NZ199974A - Pharmaceutical compositions containing 4-(3-trifluoromethylphenyl-1,2,3,6-tetrahydropyridine derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 99974 1999 Priority Date{s): ..... .U.\ Complete Specification Filed: Class: .rr. 0 ul. . r. 5 1 fW 1985 Publication Date: P.O. Journal, No: I&-TO Patents Form No.5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "PHARMACEUTICAL COMPOSITIONS HAVING AN ANORECTIC ACTION" --i,WE SANOFI, a Societe Anonyme, of 40 Avenue George V 75008 Paris, France, a French company, hereby declare the invention, for yhich i-/we pray that a patent may be granted to me/us, „and the method by which it is to be performed, to be particularly described in and by the following statement:— (fol lowed by page I A.) -la- Pharmaceutical compositions having an- anorectic action. 199974 The present invention relates to pharmaceutical compositions containing 1, 2, 3, 6-tetrahydropyridlnes or salts thereof, useful as anorectic agents.

More particularly, the invention relates to pharmaceutical compositions containing, as active ingredients, 4-(3-trifluoromethylphenylj-t, 2, 3, 6-tetrahydropyridlnes having anorectic activity, of formula ft ft N-R in which R represents hydrogen, an alkyl group of from 1 to 6 carbon atoms or a benzyl group; it also relates to the pharmaceutical^ acceptable salts thereof.

The leading compound with anorectic action is known to be amphetamine which exerts its activity by a central mechanism of biochemical action at the dopaminergic and noradrenergic system level.

Amphetamine and its derivatives, all characterised by a chemical structure comprising the following sequence C-C-N' ii present considerable drawbacks as their effect of stimulating the central nervous system as well as the possibility of habit-forming and pharmacodependence may constitute a potential danger for th« oatient.

U.S. Patent Specification No3458521 describe compounds of general formula A n-r iii In which R Is an amino, dialkylamino, cycloalkylmethyl, alkyl, alkenyl, alkynyl radical each containing less than 6 carbon atoms and Y is a substituted or non-substituted phenyl radical, which may be used as analge s ic agents, as agents provoking a loss of appetite or active on the central nervous system. 199974 U.S. Patent Specification According to what is indicated in/3458521 the compounds of form ula III above possess a central sympathomimetic stimulating property which has been confirmed by a moderate, but lasting, effect of stimulation of the central ner-5 vous system in human volunteers.

Studies have therefore been dedicated to the search for derivatives of amphetamine which present a dissociation between the stimulant activity and the anorectic action. The introduction of a trifluoromethyl group in the meta position of 10 the phenyl group of the ethyl-amphetamine led to a product, hereinafter designated by its international common name "fenfluramine", Vch2-ch-nh-ch2-ch3 ch, iv fenfluramine having an excellent anorectic activity which, instead of being stimulant, possesses a certain sedative action. 42 593 37 U.S. Patent Specification / describes a series of meta-trifluoromethylphenylpiperidines having anorectic action, characterised by the following general formula: V and, as intermediate product, a compound of formula vi U.S. Patent Specification 4213989 describes a series of metatrifluoromethylphenyl-1, 2, 5, 6-tetrahydropyri-dines having anorectic activity, of the following general formula: 199974 VII in which X is a hydrogen or chlorine atom and R represents an atom of hydrogen or an alkyl, alkenyl, alkynyl or phenyl-alkyl group and from which compound VI hereinabove is excluded.

Fenfluramine and its derivatives, for example the products having the international common names benfluorex, flucetorex, fludorex, are all characterised by a chemical structure comprising the following sequence: p / V1 (' VC-C-N- VIII CF3 Products V, VI and VII herel nabove may also be considered as derivatives of fenfluramine as they present the sequence VIII in which the nitrogen atom is connected to the carbon atom in beta position of the metatrlfluoromethylphenethyl 15 radical by a propylene or propanylidene group so as to form the ring of the piperidine or of the 1,2,-5, 6-tetrahydropyridlne.

The advantage of fenfluramine and its derivatives over amphetamine and its derivatives is due to the different mechanism of action. In fact, the anorexia provoked by amphe-20 tamine seems to be mediated by the release of cerebral noradrenaline, whilst the anorectic action of fenfluramine depends on the release of endogenous serotonin of the central neurons (Ann C. Sullivan et al. Appetite Regulation and its Modu lation by Drugs. Nutrition and Drug Interrelation, 1978, Academic 25 Press, 21-82) and on the inhibition of the uptake of the serotonin.

According to the above U.S. Patent Specification 4213989 the com pounds of formula VII also inhibit the uptake of serotonin.

However, it is known that fenfluramine, at doses very close to the anorectic dose, provokes a significant reduction in 30 the cerebral rates of serotonin (Arch. Intern. Pharmacodyri. Thcur> 19 9 9 7 1967, 170 , 27 6) and that a lasting depletion of serotonin may be considered as a sign of potential neurotoxicity (C.D. Morgan et al. Life Sci. Parti, 11_, 83; 1972), It has now been found that the 4-(3-trifluoromethyl-5 phenyl)-l, 2, 3, 6-tetrahydropyridines of formula I hereinabove and the salts thereof, show a remarkable anorectic activity associated with a very low toxicity. From the biochemical standpoint, the compounds of formula I above, as well as their salts, act as agonists of the cerebral serotonin without provo-10 king any depletion of cerebral serotonin or stimulation of the central nervous system. More particularly, the compounds of formula I above show a considerable affinity for the postsynaptic receptors of the serotonin and, by this direct stimulation of the serotoninergic system, they provoke an anorectic 15 activity without the secondary effects due to the release of serotonin.

The anorectic activity and the biochemical properties of the compounds of formula I hereinabove are unexpected and surprizing if their chemical structure is considered, which presents the sequence / \ ^ j ■C-C-C-N IX which is entirely novel.for a product having anorectic action with a mechanism of serotoninergic action and having no stimulating action on the central nervous system.

U.S. Patent No. 3 125 488 describes a series of 4- phenyl-1, 2, 3, 6-tetrahydropyridines with an analgesic, spasmolytic and sedative activity in animals, said products having the formula: KT_ R X in which R is hydrogen, a lower alkyl such as methyl, ethyl, propyl and isopropyl, an aralkyl group, particularly benzyl and phenetyl, a lower alkenyl such as allyl, a lower alkynyl such as propargyl, a lower alkyl substituted by an amino group such as dimethyiaminoethyl, and R^ is hydrogen or at least a substituent 199974 such as a halogen such as chlorine and bromine, a lower halo-alkyl such as chloromethyl and trifluoromethyl, nitro, a lower alkyl such as methyl and ethyl, a lower alkoxy such as methoxy and ethoxy, a lower carbalkoxy group such as carbomethoxy and 5 carbethoxy, or a lower alkylenedioxy such as 3, 4-methylenedioxy, both as free bases and as their salts.

Said Patent does not describe the 4-(3-trifluoromethyl-phenyl)-l, 2, 3, 6-tetrahydropyridine nor any of its derivatives of substitution on nitrogen. Neither does it suggest the possibility 10 that the novel substituted 4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridines possess a remarkable anorectic activity with a mechanism of action different from that of the known anorectic agents.

Thus the present invention relates to pharmaceutical 15 compositions containing, as active ingredients, the 4-(3-tri-fluoromethylphenyl)-l, 2, 3, 6-tetrahydropyridines of formula I hereinabove, as well as to their pharmaceutically acceptable addition salts.

The pharmaceutically acceptable salts include the 20 non-toxic salts derived from mineral or organic acids such as hydrochloride, hydrobromide, succinate, tartrate, citrate, fumarate, maleate, 4, 4'-methylenebis-(3-hydroxy-2-naphthoate), hereinafter designated "pamoate", 2-naphthalenesulfonate, hereinafter designated "napsylate", methanesulfonate, herein-25 after designated "mesylate", p-toluenesulfonate, hereinafter designated "tosylate", and the like.

The 4-(3-trifluoromethvlphenyl)-l, 2, 3, 6-tetrahydro- 3458521 pyridine is described in U . S . Patent Specifications 3209006 and / as intermediary in the synthesis of products having therapeutic 30 activity.

Its N-alkyl derivatives are known to have a vermifugal action but pharmaceutical compositions thereof have not been envisaged. Among said N-alkyl derivatives, the 4-(3-trifluoromethylphenyl)-l-methyl-35 1, 2, 3, 6-tetrahydropyridine is specifically described.

The N-benzyl derivative, namely the 4-(3-trifluo ro - methylphenyl)-l-benzyl-l, 2, 3, 6-tetrahydropyridine , is included, but without being described, in the general formula of certain intermediate products of U.S. Patent Spe ci f ication 34 5 8 5 21 mentioned above.

The other products included in general formula I above are novel.

They are prepaid by reacting the 4-(3-trifluoro-methylphenyl)-l, 2, 3, 6-tetrahydro,jyridine with a halogen derivative R-X , where X represents a chlorine, bromine or iodine atom, in an organic solvent in the presence of an alkaline condensation agent.

The organic solvent used may be an alcohol such as methanol, ethanol, n-butanol, n-pentanol or hexane, dimethyl-formamide, dimethylsui'foxide, sulfolane, acetonitrile, pyridine and the like.

The preferred alkaline condensation agents are ■ hydroxides, carbonates and alkaline bicarbonates, but organic bases such as triethylainine or N-methylpiperidine may also be used.

The reaction temperature may vary between ambient temperature (about 20°C) and 200°C and its duration varies accordingly. After 4 to 5 hours of heating at 100-150°C, the reaction is generally complete and the final product thus obtained may be isolated according to conventional techniques and possibly converted into its salts by treatment with a solution of the chosen acid in an organic solvent.

The 4-(3-trifluoromethylphenyl)-l, 2, 3, 6-tetrahydropyridines of formula I hereinabove and their salts show a remarkable, selective anorectic activity without giving any effect of the amphetaminic type. The selectivity of their action is demonstrated by the lack of secondary pharmacological activities, such as the sedative or excitant activity and the action inhibiting the locomotive activity.

The anorectic activity was assessed by the method of food-taking in the rat. Female rats weighing 200 g are used, trained for 10 days to eat for a period of 4 hours and selected 1999 on the eighth day. After the tenth day, the randomised animals were divided into a "control group" treated by the vehicle alone, and into several "treated groups". The treatment was carried out by the oral and/or intraperitoneal route 30 mins. 5 before presentation of the food and the quantity of food consumed in the course of the first hour was then measured.

Table I shows, for five representative compounds useful as active ingredients in the compositions according to the invention: - the acute toxicity, expressed as in the rat by the oral route or the intraperitoneal route (A); - the anorectic activity, expressed as oral or intraperitoneal dose inhibiting by 50% the taking of food (ED^, B); - the ratio between the acute toxicity and the anorectic activity 15 which expresses the therapeutic index associated with the acute toxicity (A/b).

The following compounds are used as representative products according to the present invention. - 4-(3 -trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine hydro-20 chloride (hereinafter indicated by its code number CM 57235), - 4-(3-trifluorometh ylphenyl)-l-benzyl-l, 2, 3, 6-tetrahydro-pyridine hydrochloride (CM 57451), - 4-(3-trifluoromethylphenyl)-l-propyl-l, 2, 3, 6-tetrahydro-pyridine hydrochloride (CM 57545), - 4-(3-trifluoromethylphenyl)-l-methyl-l, 2, 3, 6-tetrahydro-pyridine hydrochloride (CM 57548), - 4-(3-trifluoromethylphenyl)-l-pentyl-l, 2, 3, 6-tetrahydropyridine hydrochloride (CM 57756).

Fenfluramine was used as reference product. 1 9 9 9 7 4 table i Products Route of administration a B ! a/b LU50 mg/kg ED50 mg/kg CM57235 i. p. 94. 6 8. 4 11. 2 oral 346 . 7 22 CM57451 i. p. 220 14. 6 oral 600 18 33. 3 CM57545 i. p. 124 7 17. 7 oral 178 8 22. 2 CM 57548 I. p. 185. 7 12. 2 . 2 CM57756 oral 311. 4 8. 8 . 4 fenfluramine i. p. 85. 6 . 4 . 8 oral 100. 4 4. 0 . 1 This Table shows that the representative products of 15 the present invention show a good anorectic activity with low toxicity. Their efficacy is comparable, from the point of view of the therapeutic index, to that of the reference compound.

From the biochemical point of view, the 4-(3-tri-fluoromethylphenyl)-l, 2, 3, 6-tetrahydropyridines of the present 2 0 invention and their salts differ .from the fenfluramine and its derivatives in their mechanism of action. In fact, the compounds of the present invention are post-synaptic agonists of the serotonin with little effect on the presynaptic mechanisms such as the uptake and release of the serotonin, on which, on the 25 contrary, the fenfluramine acts. The mechanism of action of the compounds of the present invention comprises a remarkable anorectic activity and reduced secondary effects.

In particular, the compounds used as active ingredients of the pharmaceutical compositions of the present inven- 3 0 tion, in vivo, do not provoke depletion of serotonin at central level. Table II below summarizes the cerebral rates of serotonin, in percentage with respect to the controls, after oral or intraperitoneal adminstration of four active ingredients of the pharmaceutical compositions of the present invention. The 1 9 9 9 7 4 ■9- determination of the cerebral rates , according to Curzon and Green (Brit. J. Pharmacol. 39., 653, 1970) was effected one hour and/or two hours after administration. Fenfluramine was used as reference product.

Table II Compound Route of administration Dose mG/kg Cerebral rates of serotonin % with respect to controls 1 hr"^ 2 hrs.

CM 57235 i. p. 7. 5 106 102 112, 0 CM 57451 i. p. 30 121,2 112, 0 119. 0 CM 57545 i. p. 7- 5 15. 0 103 112 CM 57756 oral 7. 5 15 138++ 125+ fenfluramine i. p. . 0 7. 5 82. 9+ - ■ 81. 6+ 53.1 + +significant P<0. 01 - non-determined significant P^.0. 05 This Table shows that the products of the present invention, at anorectic doses, do not reduce the cerebral rates of serotonin, whilst fenfluramine, at equivalent doses, provokes a considerable reduction of cerebral serotonin. There is therefore less possibility of prolonged use of the compounds of formula I prow king secondary effects at central lavel.

The affinity of the compounds of the present invention for the post-synaptic receptors of serotonin was determined according to the method of Peroutka and Snyder (Molec. Pharmacol. 1979, 16_, 687-699) which consists in incubating cortex ' " 3 membranes of the rat with a fixed concentration of H-sero-tonin in the presence of different concentrations of product. Table III shows the molar concentration of three active ingredients representative of the present invention which gives a 50% inhibition of the binding specific to the serotoninergic receptor (ICcr.), namely the measurement of the capacity of the product 5U 3 to interact with the H-serotonin in the binding at its receptor. Fenfluramine and the 3-(3-trifluoromethylphenyl)-l-propyl-1, 2, 5, 6-tetrahvdropyridine (compound A), described in U.S. Patent Specification 4213989 were used as reference compounds.

Table III Compound serotonin binding IC-0 /M/ CM 57235 1.1 . 10"7 CM 57545 3. 3 . 10"7 CM 577 56 1. 8 . 10"7 _ ^ fenfluoramine compound A 1. 8 . 10 ^ This Table shows that the compounds of the present invention have a very good affinity for the post-synaptic serotoninergic receptor, whilst the affinity of the reference compounds for the same receptor is much less.

In the compositions of the present invention for oral, sublingual, sub-cutaneous, intramuscular, intravenous, trans- dermic or rectal administration, the active ingredients of form ula I above may be administered in unitary forms of administration, in combination with conventional pharmaceutical supports, to animals and to humans in the treatment of obesity.

Among the unitary forms of administration appropriate, there are the forms of administration by the oral route such as tablets, capsules, powders, granules and oral solutions or suspensions and the forms of sublingual administration, as well as the forms of parenteral administration useful for subcutaneous, intramuscular or intravenous administration.

In order to obtain the desired anorectic effect, the dose of active ingredient may vary between 0. 1 and 100 mg per kg of body weight and per day.

Each unitary dose may contain from 1 to 500 mg of active ingredient in combination with a pharmaceutical support. 1999 74 -li- This unitary dose may be administered 1 to 4 times per day.

When a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatine, starch, lactose, magnesium 5 stearate, talc, gum arabic or the like. The tablets may be coated with sucrose or other appropriate materials or they may be treated in another manner so that their activity is prolonged or delayed and that they continually release a predetermined quantity of active ingredient. 10 A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained in soft or hard capsules.

A preparation in the form of syrup or elixir may contain the active ingredient together with an acaloric sweetening 15 agent, methylparaben and propylparaben as antiseptics, as well as an agent giving taste and an appropriate colorant.

Water-dispersible powders or granulates may contain the active ingredient mixed with dispersing agents or wetting agents, or suspension agents such as polyvinylpyrrolidone 20 and the like , and with sweetening agents or taste correctors.

For rectal application, suppositories are prepared with binding agents melting at rectal temperature, for example cocoa butter or polyethyleneglycols.

For parenteral administration, aqueous suspensions, 25 isotonic saline solutions or sterile and injectable particular solutions are used, which contain pharmacologically compatible dispersing and/or wetting agents, for example propyleneglycol or butyleneglycol.

The active ingredient may also be formulated in the 30 form of microcapsules, possibly with one or more supports or additives.

The compositions of the present invention may contain, in addition to the 4-(3-trifluoromethylphenyl)-l, 2, 3, 6-tetrahydropyridines or one of their pharmaceutically acceptable 35 salts, oflier active ingredients such as, for example, tranquillizers, antidepressants, lipid lowering drugs, antidiabetic agents 1999 or other drugs which may be used in the treatment of obesity.

The following examples illustrate the invention without, however, limiting the scope thereof.

Example 1 A mixture of 5. 67 g of 4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine, 3. 5 ml of triethylamine and 3.15 g of 1-bromopropane in 40 ml of ethanol is heated to reflux for 5 hours, then cooled and concentrated. The residue is taken up with diethyl ether, filtered, washed in water and dried. By acidification with a solution of hydrochloric acid in isoprppanol, the 4-(3-trifluoromethylphenyl)-l-propyl-l, 2, 3, 6-tetrahydropyridine hydrochloride , designated by its code number CM 57 545, is obtained which, after crystallization in isopropanol, melts at 198-200°C; yield: 43..4%.

In the same way, by reacting the 4-(3-trifluoromethyl-phenyl)-l, 2,3, 6-tetrahydropyridine with benzyl bromide, methyl iodide, neopentyl chloride and n-pentyl chloride, respectively, the following are obtained: 4-(3-trifluoromethylphenyl)-l-benzyl-l, 2, 3, 6-tetrahydropyridine hydrochloride, designated by its code No. CM 57451; m. p. 218 to 220°C; 4-(3-trifluoromethylphenyl-l-methyl-l, 2, 3, 6-tetrahydropyridine; hydrochloride, CM 57548. m. p. 243-246°C; - 4-(3-trifluoromethylphenyl)-l-neopentyl-l, 2,-3, 6-tetrahydropyridine hydrochloride, CM 57601; m. p. 228-230°C; and, respectively, - 4-(3-trifluoromethylphenyl)-l-n-pentyl-l, 2, 3, 6-tetrahydro-pyridine hydrochloride, CM 57756, m. p. 209-211°C.

Example 2 A solution of p-toluenesulfonic acid in acetone is added to an aqueous solution of 4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine hydrochloride, hereinafter designated by its code number CM 57235.

The product which precipitates is isolated by filtration and dried.

In this way, the tosylate of 4-(3-trifluoromethyl- 199 9 phenyl)-l, 2, 3, 6-tetrahydropyridine (code no. CM 57710); m. p. 171-175°C, is obtained.

In the same way, by treatment of an aqueous solution of 4-(3-trifluoromethylphenyl)-l, 2, 3, 6-tetrahydropyridine 5 hydrochloride wifti a sdution cf:malic and, respectively maleic acid in acetone, the following are obtained: - the malate of 4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine (code No. CM 57711); m. p. 118-1200C and, respectively, - the maleate of 4-(3-trifluoromethylphenyl)-l, 2, 3, 6-tetrahydro-10 pyridine (code No. CM 57713); m. p. 150-152°C.

Similarly, by treatment of an aqueous solution of 4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine hydrochloride with an aqueous solution of 2-naphthalenesulfonic acid, the napsylate of 4-(3-trifluoromethylphenyl)-l, 2, 3, 6-tetrahydro-15 pyridine (code No. CM 57712) is obtained; m. p. 180-183°C. Example 3 Capsules are prepared, based on 4-(3-trifluoromethylphenyl)-!, 2, 3, 6-tetrahydropyridine hydrochloride (CM 57235), having the following composition: CM 57235 15 mg lactose 120 mg magnesium stearate 5 mg by intimately mixing the above ingredients and pouring the mixture into capsules of hard gelatine. • Example 4 Tablets are prepared, having the following composition: CM 57235 20 mg lactose 120 mg microcrystalline cellulose 30 mg dried cornstarch 40 mg magnesium stearate 5 mg by crushing the active ingredient to a particle dimension of 0. 4 mm, passing it through a sieve with mesh opening of 0. 4 mm, mixing the crushed material with the other constituents and compressing to form the tablets.

Tablets containing 40 mg of CM 57235 are prepared 1999 . -14- in the same way.

Example 5 By operating as described in Example 3, tablets having the following composi tion are prepared: 5 CM 57235 50 mg lactose 95 mg cornstarch 100 mg talc 4. 5 mg magnesium stearate 0. 5 mg Example 6 000 capsules wi^h a content of active substance of 50 mg are prepared, from the following constituents:500 g of 4-(3-trifluoromethylphenyl)-l-propyl-l, 2, 3, 6-tetrahydropyridine hydrochloride, 495 mg of microcrystalline cellulose, 15 5 g of amorphous silica gel. The above constituents are mixed well and introduced into capsules of hard gelatine of dimension 4.

Example 7 A sterile aqueous solution appropriate for parenteral 20 use, in ampoules, is prepared, having the following composition: 4-(3-trifluoromethylphenyl)- 1, 2, 3, 6-tetrahydropyridine hydrochloride 30 mg sodium chloride 5 mg distilled water q,s.p. 2 ml Example 8 Suppositories having the following composition are prepared: 4-(3-trifluoromethylphenyl)- 1, 2, 3, 6-tetrahydropyridine hydrochloride 50 mg lactose 250 mg Witepsol W 45 q. s. p. 1. 7 g The active substance is mixed with the lactose and the mixture is placed uniformly in suspension in the molten mass for suppositories. The suspension is poured into cooled moulds to form suppositories weighing 1.7 g. 1999 74 In the same way, suppositories are prepared, containing: 50 mg of 4-(3-trifluoromethylphenyl)-l-benzyl-l, 2, 3, 6-tetrahydropyridine hydrochloride, 50 mg of 4-(3-trifluoromethylphenyl)-l-methyl-l, 2, 3, 6-tetrahydropyridine hydrochloride, or 50 mg of 4-(3-trifluoromethylphenyl)-l-propyl-l, 2, 3, 6-tetrahydropyridine hydrochloride.

Example 9 Tablets having the following composition are pre pared: 4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine hydrochloride mg lactose 95 mg cornstarch 45 mg colloidal silica 2 mg soluble starch mg magnesium stearate 3 mg The active substance is mixed with part of the excipients and the mixture is granulated with a solution of soluble starch in water. After drying of the granulate, the rest of the excipients is added and tablets are formed by compression.

In the same way, tablets are prepared containing: 25 25 mg of 4-(3-trifluoromethylphenyl)-l-methyl-l, 2, 3, 6-tetrahydropyridine hydrochloride, mg of 4-(3-trifluoromethylphenyl)-l-propyl-l, 2, 3, 6-tetrahydropyridine hydrochloride, mg of 4-(3-trifluoromethylphenyl)-1-neopentyl-l, 2, 3, 6-30 tetrahydropyridine hydrochloride, or, respectively, mg of 4-(3-trifluoromethylphenyl)-l-benzyl-l, 2, 3, 6-tetrahydropyridine hydrochloride.

Example 10 According to the same modus operandi as described 35 in Examples 3 to 9» by replacing the active ingredient used for the pharmaceutical compositions illustrated in said Examples, by

Claims (10)

-16- 1999 74 the same quantities of 4-(3-trifluoromethylphenyl)-l-n-pentyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (CM 57756), the following are respectively obtained: - capsules containing 15 mg of CM 57756, - tablets containing 20 or 40 mg of CM 577 56, - tablets containing 50 mg of CM 577 56, - capsules containing 50 mg of CM 57756, - ampoules containing 30 mg of CM 57756, - suppositories containing 50 mg of CM 57756 and - tablets containing 25 mg of CM 57756. 5 : 10 199974 CLAIM !S> -17- GIjAIMC

1. Pharmaceutical composition having anorectic action containing, as active ingredient, a 4-(3-trlfluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine of formula pharmaceutically acceptable Baits.

2. Composition according to Claim 1 in dosage unit form, containing from 1 to 500 mg of active Ingredient per dosage unit,

3. Composition according to Claims 1 and 2, wherein It contains,as active ingredient, 4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyridine hydrochloride.

4. Composition according to Claims 1 and 2, wherein it contains, as active ingredient, 4-(3-trifluoromethylpheny3)-l-methyl-l, 2, 3, 6-tetrahydropyridine hydrochloride.

5. Composition according to Claims 1 and 2, wherein it contains, as active ingredient, 4-(3-trifluoromethylphenyl)-l-propyl- 1, 2, 3, 6-tetrahydropyridine hydrochloride.

6. Composition according to Claims 1 and 2, wherein It contains, as active ingredient, 4-(3-trifluoromethylphenyl)-l-n-pentyl 1, 2, 3, 6-tetrahydropyridine hydrochloride.

7. Composition according to Claims 1 and 2, wherein it contains, as active ingredient, 4-(3-trifluoromethylphenyl)-l-benzyl-1, 2, 3, 6-t etrahydropyrxdine hydrochloride. mixed with a pharmaceutical exclplent. 1999 7 * '> * -18-

8. Pharmaceutical compositions having anorectic activity as claimed in claim 1 or 2 substantially as herein described.

9. Preparation of pharmaceutical compositions as claimed in claim 1 or 2 substantially as herein described with reference to either of Examples 1 and 2. f

10. Capsules, tablets, ampoules and suppositories i | containing as active ingredient a pharmaceutical composition as claimed in claim 1 or 2 substantially | as herein described with reference to any one of .Examples 3 to 10. BALD