolved in 25 ml of the same solvent.

The mixture is heated to reflux for 40 minutes, then the benzene is evaporated under vacuum. The residual oil is taken- Ί up in a solution of 2N HC and the mixture is heated for one hour at 100 °C. After cooling, the reaction medium is neutralised by addition of a solution of 2N NaOH . The precipitate formed off is filtered^ dried, then recrystallised from an ether mixture of petroleum and cyclohexane. Thus there is obtained, in a yield of 43%, 4.8 of crystals identical to those obtained previously. c) The precipitate obtained previously in the crude state is dissolved in ether. To the solution is added ether saturated with hydrochloric acid. The hydrochloride precipitated is collected and recrystallised from a mixture of isopror panol and isopropyl ether. Crystals are obtained whose melting point, determined by Koefler block, is 225 C.

EXAMPLE 2 Preparation of 2-cyclohexylamino 5- -diethylaminoethyl thiazole (derivative No.2, thiazole isomer of derivative No 1).

A solution of 6g of the derivative No.1 in 100 ml of a mixture consisting of 4 volumes of glacial acetic acid to one volume of 40% aqueous hydrobromic acid is heated to reflux for 16 hours. The cooled solution is neutralised with an aqueous solution of 2N NaOH, then extracted vrith ether. The organic phase is separated, washed with water, dried over and then evaporated. 5.6g are obtained of a crude product (yield 93%) which, after recrystallisation from petroleum ether, results in crystals whose melting point is 89-90°C.

By treatment with a solution of hydrochloric acid in ether, a dihydrochloride is obtained whose melting point is 190 °C.

EXAMPLE 3 Preparation of 2-cyclohexylamino ■ 5- β-diethylaminoethyl thia2oline (derivative No. 3).

While maintaining the temperature at between 5° and 10° a solution of 7.05g (0.05 mole) of cyclohexyl isothio-cyanate in 25ml of benezene is mixed with a solution of 7.1g (0.05 mole) of 1-amino 4-diethylamino 2-butene in 25 ml of the same solvent. After 2 hours the benzene is evaportfated and 14 g of a residual oil are recovered which is dissolved in a mixture of 4 volumes of glacial acetic acid to 1 volume of a 40¾ aqueous solution of HBr.

The mixture is heated for 15 hours under reflux then cooled, diluted with ice water, neutralised by addition of a solution of 2N NaOH and extracted with ether.

The combined organic solutions are washed with water, dried over Na2 SO^ and evaporated. The solid residue is taken-up in ether and is added to a solution of HC1 in ether.

Crystals of dihydrochloride are obtained, melting point 238°-240° (yield, 901).

Many other derivatives corresponding to the formula (I) have been prepared by the process according to the invention, for example : 2-|¼ -hydroxyphenethylamino 5- (f¾-diethylaminoethylidene) /> 2-thiazoline (yield 40%; melting point : 129-131°C (derivative No.4); Rj= |¾ -hydroxy phenethyl ; R| = H ; Rj - R4 = ethyl. 2-N-diethylamino 5- [ -(N-cyclohexyl N-methyl-amino) ethylide^ej Δ2- thiazoline dioxalate (yield 33%) ; melting point : 170-172 C (derivative No. 5); Ri = R2 = etnvl ί R3 ° cyclohexyl ; R4=methyl. 2-cyclohexylamino 5-[ - (N-cyclohexyl N-methylamino) ethylidene] A2-thiazoline (yield 74%) ; melting point : 113° - 115°C (derivative No. 6) ; =» R3 = cyclohexyl ; R2 «= H ; R4 « methyl. 2-amino dihydrochl ride (yield 12%) ; melting point : 210°C (derivative No .7) . R^R^ H ; R3= 4 » ethyl. 2-cyclohexylamino 5-(¾ -morpholinoethylideneA2-thiazoline (yield 731); melting point : 144° -146°C (derivative No.8) R^cyclohexyl ; R2= H ; N ( j 4) = morpholino. 2-butylamino 5-(¾ -diethylaminoethyl thiazole dihydrochloride (yield 551) ; melting point : 188°-190°C (derivative No.9) Rj β normal butyl ; R2 = H ; R3 a R4 = ethyl. 5- ( (^-diethylaminoethylidene) 2-(N-ethyl N-cyclohexylamino) A2-thiazoline oxalate (yield 43%) ; melting point : 138° - 140°C (derivative No.10) R^ Rj= R4 - ethyl ; R2 = cyclohexyl. 5-( β -diethylaminoethylidene) 2-(N-methyl N-cyclohexylamino) thiazoline dioxalate (yield 52%) ; melting point: 172°-1740 (derivative No. 11) ° methyl ; R2=cyclohexyl ; R3=R4=ethyl . 5- (2-diethylamino ethylidene) 2-(4-methyl 1-piperazinyl)Δ2- thiazoline tetrahydrochloride (yield 23%) ; melting point:220°C (derivative No.12) N(R1R2 = 4-meth . 2-cyclohexylamino 5- ( -piperidino (yield 761); melting point 134° -136°C (derivative No.13°. R,» A cyclohexyl ; R2 = H ; )f(R3R4) =piperidino. 5- -diethylaminoethylidene 2-morpholino -- ^-thiazoline oxalate (yield 49%) ; melting point 170°-172°C (derivative No. 14) N(R1R2) a morpholino; R3 - R4 = ethyl. 2-diethylamino 5- (2-diethylamino ethylidene) -thiazoline dioxalate (yield 43%) ; melting point : 134°-135°C (derivative No. 15) Rx = R2 = R3 = R4 = ethyl. 5- (2-dimethylamino ethylidene) -thiazoline oxalate (yield 351); melting point : 145°C (derivative No. 16);R1=H;R2 = ethyl ; Rj a R^ = methyl. 2-butylamino 5- (2-diethylamino ethylidene) dihydrochloride (yield 52%) melting point; 190°-194°C (derivative No. 17) Rx = n - butyl; R2 = H ; R3 = R4 ■ ethyl. 5- ( (¾ -diethylamino ethylidene) 2- (1 , 1 , 3 , 3-tetramethyl-butyl)-ammoA2-thiazoline (yield 391) ; melting point : 200°C (derivative No.18) Rj^ = 1,1,3,3-tetramethyl-butyl ; R2=H ; R3=R4=ethyl . 2-ethylamino 5-[ 2 (1-pyrrolidinyl) -thiazoline (yield 451); melting point 84-86°C (derivative No. 19) R^ethyl; R2 - H ; N ( 3 4) = pyrrolidinyl . * 2-cyclohexylamino 5-[ 2- (Ipyrrolidinyl)cthylidene] Δ -thiazoline (yield 64%) ;melting point 133°-134°C (derivative No. 20) R = cyclohexyl ; 2 5-( -diethylaminoethylidene) 2-methylamino Δ -thiazoline oxalate (yield 50%) ; melting point 178°- 180 °C (derivative No.21) R1 ==methyl ; R2= H ; R3=R^ =ethyl. 5-β-die hylaminoethyl 2-(N-methyl N-cyclohexylamino)-thiazolr dioxalate (yield 70%) ;melting point : 80 °C(derivative No.22); R^ = methyl ; = cyclohexyl ;R^ = =ethyl .

A 2 2-benzylamino 5--diethylaminoethylidene -thiazoline dihydrochloride (yield 63%) jmelting point 235 °C(derivative No. 23). R^benzyl ;R2=H ;R3= R^=ethyl . 2 5-(p-diethylaminoethylidene) 2-isopropylamino Δ -thiazoline dicxalate (yield 46%) ;melting point : 164°-166 °C (derivative No 24) , R^- H =isopropyl ;R^= ^ =ethyl . 2 2- (4-chlorobenzyl amino) 5--diethylaminoechylidene Δ -thiazoline dihydrochloride (yield 35%) ;melting point: 210 °-220 °C(derivative No.25) R^H;R2=(4-chlorobenzyl) ; R^R^-ethyl. 2 2-cyclopentylamino 5- -diethylaminoethylidene Δ -thiazoline ( yield 47%) ;melting point : 89 °-90 °C(derivative No.26); R^ H ; R2 = cyclopentyl jR^ R^=ethyl. 2 2-cyclo-octylamino 5-p-diethylaminoethylidene A -thiazoline (yield 46%) ;melting poin : 70 °C(derivative No.27) ; = H ; R2 = c clo-oct l R» = R eth l. 2-cycloheptylarnino 5- -diethylaminoethylidene Δ -thiazoline (yield 44%) ; melting point 92 °C (derivative No.28) ; = H ; = cycloheptyl ; R^ = R^ = ethyl. 2 2-cyclododecylamino 5- -diethylaminoeth3'lidene A -thiazoline (yield 50%) ; melting point : 93 °C (derivative No.29); ^ = H ; R = cyclodoecyl ; R^ = R^ =ethyl . 2 2-allylamino 5- -diethylaminoethylidene Δ -thiazoline dihydro- chloride (yield 31%) ; melting point :190°C (derivative No.30) ; Rx = H ; R2 = allyl ; R3= R4 -ethyl. 2-dicyclohexylamino 5-p-diethylaminoethylidene ^-thiazoline oxalate (yield 40%) ; . melting point :210°C (derivative No. 31); R-^ = = cyclohexyl ; R^ - R^ = ethyl.

The results of the toxicological and pharmacological tests reported hereinafter show clearly the interesting activity of the compounds according to the invention, notably their hypocholesterolemic and anti-inflammatory activity.

I- TOXICOLOGICAL STUDY This study has clearly shown the low toxicity of the derivatives of the invention.

By way of ex h/kg of body weight measured by the method of Miller & Tainter, by the intravenous route, is, in mice, 90mg for derivative No.12; 45 mg for derivative No.18 ; 105 mg for derivative No. 14 ; 92 mg for derivative No 21, and 42 mg for derivative No.l.

During the tests for acute, chronic, or retarded toxicity,, excellent tolerance has been shown to compounds of the invention; . they have caused no difficulty, no local or general reaction and no disturbance in the test animals .

IT- PHARMACOLIGICAL STUDY 1) Hypocholesterolemic action a) . Propyl-thiouracil test (RANNEY et Coll. J.Pharmacol.

Exper. Therap .1963 , 142 , 132-136) .

The administration of propyl-thiouracil to adult rats renders them hypercholesterolemic ; in effect, the plasmatic cholesterol rate has increased by about 15%. The testing is carried out on two groups of rats, the control group receiving the propyl-thiouracil only whilst the treated group also receives 100 ,mg/kg of the compounds to be tested, by the oral route.

* On the llth day of the experim nt, the blood samples are taken and the β- lipoproteins , the free cholesterol and the total cholesterol measured. The results show that in the treated animals, the rate of free cholesterol and total cholesterol are clearly reduced. The results obtained for some of the compounds are summarised in the following table: / .

I V· b) Triton test.

The intravenous injection of Triton W-R 1339 (an alky-laryl polyetheralcchol sold by by Rc m and Haas) enables one to artifically increase, in the rat, certain lipidic fractions of serum and thus to evalute the hypocholesterolemic action of the compounds of the invention.

These are administered by the oral route in a dose of 100 mg/kg immediately after the intravenous injection of the Triton. / Eighteen hours later a blood sample is taken and the β-lipoproteins , the free cholesterol and the cholesterol are determined „ As in the preceding test, significantly low amounts 26% for derivative No.12 and 22% for derivative No, 15. 2) Anti- inflammatory action a) Localised carrageenin- induced oedema method.

A 1% solution of carrageenin . (0.1 ml) is injected into the metatarsal flexor muscles of the right hand rear paw of the rat at time "0".

The animals of the treated group also receive, by the oral route, 100 mg/kg of the compound to be tested, respectively one hour before and at the same time as the injection of the phlogogenic agent, then one hour and two-and-a-half hours after. The measurements made with the aid of a micrometer at the time "0" and one hour, two hours, three hours and five hours after the administration of the carrageenin, enable one to determine, in relation to time, the percentage of antiinflammatory activity in relation to the control group. The results are summarised in the following table: Products First Hour Second Hour Third Hour Fifth. Hour Derivative No,3 37 39 46 48 Deriva ive NoA 39 40 49 53 Derivative NctlO 44 47 52 . 56 Derivative No.22 42 40 54 56 Generalised ovalbumin- induced oedema method A simultaneous intraperitoneal injection of 1 ml of ovalbumin and of 0.5 ml of an aqueous solution of Evans Blue at 1 ml per thousand by weight is administered to rats.

For comparative purposes, 100 mg of the compound to be tested is administered orally to the animals of the group . to be treated, one hour before and at the same time as the oval-bumin. The intensity of the phenomenon thus provoked is noted by a figure 1 to 5 according to the intensity of the inflammatory syndrome .

Thus one determines the average of the .oedematic intensity and the percentage of decrease of the oedematic reaction in relation to the control animals. The results are summarised in the following table: Products Second Hour Third Hour Derivative No3 54 *60 Derivative NoA 59 65 Derivative NoIO 57 64 Derivative N¾22 52 60 The toxicological and pharmacological studies which have just been reported show that the compounds of the invention are well tolerated by the test animals and that they possess hypocholesterolemic and anti-inflammatory activities.

It will be appreciated from the above that the corn-compounds of the invention and their non-toxic salts may be used to advantage in medicine.

By regularising the metabolism of the cholesterol and of the body lipids, they can successfully protect the body from vascular attacks of atherosclerotic origin, and from the cardiac, cerebral and peripheral . complications thereof.

Moreover they intervene effectively in the inflammatory reaction, thus reducing or preventing oedema, hypersecretion, and exudation.

They are recornmendable for the treatment of hypercholesterolemia and hyperlipidemia and the complications thereof, chronic inflammatory rheumatism, degenerative rheumatism, abarticular afflictions, for acute and sub-acute otorhinolaryngological inflammations, in reparative surgery and plastic surgery and in functional re-education.

For this purpose, the compounds of the invention may be formulated for oral administration, in the form of tablets, coated tablets, capsules, drops, or syru s.

They may also be formulated for rectal administration in the form of suppositories and for parenteral administration in the form of an injectable solution.

In these formulations, the active principle is associated. .'. with an excipient or a solid carrier or a sterile and/or flavoured liquid, in dosage units form, the active principle being present in an amount of from 0.01% to 80% by. weight of the composition.

Each dosage unit advantageously contains from 0.05 g to 0.500 g of active principle, the daily dose varying from 0.050g to 1.50g according to the severity of the condition being treated and the age of the patient.

There will be given hereinafter, by way of example, some pharmaceutical formulations of the compounds of the inventior 1 TABLETS Derivative No.1 ....0.100 g Lactose °-010 8 Methyl cellulose ' 0.005 g Tartrazine Trace Microcrystalline cellulose ..0.010 g Corn starch 0.025 g Magnesium stearate 0.010 g 2 - COATED TABLETS Core : Derivative No.12 ....0.100 g Lactose 0.015 g Corn starch 0.005 g Magnesium stearate , 0.005 g Coating : Gum-lac ..0.001 g Gum arabic 0.005 g Talc 0.010 g Carnauba wax 0.003 g Orange, codex "S" Trace White sugar sufficient to make one coated tablet. 3 - CAPSULES .

Derivative No.3 0.150 g Corn starch 0.020 g Magnesium stearate . 0.010 .g 4 - SYRUP Derivative No.22 2 g Excipient .....100 ml 5 - INJECTABLE SOLUTION Derivative No.15 0.100 g Isotonic solution sufficient to make 5 ml 6 - SUPPOSITORIES Derivative No.9 0.150 g Semi-synthetic triglycerides sufficient to make one suppository.

Other examples of compounds of the invention are : 5-diethylaminoethyl 2-cyclodod$cyclamino thiazole (yield 55%) -m.p. 100-120°C. (Derivative No. 32); R = H, R2 ■ cyclododecyl; Rj = β ethyl. 2-cyclododecylamino 5-[ -(N-benZyl N-ethylamino) ethylidene] A2-thiazoline (yield 62¾) m.p. 77°C (derivative No. 33); = H, R2 s cyclododecyl ; R5 = benzyl; R^ = ethyl.

Example 34 Preparation of 5- p- 4-( p -chlorophenyl) piperazino ethylidenej 2-cyclohexylamino -thiazoline - (derivative No. 34) Rx » cyclohexyl ; R2 - H.

Into a mixture of 5g (0.019 mole) of 1-amino 4- (p-.chlorophenylpiperazino ) 2-butyne and 50 ml of chloroform is introduced, dropwise, a solution of 2.68 g (0.019 mole) of cyclohexyl isothiocyanate in 50 ml of chloroform.

The mixture is stirred for 2 hours at ambient temperature, then the solvent is evaporated. The residue is taken up in 65 ml of 2N HCl then heated for 1 hour under reflux. After cooling, the solution is neutralised by addition of a solution of 2N NaOH. The precipitate formed is filtered off, washed with water, dried, and then recrystallised from a cyclohexane/benzene mixture.

Crystals are collected (yield 44%) whose melting point, determined by Koefler block, is 180°C.

The following compounds have been prepared by the same method : 2-cyclohexylamino 5-[ -(4- phenyl piperazino) ethylidene] (derivative No. 35); yield 52% - melting point 145°C. R1 - cyclohexyl ; R2 » H ; 2-cyclohexylamino 5-[ -[4- (me-le-trifluoromethylphenyl) piperazino] ethylidene] Z_\ 2-thiazoline (derivative No. 36) - yield 47¾ , melting point 192 °C. » cyclohexyl ; R2 =» H ; 5-[β -[4- ( o-chlorophenyl) piperazino] ethylidene ] 2-cyclohexylamino (derivative No. 37) -yield 581 - melting point 175°C. R^ cyclohexyl ; R2 0 H ; and 2-cyclohexylamino 5-[β-[4-( p -methoxyphenyl) piperazino] -ethylidene ] (derivative No. 38) ; yield 471 - melting point 160°C; R^ » cyclohexyl ; R2 = H.

III. Toxicological Study The derivatives os. 34 to 38 have been shown to be very well tolerated in all our tests and they have not given rise to any undesirable secondary reaction at therapeutic doses.

By way of example, the hours/kg of body weight determined by the method of Miller & Tainter, by the intravenous route, is 35 mg for derivative No. 34, 48 mg for derivative No. 35, 65 mg for derivative No. 36, 57 mg for derivative No. 37 and 52 mg for derivative No. 38.

IV. Pharmacological Study 1) Hypocholesterolemic action a) PropYl-thiouracil test (Ranney et Coll.

J. Pharmacol.Exper.Therap.1963, 142, 132-136) : This test has shown the clearly favourable action of the derivatives according to the invention, at a dose of 50 mg/kg.

The results are summarised in the following table: b) Triton test This test, which enables one to evaluate the h ocholesterolemic action of the derivatives to be tested, on serum levels of certain lipid fractions, has shown the remarkable effect of the compounds according to the invention. Our tests have shown that the levels of free cholesterol and total cholesterol are considerably reduced in the animals treated with oral doses of 50 mg/kg of the compounds according LO the invention.

These reductions are of the order of 34% for derivative No. 34; of 29% for derivative No. 35; of 27% » for derivative No. 36; of 41% for derivative No. 37; and 44% for derivative No.. 38. 2) Antl- inflammatory reaction a) method of localised carrageenin-induced oedema The oral administration of 50 mg/kg of the derivatives to be tested produces a clear reduction of the inflammatory reaction provoked.

The results are summarised in the following table: 1st 2nd 3rd 4th 5th Products • hour • hour hour hour hour Derivative No. 34 40 44 50 53 55 Derivative No. 35 45 46 55 57 58 Derivative No. 36 46 50 59 61 62 Derivative No. 37 38 43 48 52 57 b) method of generalised ovalbumin- induced oedema The percentages of reduction of oedematic reaction, in the test animals, in subjects treated by the oral route by the administration of 50 mg/kg of the compound to be tested show the clear anti- inflammatory action of the compounds according to the invention. /

Claims (1)

1. 44845/3 CLAIMS : 1. Compounds of the formula : wherein E, F and G are hydrogen or E and G taken together or F and G taken together represent a carbon to carbon bond, R^ and which may be the same or different, are hydrogen atoms or alkenyl, alkyl, cycloalkyl, phenyl, phenyl lower-alkyl groups (which groups may be substituted by halogen or hydroxy) or form, together with the nitrogen atom to which they are linked, a saturated heterocyclic ring having 4 to 8 ring members and optionally containing a nitrogen or oxygen atom as a second heteroatom and being optionally substituted by an alkyl group; and R^ and R^ , which may be the same or different, are hydrogen atoms, alkyl or cycloalkyl groups, or form, together with the nitrogen atom to which they are linked, a saturated heterocyclic ring having 5 or 6 ring members and optionally containing oxygen or nitrogen as a second heteroatom which (in the case of nitrogen) is optionally substituted by a phenyl group which may be substituted by a halogen atom or a trifluoromethyl or lower alkoxy group; and the salts thereof. 44845/3 2. Compounds as claimed in claim 1 wherein R_ and R, J 4 ' are independently hydrogen atoms or alkyl or cycloalkyl groups, or, together with the nitrogen atom to which they are linked, form a saturated heterocyclic ring having 5 or 6 ring members and optionally containing oxygen or nitrogen as a second heteroatom, said second heteroatom being unsubstituted. 3. Compounds as claimed in claim 1 or claim 2 possessing two heterocyclic rings. 4. Compounds as claimed in any one of the preceding claims possessing a heterocyclic ring containing two nitrogen atoms, one of said nitrogen atoms being substituted by an alkyl group. 5. Compounds as claimed in any one of the preceding claims wherein R^ or is a cycloalkyl group. 6. Compounds as claimed in claim 5 wherein R^ or is a cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclododecyl group. 7. Compounds as claimed in any one of claims 1 to 4 wherein R^ or R2 is independently a hydrogen atom or a methyl, ethyl, butyl, hydroxyphenethyl, benzyl or chlorobenzyl group. 8. Compounds as claimed in any one of the preceding claims wherein and together with the nitrogen atom to which they are linked, form a piperazino, methylpiperazino, morpholino, piperidino or pyrrolidino group. 44845/3 9 Compounds as claimed in any one of the preceding claims . wherein R0 and R . , together with the nitrogen atom to which 3 4 they are linked, form a piperazino, morpholino or piperidino group-. 10. Compounds as claimed in claim 1 wherein and ^ together with the nitrogen atom to which they are linked, form a methylpiperazino , or 4- (trifluoromethylphenyl) piperazino group. 2 11. 2-Cyclohexylamino-5-p--diethylaminoethylidene Δ - thiazoline. 12. 2-Cyc1ohexylamino- 5-β-diethylaminoethy1thiazole . 2 13. 2-Cyclohexylamino-5- -diethylaminoethyl Δ -thiazolinp . 14. 2- -Hydroxyphenethylarnino 5- (3-~diethyl rninoethylidene ) 2 -Δ -thiazoline. 15. 2-N-Diethylamino 5- [ β- (N-cyclohexyl N-methyl-amino) - 2 ethylidene] Δ -thiazoline dioxalate. 16. 2-Cyclohexylamino 5- [ β- (N-cyclohexyl N-methylamino) - 2 ethylidene] Δ -thiazoline. 2 17. 2-Amino 5-β- (N-diethylaraino) ethylidene Δ -thiazoline dihydrochloride . 18. 2-Cyclohexylamino 5-£-morpholinoethylidene A2-thiazoline , 19. 2-Butylamino 5-6-diethylaminoethyl thiazole dihydrochloride. 20. 5-(p-Diethylaminoethylidene) 2-N~ethyl -cycio- 2 hexylaiino) Δ -thiazoline oxalate. 21. 5- (β-Diethylaminoethylidene) 2-(N-methyl N-cyclo- 2 hexylamino) Δ -thiazoline dioxalate. 22. 5-(2-Diethylaminoethylidene) 2-(4-jne hyl 1- 2 piperazin l) Δ -thiazoline tetrahydrochloride „ 23. 2-Cyclohexylamino 5- (β-piperidyl-l0 Δ2- thiazoline. 2 24. 5-p~Diethylaminoethylidene 2-morpholino Δ -thiazoline oxalate. 2 25. 2-Diethylamino 5-(2-diethyl mino ethylidene) Δ - thiazoline dioxalate0 2 26. 5- (2-Dimethylamino ethylidene)2-ethylamino Δ - thiazoline oxalate. 2 27. 2-Butylamino 5- (2-diethylamino ethylidene) Δ - thiazoline dihydrochloride . 28. 5- (β-Diethylamino ethylidene) 2- (1, 1, 3; 3-tetrameth.yl- 2 butyl-araino) Δ -thiazoline. 2 29. 2-Ethylamino 5-[2(l-pyrrolidinyl)ethylidene] Δ -thiazoline. 30. 2-Cyclohexylamino 5-[2- (l-pyrrolidinyl)ethylidene] 2 Δ -thiazoline. 2 31. 5- (β-Diethylaminoethyliclene) 2-meth lamino Δ - thiazoline oxalate. 32. 5-p-Diethylaminoethyl 2-(N-methyl N-cyclohexylamino)- thiazole dioxalate. 2 33. 2-Benzylamino 5- -diethylaminoethy0lidene Δ -thiazoline dihydrochloride . 34. 5- (β-Diethylaminoethylidene) 2-isopropylamino 2 Δ -thiazoline dioxalate. 35. 2- (4-Chlorobenzylamino) 5-p-diethylaminoethylidene 2 Δ -thiazoline dihydrochloride. 2 3b. 2-Cyclopentylamino 5- -die >i.ylaminoe hylidene Δ - thiazoline. 2 37. 2-Cyclo-octylamino 5- -diethylaminoethylidene Δ - thiazoline. 2 38. 2-Cycloheptylamino 5- -diethylaminoethylidene Δ - thiazoline. 2 39. 2-Cyclododecylamino 5-p-diethylaminoethylidene Δ - thiazoline. 2 40. 2-Allylamino 5-p-diethylaminoethyiidene Δ -thiazoline dihydrochlo ide. 2 41. 2-Dicyclohexylamino 5- -diethylaminoethylidene Δ - thiazoline oxalate. 42. 5-Diethylarninoethyl 2-cyclododecylamino thiazole. 43. 2-Cyclododecylamino 5- [¾ - (N-benzyl N-ethylamino) - · ethylidene] 2-thiazoline . 44. 5- β-[4 -(p -chlorophenyl) piperazino] ethylidene] 2-cyclohexylamino -thiazoline. (phenyl) piperazino-ethyli- dene]Z- ^-thiazoline. 46. 2-Cyclohexylamino 5-|^' 4- ( trifluoromethylphenyl) piperazino] ethylidene -thiazoline. 47. 5-[β- [4-(ο -chlorophenyl) piperazino] ethylidene] 2 - cyclohexylamino -thiazoline. 48. 2-Cyclohexylamino 5- | -[4-(ρ -methoxyphenyl) pipera¬ -thiazoline. 49. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims together with a physi logically acceptable carrier or excipient. 50. A composition as claimed in claim 49 in a form suitable fo oral, rectal or parenteral administration. 51. A composition as claimed in claim 49 or claim 50 in dosage unit form, each unit containing 0.05 to 0.5 g of said compound. 52. A composition as claimed in any one of claims 49 to 51 comprising a compound as claimed in claim 2. 53. A composition as claimed in claim 49 substantially as described herein with reference to any one of the Examples. 54. A process for the preparation of a compound as claimed in claim 1 which comprises reacting an amine of the formula AH with an isothiocyanate of the formula B-N = C » S (wherein A is -N (Rj 2) and B is -CH2R0-CH2-N (R3R4) i or, when R2 is hydrogen, wherein A is N R3R4) -CH2-R0-CH2-NH- and B is ^ -, RQ 44845/3 being the group -CH=CH- or -C≡C- ) to form an intermediate of formula cyclising the intermediate to form a thiazoline of formula wherein E, F and G are hydrogen when RQ is vinylene, or G and E are a carbon to carbon bond, when RQ is ethynylene; and, when a thiazole as claimed in claim 1 is required wherein F and G are carbon to carbon bond, isomerising a thiazoline. as just defined wherein E and F are a carbon to carbon bond. 55. A process as claimed in claim 54 wherein the cyclisation is effected by heating in acidic solutions. 56. A process as claimed in claim 54 or claim 55 whereby a compound as claimed in claim 2 is prepared. 57. A process for the preparation of a compound as claimed in claim 1 substantially as described herein with reference to any one of the Examples. 58. A compound of formula I when prepared by a process as claimed in any one of claims 54 to 57. plicanls COHN AND PARTNERS