IE43413B1

IE43413B1 - Heterocyclic compounds

Info

Publication number: IE43413B1
Application number: IE1719/76A
Authority: IE
Original assignee: Kefalas As
Priority date: 1975-08-13
Filing date: 1976-08-04
Publication date: 1981-02-25
Also published as: AU500540B2; ZA764544B; DK363476A; AT345826B; CH621786A5; PL98033B1; SE7607300L; NL7608822A; ES450128A1; JPS5239682A; FI762172A; FI60008B; BE845057A; DE2631389A1; AU1651576A; IE43413L; HU171915B; NO762748L; FR2320740B1; FI60008C

Abstract

There are prepared novel behenic acid esters of the formula in which X denotes an N atom or a CH group, the isomers thereof and the acid addition salts thereof with pharmaceutically tolerable acids. These compounds are obtained by reacting an appropriate alcohol with a reactive derivative of behenic acid. The compounds of the formula I are obtained as the free base or as non-toxic acid addition salts. They are present either in the form of the individual isomers or as an isomer mixture. The resulting compounds can be used in neuroleptic agents.

Description

The present invention relates to novel behenic acid esters of the following general formula; wherein X is nNn or ΌΗ, the non-toxic acid addition salts thereof, a method for the preparation of said esters and therapeutic compositions thereof having prolonged effect.

In recent years esters of neuroleptic active thiaxanthenes have been suggested and found useful in preparations having prolonged effect when administered parenterally. The esters which have been found most useful are the decanoic and palmitic acid esters of alpha-flupenthixol which are mostly administered as sterile solutions in vegetable oils which solutions are injected intramuscularly. The neuroleptic effect of such solutions may last for as long as 18 days.

Also aliphatic carboxylic acid esters of some very strong neuroleptic thiaxanthenes having a fluorine atom in the 643413 3.position have been suggested and include esters of aliphatic carboxylic acids having up to and including 17 carbon atoms, especially the decanoic and palmitic acid esters.

During continued work with such esters in pharmacological 5 experiments it was found that the decanoic and palmitic acid esters of the very strongly neuroleptic alpha-isomers of 2trifluoromethyl-6-fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl) propylidene)-thiaxanthene and 2-trifluoromethyl-6-fluoro-9-(3(4-(2-hydroxyethyl)-1-piperazinyl)propylidene)-thiaxanthene when administered in ordinary doses as oily solutions by Injection tended to give too high concentrations at the start causing a pronounced sedation in the first week.

It has now surprisingly been found that the behenic acid esters of formula I not only have a more prolonged effect but also cause no sedation in the test animals when injected in the form of oily solutions of the most active isomer, hereinafter referred to as the alpha-isomer.

It is a well-known fact that thiaxanthenes having a double bond between ring carbon atom 9 and the side chain and being unsymmetrically substituted in the phenyl rings exist in the form of geometric isomers of the cis-trans type. The individual isomers possess the desired pharmacological effects to different degrees. For the sake of convenience, the isomers having the most pronounced neuroleptic activities are here and in the following termed alpha-isomers. According to the invention the alpha-isomers of the behenic acid esters of formula I are prefened from the point of view of activity and margin of safety.

The compounds of formula I may be prepared - according to the method of the inventio^,- by reacting a compound of the following general formula: XI •ch2*ch2oh '43413 4.wherein X is as defined before, either in the form of an individual isomer or as a mixture of isomers, with a reactive derivative of behenic acid, such as an acid'halide or the anhydride, whereupon the compound of formula I formed by the reaction is isolated as the free base or as a non-toxic acid additive salt thereof and, if the compound of formula I is obtained as a mixture of isomers the individual isomers, if desired, are separated for example by fractional crystallization.

When preparing the individual isomers of the compounds of formula I it is preferred, according to the invention, to separate the isomers of the compound of formula II before the esterification process, as it is more difficult to separate the isomers after the esterification.

The esterification process according to the invention is preferably carried out in the presence of an inert organic solvent such as a ketone, preferably acetone, or an ether such as diethylether.

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

The non-toxic acid addition salts of the compounds of formula I are preferably salts of pharmaceutically acceptable acids such as mineral acids, for example hydrochloric acid, hydrobromic acid, phosphoric acid and sulphuric acid and organic acids such as acetic acid, tataric acid, maleic acid, citric acid and methane sulphonic acid.

The following examples illustrate the method of the invention : .- 43413 Example 1 The behenic acid ester of the alpha-isomer of 2-trifluoromethyl-6-fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl)propylidene)-thiaxanthene and its hydrochloride. 100 Grams of 2-trifluoromethyl-6-fluorothioxanthone were added to a Grignard solution made from 80 grams of allylbromide and 95 grams of magnesium turnings in 500 milliliters of ether. The mixture was refluxed for 15 minutes and after cooling the reaction mixture was poured into an ammonium chloride solution. The ether phase was separated off, extracted three times each with 300 milliliters of water and evaporated in vacuum. The residue was dissolved in 300 milliliters of benzene and a mixture of 35 milliliters of acetic anhydride, 2 milliliters of acetyl chloride and one drop of concentrated sulphuric acid added. The mixture was heated on a steam bath at about 65 degrees Centigrade until the dehydration started and thereafter for further 15 minutes.

Then the mixture was poured onto crushed ice, made alkaline with sodium hydroxide solution and extracted with 500 milliliters of ether. The etherphase was washed three times each with 100 milliliters of water, dried over anhydrous magnesium sulphate and evaporated in vacuum. The residue which was a yellow oil consisted of somewhat impure 2-trifluoromethyl-6fluoro-9-(2-prOpenylidene)-thioxanthene. Yield: 105 grams. 150 Grams of 2-trifluoromethyl-6-fluoro-9-(2-propylidene)thiaxanthene and 300 grams of 4-(2-hydroxyethyl)-piperidine were heated at 90 degrees Centigrade for 17 hours.

The mixture was poured into 2 liters of water which subsequently was extracted with 2 liters of ether. The ether phase was separated, washed three times each with 500 milliliters of water, dried over anhydrous magnesium sulphate and evaporated in vacuum. The oxalate was precipitated and recrystallized from acetone. Yield: 118 grams of 2-trifluoromethyl-6-fluoro-9-(3-(4-X2-hydroxyethyl)-1-piperidyl) propylidene)thiaxanthene oxalate in the form of a mixture of Isomers melting at 142-144 degrees Centigrade. 6.The pharmacologically inactive beta-isomer was isolated in the form of its oxalate by five recrystallizations from 2-propanol : methanol (lsl) and melts at 150-153 degrees Centigrade.

The pharmacologically active alpha-isomer was isolated by boiling 5 the mixture of oxalates with acetone. By evaporation of the acetonesolution in vacuum a mixture containing about 80% of the active isomer was obtained. The base was precipitated with dilute sodium hydroxide solution and extracted with 200 milliliters of ether, which vas washed three times each with 50 milliliters of water, dried over anhydrous magnesium sulphate and evaporated in vacuum.

The residue was dissolved in acetone and precipitated with dry hydrogen chloride in ether. The hydrochloride of the active alphaisomer was obtained as a white crystalline substance which melted at 166-168 degrees Centigrade. The inactive isomer may be converted ; in part to the active isomer by boiling with a solution containing a strong alkaline substance such as sodium ethylate and isolating the active isomer as described above.

The base of the active alpha-isomer was isolated in conventional manner and melted at 128-129 degrees Centigrade. grams of the alpha-isomer of 2-trifluoromethyl-6-fluor-9-(3-(4{2-hydroxyethyl)-l-piperidyl)propylidene)-thiaxanthene were dissolved in 100 milliliters of dry acetone, whereupon 25 grams of behenic acid chloride were added and the mixture refluxed for one hour and then evaporated in vacuum. The residue was recrystallized from ethylacetate which resulted in the crystallization of the hydrochloride of the behenic acid ester of the alpha-isomer of 2trifluoromethy1-6-fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl) propylidene)-thiaxanthene. The corresponding free base was liberated by addition of aqueous ammonia followed by extraction with ether, washing of the ether phase with water, drying and evaporation in vacuum. The resulting oil crystallizes from pentane.

Yield; 32 grams of white crystals which melt at 59-61 degrees Centigrade Example 2 The behenic acid ester of the alpha-isomer of 2-trifluoromethy1-6-fluoro-9-(3-(4-(2-hydroxyethyl)piperazine-l-yl)propylidene)-thiaxanthene.

When example 1 was carried,out using the alpha-isomer of 2-trifluoromethyl-6-fluoro-9-(3-(4-(2-hydroxyethyl)piperazin-l-yl)propylidene)thiaxanthene instead of the alpha-isomer of 2-trifluoromethyl-6fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl)propylidene)-thiaxanthEne the behenic acid ester of the alpha-isomer of 2-trifluoromethyl-6fluoro-9- (3- (4- (2-hydroxyethyl)piperazin-l-yl) propylidenej-thiaxar.the was obtained. 7.4 3 413 The invention further provides pharmaceutical compositions with prolonged action comprising, as active ingredient, a compound of Formula X, preferably in the form of an alphaisomer, or one of its non-toxic acid addition salts together with a pharmaceutical carrier or excipient.

They may be administered to animals including human beings both orally, parenterally and rectally and may take the form of e.g. sterile solutions or suspensions for injection, tablets, suppositories, capsules, and syrups.

Results upon administration to human beings of the compositions of the invention have been very gratifying.

Preferably, however, the compositions are in the form of sterile solutions or suspensions for injection, and in a preferred embodiment of the invention injectable solutions may be prepared from a non-toxic injectable fat or oil, e.g. light vegetable oil, sesam oil, olive oil, arachis oil or ethyl oleate, and they may additionally contain gelling agents, e.g. aluminium stearate, to delay absorption within the body. Such oily solutions have a very prolonged activity when injected intramuscularly, and satisfactory neuroleptic action has been produced by a single intramuscular injection of about 25-40 mg of a compound of Formula I, dissolved in a light vegetable oil, for as long as 3-6 weeks. Preferably, the active ingredient is present in an amount of at least 0.5 milligrams per millilitre and more preferably, at least 1 milligram per millilitre.

The preferred compound of Formula I for use in the pharmaceutical compositions according to the invention is the behenic acid ester of the alpha-isomer of 2-trifluoromethyl6-fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl)propylidene)thiaxanthene (Lu 13-013) in the following called Lu 13-063 for short.

The following examples illustrate the injectable oily solutions according to the present invention: 8.Lu 13-063 ............................ 16 grains Sterile, light vegetable oil ...... ad 1000 ml Lu 13-063 ............................ 32 grams Sterile sesam oil................. ad 1000 ml Lu 13-063 ............................ 100 grams Aluminium mono stearate .............. 20 grams Sterile,light vegetable oil....... ad 1000 ml Lu 13-063 ............................ 16 grams Sterile olive oil ................. ad 1000 ml The solutions are placed in, for example, ampoules each containing 1 ml solution.

The active ingredient of Formula I may also be administered in the form of a suspension of micronized active ingredient or a salt thereof in sterile physiological saline.

Any other pharmaceutical adjuvants may be used provided that they are compatible with the active ingredient, and additional compositions and dosage forms may be similar to those presently used for neuroleptics. Also combinations of a compound of Formula I as well as its pharmacologically acceptable nontoxic acid addition salts with other active ingredients especially other neuroleptics, thymoleptics fall within the scope of the present invention. 413 9.When testing the behenic acid esters of Formula I it has been found advantageous to use the we11recognized test which is based upon the fact that strong neuroleptics antagonize apomorphine induced vomiting in dogs.

The test is described by P.A.J. Janssen, C.J.E. Niemegeers and K.H.L. Schellehaus: Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillisers) from animal data ?, Part II, Arzneimittel Forschung, 15, 1196-1206, 1965.

In order to evaluate esters of the compounds of Formula I a modified method is described by M. Nymark et al. in Acta pharmacol. et toxicol. 1973,. 33, 363-376.

The test may be described shortly as follows: Apomorphine antagonism in dogs As animals were used adult purebred Beagle dogs of either sex. The threshold-dose of apomorphine hydrochloride for the induction of vomiting in the dogs has been determined to be 0,025 mg/kg intravenously. After this dose vomiting occurs within a few minutes of the injection. Four dogs were used for each dose level of the drug, which was injected subcutaneously at the back of the neck. At different times after the drug administration the dogs were then challenged with apomorphine according to an up-and-down schedule using the dose-range 0.025 - O.4OO mg/kg intravenously geometrically spaced. Thus, if for example a dog vomited after 0.1 mg/kg the next dog was given 0.05 mg/kg, or 0.2 mg/kg if the first dog did not vomit, and so on. In this way it was possible to estimate at which level of apomorphine the dogs were protected at a given time. The dogs were fed half an hour before testing to ensure an easy vomiting.

Esters such as enanthic and decanoic acid esters of strong neuroleptics have previously been suggested, and the decanoic acid ester of alpha-flupentixol has, in fact, found use in recent years in the form of oily solutions for injection having sustained release effect. - It has now been found that Lu 13-063 seems to be more favourable than the corresponding 3 41 3 .palmitic acid ester by causing less sedation in the first week when injecting 1 mg/kg subcutaneously calculated as Lu 13-013 of these esters in the dogs.

In the case of Lu 13-063 (1.6 mg/kg s.c. of ester 1 mg/kg of Lu 13-013) maximal protection (16 x threshold dose of apomorphine) was recorded during 15 days and still 21 days after the injection a strong protection (~ 12 x threshold dose) was recorded. The effect had disappeared after 26 days. No sedation of the test animals was observed at any time.

LO In comparison the decanoic acid ester of alpha-flupentixol (2 mg/kg s.c.) only yielded a comparatively low degree of protection (3 x threshold dose), and the effect had disappeared on day 11 after the injection.

In another well-recognized test useful for evaluation of neuro5 leptic drugs and described by P.A.J.Janssen, C.J.E.Niemegeers, K.H.L.Schellehaus and F.M.Lenaerts: Is it possible to predict the clinical effect of neuroleptic drugs (major tranquillizers) from animal data ?, Part IV, Arzneimittel-Forschung, 17, 841854, 1967, the antagonistic effect of neuroleptics against amphetamine-induced stereotyped behaviour in rats is used.

The modification used by us was as follows: Rats (230-270 g) were given a subcutaneous or an oral dose of the drug under investigation, and immediately thereafter 13,6 mg/kg of amphetamine sulphate ( 10 mg/kg of amphetamine) i was injected intravenously. The animals were then placed in Individual cages. After 55 and 65 minutes the rats were observed for stereotyped movements of head and forlegs for one minute. The absence of stereotypy was interpreted as a drug effect. ED^gValues for protection against stereotypy were determined.

All compounds were tested at a minimum of three dose levels using 10 rats per dose, and the observer was kept unaware of the identity of the groups until after the experiment.

Following oral administration of Lu 13-013 the amphetamine antagonistic effect has been determined at different times.

Peak effect occured 24 hours after administration, the Εϋ^θ being 0.04 mg/kg. At 48 h EDgQ= 0.2 mg/kg, at 72 h ED5q= 0«9 mg/kg, and at 96 h Ε05θ= 2.3 mg/kg. Thus the effect of Lu 13-013 is rather weak when tested 4 days after oral administration. 11.43413 When the palmitic acid ester of Lu 13-013 was injected (2-5mg/kg s.c.) a pronounced sedation lasting for several days was observed and amphetamine antagonism was not evaluated.

When Lu 13-063 was injected (5 mg/kg s.c.) hardly any sedation was observed but, protection against amphetamine-induced stereotypes lasted for a period of 21 days.

Claims

1. A behenic acid ester of the general formula: cf 3 CH-CH 2 'CH 2 Αχ “2 ™ 2 0-C (CH,) 20 CH_ F wherein X is N or CH, geometric isomers thereof, and acid addition salts thereof with pharmaceutically acceptable acids.

2. A behenic acid ester according to claim 1 of the general formula: CH2‘CH 2 O C- (CH 2 )2o'CH 3 0 wherein X is N or CH

3. A behenic acid ester according to claim 1 or 2 of the general formula

4. A behenic acid ester according to claim 1 or 2 of the following formula: CF·, ! \__7 CH 2 .CH 2 O.C.(CH 2 ) 2o -CH 3 li An alpha-isomer of a compound according to claim 1. An alpha-isomer of a compound according to claim 2. An alpha-isomer of a compound according to claim 3. An alpha-isomer of a compound according to claim 4. A method for the preparation of a behenic acid ester of

5.

6.

7.

8.

9. the general formula: .CF-, C = CII.CH 2 .CI1 2 -N Z X- cil 2 · CH 2 O. C. (CU 2 ) 20 . CII 3

10. A method according to claim 9 in which the reactive derivative of behenic acid is the acid chloride.

11. A method according to claim 9 or 10 in which the compound of formula II is in the form of the alpha-isomer.

12. A method according to claim 9, 10 or 11 in which the alpha-isomer of 2-trifuoromethyl-6-fluoro-9-(3-(4-(2hydroxyethyl)-1-piperidyl)-propylidene)-thiaxanthene is reacted with behenic acid chloride, whereupon the ester formed is isolated in the form of the free base or as a nontoxic acid addition salt thereof.

13. A method according to claim 9, 10 or 11 in which the alpha-isomer of 2-trifluoromethyl -6-fluoro-9-(3-(4-(2hydroxyethyl)-piperazin-l-yl)-propylidene)-thiaxanthene is reacted with behenic acid chloride, whereupon the ester formed is isolated in the form of the free base or as a non-toxic acid addition salt thereof. 13.4 3 41 3 CH.CH 2 .CH 2 CI<, •N\_^h-ch 2 -ch 2 o-c· (ch 2 ) 20 -ch 3

14.wherein X is N or CH”, geometric isomers thereof, and acid addition salts thereof with pharmaceutically acceptable acids, in which a compound of the general formula: F II wherein X is as defined above, either in the form of an individual isomer or as a mixture of isomers, is reacted with a reactive derivative of behenic acid, whereupon the compound of formula I formed by the reaction is isolated as the free base or as a non-toxic acid addition salt thereof, and if the compound of formula I is obtained as a mixture of isomers, if desired, are separated in well-known manner.

15. A method according to claim 9, 10,11 or 13 in which the alpha-isomer of 2-trifluoromethyl-6-fluoro-9-(3-(4-(2hydroxyethyl)-piperazin-l-yl)propylidene)-thiaxanthene is reacted with behenic acid chloride, whereupon the ester formed is isolated in the form of the free base. 15.14. A method according to claim 8, 10, 11 or 12 in which the alpha-isomer of 2-trifluoromethyl-6-fluoro-9-(3-(4-(2hydroxyethyl)-1-piperidyl)-propylidene)-thiaxanthene is reacted with behenic acid chloride, whereupon the ester formed is isolated in the form of the free base.

16. A pharmaceutical composition comprising a major quantity of a pharmaceutical carrier and a pharmaceutically effective dose of a compound according to claim 1.

17. A composition according to claim 16, wherein the active ingredient is the alpha-isomer of 2-trifluoromethyl-6-fluoro9-(3-(4-(2-hydroxyethyl)-1-piperidyl)propylidene)-thiaxanthene.

18. A composition according to claim 16, wherein the active ingredient is the alpha-isomer of 2-trifluoromethyl-6-fluoro9-(3-(4-(2-hydroxyethyl)-piperazine-l-yl)propylidene)-thiaxanthene.

19. A pharmaceutical composition in injectable form suitable for use in the treatment of psychotic disorders containing as active ingredient an alpha-isomer of a behenic acid ester according to claim 1 and a non-toxic injectable oil or fat.

20. A composition according to claim 19, wherein the active ingredient is present in an amount of at least 1 milligram per millilitre.

21. A composition according to claim 19, wherein the active ingredient is present in an amount of at least 0.5 milligram per millilitre.

22. A composition according to claim 19, 20 or 21, wherein the active ingredient is the alpha-isomer of 2-trifluoromethyl -6-fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl)propylidene)thiaxanthene.

23. A composition according to claim 19, 20 or 21, wherein the active ingredient is the alpha-isomer of 2-trifluoromethyl 6-fluoro-9-(3-(4-(2-hydroxyethyl)-piperazin-l-yl)propylidenethiaxanthene.