FI60008C - PROCEDURE FOR THE FRAMSTATION OF THE THERAPEUTIC ACID BEHENSYRAESTER OF THE ALPHA ISOMER AV 2-TRIFLUORMETHYL-6-FLUOR-9- (3- (4- (2-HYDROXYETHYL) -1-PIPERIDYL) - (PIPERATYL) - - Google Patents

Description

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Patent · och registerstyrelsen Aradkui uttajd och utl. «Krift * n publicarad 31.07. oi (32) (33) (31) Requested request — Begird priority 13.08.75 USA (US) 60UU62 (71) Kefalas A / S, Ottiliavej 7 ~ 9 »2500-Ktfbenhavn-Valby, Denmark-Danmark (DK) (72 ) J «5rn Lasse Martin Buus, Bjaeverskov, Niels Lassen, Gentofte, Allan Johan Bigler, K ^ benhavn, Denmark-Danmark (DK) (7 ^) Oy Kolster Ah (5 * 0 Method for therapeutic use of 2-trifluoromethyl-6-fluoro - for the preparation of the hexanoic acid ester of the c * isomer of 9- [3 - ((2-hydroxyethyl) -1-piperidyl (or piperazinyl)) -propyl de en i] thiaxanthene -For the preparation of the therapeutic acid ester of the c * isomer 2-Trifluoromethyl-6-fluoro-9- [3 ”(k- (2-hydroxyethyl) -1-piperidyl (or piperazinyl)) - propylidene / thiacanter

The invention relates to a process for the preparation of thiazxanthene compounds of the formula neuroleptics of the formula / 3 VV 1 _99 = CH-CH2-CH2-i / \ -CH2-CH2-OC- (CH2) 20-CH3 6> 8) \ 7 / F / 2 60008 isomers of benzoic acid esters and their pharmaceutically acceptable acid addition salts, wherein X is N or CH.

The compounds of the formula I are prepared according to the invention by reacting the compounds of the formula

S c = CH-CHo-CHO-N X-CHo-CHoOH

The oC isomer of the compound of formula 2 wherein N has the meaning given above to react with a reactive derivative of behenic acid, after which the compound obtained is isolated as the free base or a pharmaceutically acceptable acid addition salt.

The esterification step according to the invention is preferably carried out in an inert solvent such as a ketone, preferably acetone, or an ether such as diethyl ether.

The reactive derivative of behenic acid is preferably an acid halide, especially an acid chloride, or an acid anhydride.

The acid addition salts of the o <-isomers of the compounds of formula I are preferably salts of pharmaceutically acceptable acids, which may be mineral acids, for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like, and organic acids such as acetic acid, tartaric acid, tartaric acid, maleic acid, maleic acid, maleic acid and the like.

In recent years, neuroleptically active thiaxanthene esters have been proposed for use in pharmaceutical preparations having a prolonged effect when administered parenterally, and the use of said esters has already been found to be useful, cf. FI patent publications 51 194 and 55 341, The most useful esters are the decanoic acid and palmitic acid esters of o <-flupentixol, which are most often administered as sterile vegetable oil solutions which are injected

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3 60008 intramuscularly. The neuroleptic effect of such solutions may last up to 18 days,

Aliphatic carboxylic acid esters of some very potent neuroleptic thiaxanthene compounds having a fluorine atom in the 6-position have also been proposed for use and include those esters of aliphatic carboxylic acids having up to 17 carbon atoms in the acid moiety, especially decanoic acid and palmitic acid.

In continuous pharmacological experiments with such esters, 2-trifluoromethyl-6-fluoro-9- (3- (4- (2-hydroxyethyl) -1-piperidyl) propylidene) -thiaxanthene and 2-trifluoromethyl-6-fluoro-9- Decanoic acid and palmitic acid esters of the neuroleptically very strong o <-isomers of (3- (4- (2-hydroxyethyl) -1-piperazinyl) -propylidene) -thiaxanthene tend to initially lead to excessive concentrations when these compounds were injected as oil solutions and this in turn caused pronounced sedation during the first week.

It has now surprisingly been found that the behenic acid esters of the formula I not only have a longer effect than before, but also do not cause over-calming (boredom) of the experimental animals when the more active α-isomers of these compounds are injected in the form of oily solutions.

It is a well known fact that those thiaxanthenes which have a double bond between the ring carbon atom 9 and the side chain and whose phenyl rings are asymmetrically substituted exist in the form of cis-trans type geometric isomers. The individual isomers have varying degrees of desired pharmacological potency. For practical reasons, the isomers with the most pronounced neuroleptic effects are referred to herein as the o4 isomers.

Pharmaceutical compositions containing as an effective ingredient a compound of formula I e <isomer, or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutical carrier or excipient may be administered to animals, including humans, orally, parenterally or rectally and may for example be sterile solutions, or in the form of suspensions, tablets, soups, capsules and syrups for injection. The results have been very good when J i * · »4 60008 these compositions have been administered to humans.

However, the pharmaceutical preparations are preferably in the form of sterile solutions or suspensions for injection. When injected intramuscularly, such oily solutions have a considerably prolonged effect, and a satisfactory neuroleptic effect is obtained for 3 to 6 weeks by a single intramuscular injection containing 25 to 40 mg of a compound of formula I dissolved in a light vegetable oil.

The preferred compound of formula I for use in these pharmaceutical preparations is the benzoic acid ester of the 2-trifluoromethyl-6-fluoro-9- (3- (4- (β-hydroxyethyl) -1-piperidyl) propylidene) -thiaxanthene (Lu 13-013) isomer. and hereinafter it is referred to as Lu 13-063 for brevity.

The following examples illustrate injectable oil solutions: 1. Lu 1 3-063 1 6 g

Sterile, light vegetable oil ad 1,000 ml 2. Lu 13-063 32 g

Sterile sesame oil ad 1,000 ml 3. Lu 13-063 100 g

Aluminum monostearate 20 g

Sterile, light vegetable oil ad 1,000 ml 4. Lu 13-063 16 g

Sterile olive oil ad 1,000 ml

For example, the solutions are filled into ampoules containing 1 ml of solution each.

The active ingredient of the formula I can also be administered in the form of a suspension in which the micronized active substance or a salt thereof is suspended in sterile physiological saline.

'4! '' 5 60008

Other pharmacological additives may be used provided that they are compatible with the active ingredient, and other compositions and dosage forms used in neuroleptics may also be used,

To determine the activity of the behenic acid esters of the formula I, a known test is used based on the fact that potent neuroleptics counteract apomorphine-induced vomiting in dogs, P.A.J. Janssen, C.J.E. Niemegeers and K.H.L. Schellehaus describes the experiment in the article "Is it possible to predict the clinical effects of neuroleptic drugs (major tranguillisers) from animal data?", Part II, Arzneimittel Forschung, 15, 1196-1206, 1965. In order to evaluate the effect of esters of compounds of formula I is The modified method is described by M. Nymark et al in Acta Pharmacol et al., 1973, 33, 363-376.

The experiment is briefly described below:

Interaction with amomorphine in dogs

Pure-bred Beagle dogs of both sexes were used as experimental animals. The threshold dose of apomorphine hydrochloride leading to the onset of vomiting in dogs is 0.025 mg / kg when injected intravenously. After such a dose, vomiting occurs a few minutes after the injection. For each dose of the substance, four dogs were injected subcutaneously in the neck. After various periods of administration, the dogs were given apomorphine according to an "up and down" program, with doses ranging from 0.025 to 0.400 mg / kg given intravenously. Thus, if the dog vomited, for example, at 0.1 mg / kg, the following the dog was given 0.05 mg / kg, or 0.2 mg / kg unless the first dog vomited, and so on.

In this way, it was possible to estimate the amount of apomorphine against which dogs were protected at a given time. The dogs were fed for half an hour before the experiments to ensure easy vomiting.

Esters of potent neuroleptics such as esters of enanthic acid and decylic acid have been proposed in the past, and decylic acid ester of o (-fupen-thixol) has been used in recent years as oily injectable solutions with a sustained release effect of 6 60008 substances. It has now been found that Lu 13-063 is more advantageous than the corresponding palmitic acid ester in that it causes less sedation during the first week when the latter ester was injected subcutaneously at a dose of 1 mg / kg (calculated as Lu 13-013) in dogs. mg / kg ester under the skin corresponds to about 1 mg / kg Lu 13-013: a) maximal protection (1 6-fold threshold dose of apo'morphine) was observed over 15 days, and a strong (approximately 12- The effect disappeared after 26 days, and no sedation was observed in experimental animals.

For comparison, e <-flupentixol decylic acid ester (2 mg / kg, subcutaneously) provided a relatively low degree of protection (3 times the threshold dose), and the effect disappeared after 11 days.

In another well-known experiment for the evaluation of neuroleptic drugs described by P.A.J, Janssen, C.J.E. Niemegeers, K.H.L, Schellehaus and F.M. Lenaerts, in his article "Is it possible to predict the clinical effect of neuroleptic drugs (major tranquillizers) from animal data?", Part IV, Arzneimittel-Forschung, 17 841-854, 1967, exploit the effect of neuroleptics on amphetamine-induced stereotypic behavior in rats .

The transformation we used for this was as follows:

Rats (230-270 g) were administered a dose of test drug subcutaneously or orally, followed immediately by intravenous injection of 13.6 mg / kg amphetamine sulfate (10 mg / kg amphetamine). The animals were then placed in individual cages. After 55 and 65 minutes, the stereotypical movements of the rats' heads and forelegs were studied over one minute. The absence of stereotypical movements was interpreted as a drug effect. ED 2 values for protection against stereotype were determined. All compounds were tested at at least three different dose levels, and 10 rats were used for each different dose level, and the experimenter was considered unaware of group identification until the experiment was completed, Lu 13-013 was administered orally, and its anti-amphetamine activity was observed at different times. The peak of effect occurred 24 hours after administration, with an ED 2 -q of 0.04 mg / kg, after 48 hours the ED 2 -q = 0.2 mg / kg, after 72 hours the ED 2 -q = 0.9 mg / kg, iAv "7 60008 and after 96 hours ED ^ -g - 2.3 mg / kg. Thus, the effect of Lu 13-013 is moderately weak 4 days after oral administration,

When palmitic acid ester of Lu 13-013 was injected (2-5 mg / kg subcutaneously), marked sedation lasting several days was observed, and the anti-amphetamine effect was not evaluated.

When Lu 13-063 was injected (5 mg / kg subcutaneously), no sedation was observed, but protection against amphetamine-induced stereotyping lasted for 21 days.

The following examples illustrate the method of the invention.

Example 1 Benoic acid ester of 2-trifluoromethyl-6-fluoro-9- (3- (4- (2-hydroxyethyl) -1-piperidyl) propylidene) -thiaxanthene isomer and its hydrochloride 100 g of 2-trifluoromethyl-6- fluorothioxanthen-9-one was added to a Grignard solution prepared by dissolving 80 g of allyl bromide and 95 g of magnesium turnings in 500 ml of ether. The mixture was refluxed for 15 min, and after cooling, the reaction mixture was poured into ammonium chloride solution, the ether phase was separated and extracted three times with 300 ml of water each time, after which the ester was evaporated in vacuo. The residue was dissolved in 300 ml of benzene, and then a mixture of 35 ml of acetic anhydride, 2 ml of acetyl chloride and one drop of concentrated sulfuric acid was added. The mixture was heated in a steam bath at about 65 ° C until dehydration started, and then for another 15 min. The mixture was then poured onto crushed ice, basified with sodium hydroxide solution and extracted with 500 ml of ether. The ether phase was washed three times with 100 ml of water each time, dried over anhydrous magnesium sulphate and evaporated in vacuo to give a yellow oil. fluoro-9- (2-propenylidene) -tioksanteenista. Yield 105 g, 150 g of 2-trifluoromethyl-6-fluoro-9- (2-propenylidene) -thiaxanthene and 300 g of 4- (2-hydroxyethyl) -piperidine were heated at 90 ° C for 17 hours. The mixture was poured into 2 liters of water, which was then extracted with 2 liters of ether, the ether phase was separated, washed three times with 500 ml of water each time, dried over anhydrous magnesium sulphate and evaporated in vacuo. The oxa plate was doped and recrystallized from acetone. Yield 118 g of 2-trifluoromethyl-6-fluoro-9- (3- (4- (2-hydroxyethyl) -1-piperidyl) propylidene) thiaxanthene oxalate in the form of an isomeric mixture having a melting point of 1H2-144 ° C.

The pharmacologically inactive γ-isomer was isolated in the form of its oxalate salt by recrystallization 5 times with 2-propanol: methanol 1: 1, and the melting point of the isomer is 150-153 ° C.

The pharmacologically effective ° <isomer was isolated by boiling the oxalate mixture in acetone. Evaporation of the acetone solution in vacuo gave a mixture containing 80% of the effective isomer. The base was precipitated with dilute sodium hydroxide solution and extracted with 200 ml of ether, washed three times with 50 ml portions of water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was dissolved in acetone and precipitated with dry ethereal hydrogen chloride solution. The hydrochloride of the efficient cis-isomer was obtained as a crystalline substance with a melting point of 166-168 ° C. The ineffective isomer can be partially converted to the inert isomer by boiling it in a solution containing a strong alkaline substance such as sodium ethylate and isolating the effective isomer as described above.

The base of the efficient <7 <isomer was isolated by conventional methods and had a melting point of 128-129 ° C.

25 g of the cis isomer of 2-trifluoromethyl-6-fluoro-9- (3- (4- (2-hydroxyethyl) -1-piperidyl) -propylidene) -thiaxanthene were dissolved in 100 ml of dry acetone, followed by the addition of 25 g of behenic acid chloride and the mixture was refluxed for 1 hour and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give the hydrochloric acid ester of 2-trifluoromethyl-6-fluoro-9- (3- (4- (2-hydroxyethyl) -1-piperidyl) propylidene) -thiaxanthene o (isomer) of the benzoic acid ester. aqueous ammonia solution followed by extraction with ether, washing of the ether phase with water, drying and evaporation in vacuo The oil formed crystallizes from pentane Yield: 32 g of white crystals melting at 59-61 ° C.

Example 2 Benzene Acid Ester of 2-Trifluoromethyl-6-Fluoro-9- (3- (4- (2-Hydroxyethyl) -piperazin-1-yl) -propylidene) -thiazanthene

V

60008 9

The procedure of Example 1 was repeated using the ε-isomer of 2-trifluoromethyl-6-fluoro-9- (3- (4- (2-hydroxyethyl) -1-piperazinyl) propylidene) thiaxanthene 2-trifluoromethyl instead of the? Benoic acid ester of the cis isomer of (4- (2-hydroxyethyl) -1-piperazinyl) -propylidene) -thiaxanthene, m.p. 34-36 ° C.

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Claims (2)

60008 1 o Claim A process for the preparation of a 2-trifluoromethyl-6-compound of the formula F3 OV = \ / ~ \ S £ = CH-CH 2 -CH 2 -N X -CH 2 -CH 2 -OC- (CH 2) 2 O-CH 3 0 w 'F fluoro-9- [3- (4- (2-hydroxyethyl) -1-piperidyl (or piperazinyl)) propylidene] thiaxanthene for the preparation of the o (-isomer) behenic acid ester and its pharmaceutically acceptable acid addition salts, wherein X is N or CH, characterized in that that C = CH-CH, -CH, -N X-CH, -CH »0H yj w 2 of the formula / CF3 ö / \ / \ s 2 F -isomer of the compound of formula F, wherein X is the same as above for reacting with a reactive derivative of behenic acid, after which the obtained compound is isolated as the free base or a pharmaceutically acceptable acid addition salt,