CH626356A5 - Process for the preparation of substituted anilino-2-oxazolines and -thiazolines - Google Patents

Description

The invention relates to a process for the preparation of substituted anilino-2-oxazolines and thiazolines and the pharmaceutically acceptable acid addition salts of these compounds.

The substituted anilino-2-oxazolines and thiazolines have the general formula

50

(I),

wherein

R represents hydrogen or a lower alkyl radical with up to 6 carbon atoms,

Ri, R2 and R3 independently for hydrogen, bromine, chlorine,

Fluorine, nitro, lower alkyl radicals, lower alkoxy radicals or lower alkanoyloxy radicals,

Y for hydrogen, chlorine or fluorine,

Xi for oxygen or sulfur,

X2 for J ^ C = O or J> CH2 and

Z for hydrogen, chlorine, fluorine, hydroxy, a lower one

Alkoxy radical or lower alkanoyloxy radical are provided that in cases where Z is a

Hydroxyl group and Xi is an oxygen atom, X for ^ TC = 0

stands.

The compounds of the general formula (I) have valuable therapeutic effects, in particular a valuable antihypertensive effect.

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626 356

Unless otherwise stated, “lower alkylene radicals”, “lower alkoxy radicals” and “lower alkanoyloxy radicals” are radicals with up to 6 carbon atoms. Examples of such residues are: alkyl residues, e.g. Methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, and their corresponding branched isomers, alkoxy, e.g. Methoxy, ethoxy, isopropoxy and butoxy, and alkanoyloxy, e.g. Acetoxy, propionyloxy and butyryloxy, and the corresponding branched isomers of the radicals mentioned. Examples of pharmaceutically acceptable acid addition salts are the salts formed with maleic acid, acetic acid, phthalic acid, succinic acid, lactic acid, tartaric acid, citric acid, malic acid, cinnamic acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

R is preferably a lower alkyl radical with up to 4 carbon atoms, in particular a methyl radical. R3 is preferably hydrogen, and Ri and R2 are preferably hydrogen or lower alkyl radicals.

^, CF2Y

The grouping -C Z

^ CYa

^ CFaY

is preferably a group of the formula -C OH

^ CFzY

wherein Y has the meaning given for the formula I and is preferably a fluorine atom.

A preferred compound of the general formula (I) in which Xi is sulfur and X2 is ^> CH2 is the compound 2- [4- (hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] - 2-thiazoline. Examples of other thiazolines include:

2- [4- (Hexafluoro-2-hydroxy-2-propyl) -N-ethylanilinoJ-2-thiazoline, 2- [N, 2,6-trimethyl-4- (hexafluoro-2-hydroxy-2-propyl) - anilino] -2-thiazoline and 2- [4- (tetrafluoro-1,3-dichloro-2-hydroxy-2-propyl) -N-methylanilino] -2-thiazoline.

Examples of compounds of the general formula (I) in which Xi is oxygen and X2 stands for are:

2- [4- (hexafluoro-2-methoxy-2-propyl) -

N-methylanilino) -2-oxazoline,

2- [4- (hexafluoro-2-acetoxy-2-propyl) -

N-methylanilino] -2-oxazoline and

2- [4- (2-chlorohexafluoro-2-propyl) -

N-methylanilino] -2-oxazoline.

As preferred compounds of the general formula I in which Xi is oxygen or sulfur and X2 for O

is 2- [4- (hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazolin-4-one and 2- [4- (hexafluoro-2-hydroxy-2-propyl ) -N-methylanilino] -2-thiazolin-4-one to name. 2- [4- (Hexafluoro-2-hydroxy-2-propyl) anilino] -2-oxazolin-4-one should also be mentioned.

The process according to the invention for the preparation of the compounds of the general formula (I) is characterized in that a compound of the general formula

10 t

(III),

wherein R, Ri, R2, R3, Xi, X2, Y and Z have the meanings given for the formula I and Q is a reactive group which can be removed under the reaction conditions used as HQ, cyclizes and the compound of the general formula (I) isolated in free form or in the form of a pharmaceutically acceptable acid addition salt. Group Q can generally be a labile leaving group, e.g. Halogen, preferably chlorine, or a sulfonic acid ester component, e.g. Tosyl or Mesyl.

To prepare compounds of the general formula (I) in which Xi is oxygen and X2 is C = 0 or CH2, 25 a substituted aniline of the general formula can be used as the starting material

(II),

40 in which R, R 1, R 2, R 3, Y and Z have the meanings given for the formula (I), are reacted with chloroacetyl or 2-chloroethyl isocyanate, an intermediate of a compound of the general formula (III) being obtained, where Xi is oxygen, X2 is O or J ^ Œh

«And Q represents chlorine and R, Ri, R2, R3, Y and Z have the meanings given for the formula (I). The desired compound of general formula (I) is obtained by cyclization of the intermediate of formula (III). The cyclization can be carried out in any suitable manner, such as when X2 is a group of the formula C = O

cyclization is preferably carried out using a base, e.g. Potassium t-butoxide, in a suitable solvent, e.g. Tetrahydrofuran, diethoxyethane or preferably dimethoxyethane. If X2 is a 55 group of the formula ^: CH2

, the cyclization is preferably carried out by heating in an aqueous alcoholic medium, preferably in the presence of a mineral acid.

The starting material of the general formula (II) in which Z «o is a hydroxyl group can be obtained by appropriately introducing the required hydroxypolyhaloisopropyl group, e.g.

by reacting the suitable polyhalogen ketone or its hydrate with an appropriately substituted aniline (see, for example, E. E. Gilbert, J. Org. «5 Chem. 30 [1965] 1001). The hydroxyl group in this starting material can then be converted into compounds in which Z has different values by known methods.

626356

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The compounds of the general formula (I) in which Xi is sulfur and X2 for O

stands, can be prepared in an analogous manner, as described above, using chloroacetyl isothiocyanate instead of chloroacetyl isocyanate. In this case, however, the intermediate product, which corresponds to the intermediate product of the formula (III), cyclizes spontaneously to the hydrochloride of the thiazoline-4-one.

For the preparation of compounds of formula (I) in which Xi is sulfur and X2 is a starting material of general formula (II) with chloro- or bromoethyl isothiocyanate can conveniently be obtained by heating the materials in an inert solvent, e.g. Benzene, are produced under reflux, the intermediate of the general formula (III) thus formed being cyclized spontaneously.

The pharmaceutically acceptable acid addition salts of the compounds of the general formula (I) can be prepared in a customary manner by treating a solution of the free base in a suitable organic solvent with the corresponding acid with precipitation of the desired salt. Further purification can be carried out, for example, by recrystallization.

The invention is further illustrated by the following examples.

example 1

2- [4- (Hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-thiazoIin

11.0 gp- (hexafluoro-2-hydroxy-2-propyl) -N-methylaniline (0.04 mol) and 9.7 g 2-chloroethyl isothiocyanate (0.08 mol) are mixed in 100 ml benzene. The mixture is heated for 3 hours on a reflux condenser and then the solid material is filtered off. The solid material is dissolved in 300 ml of water and made basic with sodium carbonate. The solution is extracted with diethyl ether, dried and the ether extract is concentrated, and the residue obtained is recrystallized from a mixture of ether and diethyl ether, crystals of melting point 160 to 163 ° C. being obtained. The fumarate produced in methanol has a melting point of 175 to 177 ° C.

Other thiazolines of general formula (I) can be prepared using the appropriately substituted aniline as a starting material in the process described above, e.g. 2- [4- (hexafluoro-2-hydroxy-2-propyl) -N-ethylanilino] -2-thiazoline, 2- [N, 2,6-trimethyl-4- (hexafluoro-2-hydroxy-2-propyl) -anilino] -2-thiazoline and 2- [4- (tetrafluoro-1,3, (dichloro-2-hydroxy-2-propyl) -N-methylanilino] -2-thiazo-lin.

Example 2 2- [4- (2-chlorohexafluoro-2-propyl) -N-methylanilino] -2-oxazoline

41.0 g (0.15 mol) of 4- (hexafluoro-2-hydroxy-2-propyl) -N-methylaniline (Gilbert, J. Org. Chem. 30 [1965] 1001) and 19 g (0, 18 mol) of 2-chloroethyl isocyanate to 400 ml of Et20. The mixture is left to stand overnight and then concentrated to give a beige solid. It is recrystallized from a diethyl ether-hexane mixture,

whereby N- (2-chloroethyl) -N '- [4- (hexafluoro-2-hydroxy-2-prop) l) phenyl] -N / -methylurea is obtained as an off-white solid with a melting point of 120-121 ° C.

5.5 g of a 57% sodium hydride solution in mineral oil (0.13 mol) are added to a solution of 22.7 g of N- (2-chloroethyl) -N '- [4- (hexafluoro-2-hydroxy-2- propyl) phenyl] -N'-methylurea (0.06 mol) in 100 ml of 1,2-dimethoxyethane. The mixture is stirred for one hour and then 15.1 g of thionyl chloride (0.13 mol) are slowly added. After an hour, the mixture is poured in

800 ml of water, the solid is filtered off, dissolved in 200 ml of methanol and decanted from the mineral oil. 16 g of sodium borohydride (0.4 mol) are added to the methanol. The mixture is concentrated and the residue is dissolved in ether, washed with water and concentrated to give a cream-colored solid. The solid thus obtained is dissolved in 40 ml of 2N sulfuric acid and 40 ml of methanol. The mixture is heated for one hour on a reflux condenser and the mixture is then partly concentrated, divided between ethyl acetate and aqueous sodium bicarbonate, dried and the ethyl acetate is evaporated off. The oil obtained as a residue is treated in ether with ethereal sulfuric acid and the solid is filtered off. It is divided between ethyl acetate and aqueous sodium bicarbonate, the ethyl acetate is dried, concentrated and distilled. Boiling point 123-131 ° C (0.1 mm Hg). The distillate is treated in ether with ethereal sulfuric acid and the bisulfate is obtained with a melting point of 143-146 ° C.

Example 3

2- [4- (hexafluoro-2H-2-propyl) -N-methylanilino] -

2-oxazoline

To a solution of 1.6 g of 2- [4- (2-chlorohexafluoro-2-propyl) -N-methylanilino] -2-oxazoline bisulfate (0.003 mol), prepared in the manner described in Example 2, in 40 ml Ethanol is given 0.1 g of 5% palladium carbon. It is shaken for 3 hours with hydrogen under a pressure of 3 atmospheres, filtered and concentrated. It is divided between ethyl acetate and aqueous sodium bicarbonate. The ethyl acetate is dried and evaporated, the oil remaining as a residue is treated with 0.2 g of orthophosphoric acid in methanol, diluted with ether and filtered, the phosphate of the desired compound having a melting point of 93 to 97 ° C. being obtained.

Example 4

2- [4- (Hexafluoro-2-methoxy-2-propyl) -N-methylanilino] -2-oxazoline 8.3 g K2CO3 (0.06 mol) are added to a solution of 11.3 g N- (2nd -Chloräthy]) - N '- [4- (hexafluoro-2-hydroxy-2-propyl) phenyl] -N'-methylurea (0.03 mol) and 17.0 g (0.12 mol) methyl iodide in 120 ml of acetonitrile. The mixture is stirred for 4 days, filtered and the filtrate is concentrated. The residue is dissolved in ether and washed with water, dried and the ether evaporated. The residue is heated in 100 ml of 50% methanol for 1 hour on a reflux condenser. The mixture is concentrated and divided between diethyl ether and 1N hydrochloric acid. The aqueous layer is neutralized with sodium bicarbonate, extracted with diethyl ether, dried and the ether is evaporated off. The oil obtained is dissolved in 10 ml of methanol and treated with 2.0 g of fumaric acid. The solution is poured into diethyl ether and filtered, giving the fumarate of the desired compound of melting point 89-91 ° C.

Example 5 2- [4 - (2-Acetoxyhexafluor-2-propyl) -N-methylanilino] -2-oxazoline 2.2 g (0.05 mol) of a 57% solution of sodium hydride in mineral oil are added to a solution 17.1 g of 2- [4- (hexa-fluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazoline in 150 ml of 1,2-dimethoxyethane. After one hour, 3.9 g (0.05 mol) of acetyl chloride are added. After a further hour, the mixture is filtered and the filtrate is concentrated. The residue thus obtained is dissolved in diethyl ether and 1N hydrochloric acid. The aqueous diethyl ether solution is neutralized with sodium bicarbonate, extracted with diethyl ether and dried over magnesium sulfate. The solution is treated with ethereal hydrochloric acid, the solid is isolated and recrystallized from methanol-ether, the hydrochloride of the desired compound having a melting point of 102-104 ° C.

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Example 6 2- [4- (Hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazolin-4-one To 12.0 g (0.044 mol) of N-methyl-4- (hexafluoro-2 -hydroxy-2-propyl) -aniline in 200 ml of benzene, 7.2 g (0.06 mol) of chloroacetyl isocyanate are added and the mixture is stirred for one hour. The solid product is filtered off and washed with benzene, giving N'-methyl-N-chloroacetyl-N / - [4- (hexafluoro-2-hydroxy-2-propyl) phenyl] urea, melting point 158-160 ° C. receives. 2.24 g (0.02 mol) of potassium t-butoxide are added to 3.93 g (0.01 mol) of this product in 100 ml of dimethoxyethane and the mixture is stirred for 30 minutes. The mixture is concentrated, 100 ml of water are added and the mixture is acidified with concentrated HCl. It is neutralized with sodium bicarbonate and then extracted with diethyl ether, the ether extract is dried and then concentrated. The crude product obtained is triturated with diethyl ether and the solid is filtered off, giving the desired compound of melting point 225-227C.

Example 7

2- [4- (Hexafluoro-2-hydroxy-2-propyl) anilino] -2-oxazolin-4-one To 9.7 g (0.026 mol) of N-chloroacetyl-N '- [4- (hexafluoro-2- hydroxy-2-propyl) phenyl] urea in 500 ml of dimethoxyethane are 5.7 g (0.051 mol) of potassium t-butoxide. The mixture is stirred for 16 hours, concentrated, water is added, acidified with concentrated hydrochloric acid, neutralized with sodium bicarbonate and then extracted with diethyl ether. It is dried, concentrated and the residue is recrystallized from diethyl ether, the desired product having a melting point of 272-274 ° C. being obtained.

Example 8

2- [4- (Hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-thiazolin-4-one To 2.73 g (0.01 mol) of p- (hexafluoro-2-hydroxy-2 -propyl) -N-methylaniline in 40 ml of dimethoxyethane, 1.50 g (0.011 mol) of chloroacetyl isothiocyanate are added and the mixture is stirred for one hour. The reaction mixture is poured into water and neutralized with sodium bicarbonate, the mixture is extracted with diethyl ether, the extract is dried and then concentrated. The residue is recrystallized from diethyl ether and the desired compound of melting point 240-242 ° C. is obtained.

The following representative oxazolin-4-ones of the general formula (I) can be prepared in an analogous manner to that described in Examples 6 and 7 above:

2- [4- (1,3-dichloro-1,3,3,3-tetrafluoro-2-hydroxy-

2-propyl) -N-methylanilino] -2-oxazolin-4-one

2- [2,6-diisopropyl-4- (hexafluoro-2-hydroxy-

2-propyl) -N-methylanilino] -2-oxazolin-4-one

2- [4- (1,1,1-trifluoro-2-hydroxy-2-propyl) -

N-methylanilino] -2-oxazoline-4-one

2- [4- (chloropentafluoro-2-hydroxy-2-propyl) -

N-methyl-anilino} -2-oxazolin-4-one

2- [2,6-dichloro-4- (hexafluoro-2-hydroxy-

2-propyl) -N-methylanilino] -2-oxazolin-4-one

2- [2,6-diethyl-4- (hexafluoro-2-hydroxy-

2-propyl) -N-methylanilino] -2-oxazolin-4-one

2- [4- (hexafluoro-2-hydroxy-2-propyl) -

2-methoxy-N-methylaniIino] -2-oxazolin-4-one

2- [2-fluoro-4- (hexafluoro-2-hydroxy-

2-propyl) -N-methylanilino] -2-oxazolin-4-one

626 356

>

2- [4- (Hexafluoro-2-hydroxy-2-propyl) -2,6-dimethoxy-N-methylanilino] -2-oxazolin-4-one and 2 - [N-ethyI-4- (hexaf Iuor-2 -hydroxy-2-propyl) anilino] -2-oxazolin-4-one

The corresponding thiazolin-4-ones of the general formula (I) can be prepared in the manner described in Example 8, e.g.

2- [4- (Hexafluoro-2-hydroxy-2-propyl) -N-ethylanilino] -2-thiazolin-4-one 2- [N, 2,6-trimethyl-4- (hexafluoro-2-hydroxy-2 -propyl) anilino] -2-thiazolin-4-one and 2- [4- (1,3-dichloro-1,1,3,3-tetrafluoro-2-hydroxy-2-propyl) -N-methylanilino ] -2-thiazolin-4-one

A number of agents are known for the treatment of hypertension or hypertension. Some of these means, e.g. Reserpine, effective in lowering blood pressure in some patients, leads to undesirable and known side effects in other patients. Other known agents are not sufficiently effective or lead to tolerance towards the agent.

It has been found that the compounds of the general formula I have good antihypertensive activity. Representative compounds have also been found to be particularly effective antihypertensive agents, while they do not, or only in a mitigated form, have some of the deleterious side effects associated with known antihypertensive agents. On the basis of laboratory tests and examinations, it can be established that the effective dose, the ED 50, when the compounds according to the invention are administered orally is generally in the range from 0.01 to 10.0 mg / kg of body weight in warm-blooded animals.

The effective minimum dose in rats was determined for a number of the compounds according to the invention, the results given below being obtained. Hypertensive rats (SHR) were used spontaneously as experimental animals. The method described by Bunag in Journal of Applied Physiology 34 (1973) 279 was used.

connection

Effective

Minimum dose

mg / kg

2- [4- (hexafluoro-2-hydroxy-2-propyl) -

N-methylanilino] -2-oxazolin-4-one

0.25

2- [4- (hexafluoro-2-hydroxy-2-propyl) -

N-methylanilino] -2-thiazolin-4-one

0.25

2- [4- (hexafluoro-2-hydroxy-2-propyl) -

N-methylanilino] -2-thiazoline

0.50

The above compounds were not lethal at a dose of 100 mg / kg.

The required daily dose can be administered in divided doses at once. The exact dose to be administered will, of course, depend on where the particular compound is in the above dose range and the age and weight of the recipient

The compound of the general formula (I) is preferably administered orally, but administration by injection is also possible. The compounds can be combined in a customary manner with any suitable pharmaceutical carriers to give a wide variety of formulations, such as tablets, capsules, syrups, elixirs or suspensions.

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Claims (11)

626 356 2nd PATENT CLAIMS 1. Process for the preparation of compounds of the general formula J (I), wherein R represents hydrogen or a lower alkyl radical with up to 6 carbon atoms, Ri, R2 and Rî independently for hydrogen, bromine, chlorine, Fluorine, nitro, lower alkyl radicals, lower alkoxy radicals or lower alkanoyloxy radicals, Y for hydrogen, chlorine or fluorine, Xi for oxygen or sulfur, X2 for ^> C = O or J ^> CH2 and Z for hydrogen, chlorine, fluorine, hydroxy, a lower one Alkoxy radical or a lower alkanoyloxy radical are provided with the proviso that in cases in which Z is a hydroxyl group and Xi is an oxygen atom, X2 stands for C = O, and their pharmaceutically acceptable acid addition salts, characterized in that a compound of the general formula 20th (III), wherein R, Ri, R2, R3, Xi, X2, Y and Z have the meanings given for formula (I) and Q is a reactive group which can be eliminated as HQ under the reaction conditions used, cyclizes and the compound of formula I in free form or isolated as a pharmaceutically acceptable acid addition salt. 2. The method according to claim 1, characterized in that one cyclizes a compound of formula III in which Q is halogen. 3. The method according to claim 2, characterized in that one cyclizes a compound of formula III in which Q is chlorine. 4. The method according to any one of claims 1 to 3, characterized in that one cyclizes a compound of formula III in which R is lower alkyl. 5. The method according to any one of claims 1 to 4, characterized in that one cyclizes a compound of formula III, in which Ri, R2 and R3 are each hydrogen and Z is a hydroxy group. 6. The method according to any one of claims 1 to 5, characterized in that one cyclizes a compound of formula III in which Y is fluorine. 55 60 7. The method according to any one of claims 1 to 6, characterized in that one cyclizes a compound of formula III in which Xi is oxygen or sulfur and X2 a Group of formula O is. 8. The method according to any one of claims 1 to 6, characterized in that one cyclizes a compound of formula III in which Xi is sulfur and X2 is a group of the formula > Is CH2. 9. The method according to any one of claims 1 to 3, characterized in that a compound of the formula III is cyclized, in which R is methyl, R 1, R 2 and R 3 are hydrogen, Y is fluorine, Z is a hydroxyl group and Xi is oxygen and X2 represents a group of the formula ^; C = O. 10. The method according to any one of claims 1 to 3, characterized in that a compound of formula III is cyclized, in which R is methyl, R 1, R 2 and R 3 are hydrogen, Y is fluorine, Z is a hydroxyl group and Xi is sulfur and X2 is a group of the formula ^ C = O. 11. The method according to any one of claims 1 to 3, characterized in that a compound of formula III is cyclized, in which R is methyl, R 1, R 2 and R 3 are hydrogen, Y is fluorine, Z is a hydroxyl group and Xi is sulfur and X2 represents a group of the formula ^> CH2. 30th