NZ202724A - Tropyl and pseudotropyl benzoate derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02724 202724 No: Date: Priority Date(s): Complete Specification Filed: 7^.7.

Class: C.Q.l-.Q/h-t?)U.ftbl.J<3»J4-6 ., Publication Date: ..

P.O. Journal, No: JJ2.7V?.' NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION TROPYL AND PSEUDOTROPYL ALKYL-BENZOATES AND THEIR USE IN MIGRAINE TREATMENT We MERRELL TORAUDE ET COMPAGNIE, a French Body corporate, of 16 Rue d'Ankara, 67084 Strasbourg, France hereby declare the invention for which we pray that a patent may be granted, to us3 and the method by which it is to be performed3 to be particularly described in and by the following statement:- (followed by page la) 202724 - 1 C*~ — M-tHr3-8-S TROPYL AND PSEUDOTROPYL ALKYL BENZOATES A&ft THEIR USE IN MIGRAINE TREATMENT FIELD OF THE INVENTION 05 The invention relates to the treatment of migraine with certain tropyl and pseudotropyl alkyl-benzoates and provides pharmaceutical compositions comprising said compounds and methods of treating migraine using said compounds. Further, the invention 10 also provides said compounds for use in treating migraine and, when said compounds are novel, it provides said novel compounds per se.

BACKGROUND OF THE INVENTION Acute attacks of migraine are usually treated 15 with a peripheral vasoconstrictor, such as ergotamine, which may be co-administered with caffeine, and dihydroergotamine; an antipyretic analgesic, such as acetylsalicylic acid or p-acetylaminophenol; and/or an anti-emetic such as cyclizine, metoclopramide and 20 thiethylperazine. It has also been reported (J.B. Hughes; Med. J. Aust. 2, No. 17, 580, 1977) that immediate relief of acute migraine attack can be obtained by slow intravenous injection of metoclopramide (10 mg).

It is believed that 5-hydroxytryptamine (5-HT) is the naturally occurring substance most likely to play a role in the pathophysiology of migraine. Increased 202724 amounts of 5-HT and its metabolite 5-hydroxyindole-acetic acid are excreted in the urine during most attacks. Further, plasma and platelet 5-HT concentrations fall rapidly at the onset of an attack 05 and remain low whilst the headache persists.

Moreover, attacks of migraine have been clearly associated with periods of thrombocytopaenia in certain patients. It has been proposed that compounds which block the activity of 5-HT would be of use in 10 the treatment of migraine (J.R. Fozard, International Headache Congress 1980) reported in Advances in Neurology, Vol 33, Raven Press, New York 1982).

The known migraine prophylactic drugs methysergide, propranolol, amitriptyline, and 15 chlorpromazine have widely different pharmacological activities but are all 5-HT D-receptor antagonists at the doses used clinically for the treatment of migraine. Metoclopramide is a potent 5-HT M-receptor antagonist and it has been proposed (J.R. Fozard 20 supra) that blockade of the M-receptor present on afferent sensory neurones affords symptomatic relief in an acute migraine attack.

The potency as 5-HT M-receptor antagonists of (-) cocaine and some related compounds, including benzoyl 25 pseudotropine (i.e. pseudotropyl benzoate) and benzoyl tropine (i.e. tropyl benzoate), has been reported 202724 (J.R. Fozard et al, Eur. J. Pharmacol., 59(1979), 195-210) but, with the exceptions of nor(-)cocaine and benzoyl tropine, none are as potent as metoclopramide. The pA2 values reported for nor(-)cocaine, 05 benzoyl tropine, and benzoyl pseudotropine are 7.7, 7.2 and 7.0 respectively whilst the pA2 5-HT value determined for metoclopramide by the same procedure is 7.2 (J.R. Fozard ejt a^. Eur. J. Pharmacol., 49(1978), 109-112).

It has been reported in New Zealand Patent Patent Application No. 201397 «(a-a yet unpubliahad1)' that substitution of tropyl benzoate with alkyl, alkoxy or halogen in the 3,4 and 5, or 3,4, and 5 positions of the benzene ring surprisingly enhances its potency as 15 a 5-HT M-receptor antagonist. Tests conducted with tropyl-4-chlorobenzoate (pA2 7.0), tropyl-4-methy1-benzoate (pA2 7.8), tropyl-3,4-dichlorobenzoate (pA2 7.8) and tropyl-3,4-dimethoxybenzoate (pA2 7.2), indicated that corresponding substitutions 20 elsewhere in the benzene ring would not provide the same order of increase in potency. Further, tests conducted with pseudotropy1-3,5-dimethoxybenzoate (pA2 6.6), and pseudotropyl-3,4,5-trimethoxybenzoate (pA2 5.7) indicated that corresponding substitutions 25 in the benzene ring of pseudotropyl benzoate actually would reduce its potency as a 5-HT M-receptor antagonist. However, it has now surprisingly been 202724 4 found that substitution by alkyl in at least the 2 position or in the 3,4 position of the benzene ring of tropyl benzoate and pseudotropyl benzoate and in the 3, 3 and 5, or 3, 4 and 5 positions of the benzene 05 ring of pseudotropyl benzoate does substantially enhance potency as a 5-HT M-receptor antagonist.

All the tropyl benzoate derivatives of Formula I . except tropyl—2-methylbenzoate, and all the pseudotropyl benzoates of Formula 1 are believed-to-be novel compounds. Tropy1-2—methylbenzoate is disclosed'in Al—yahya et al (J. Chem. Soc. Perkins Trans. 1, 1979 (9), 2130-2) but no pharmacological use has been reported for the compound.

SUMMARY OF THE INVENTION According to a first aspect of the invention, there are provided for use in the treatment of migraine and other vascular headaches a tropyl or pseudotropyl benzoate derivative of the following general Formula I:- CH CH-.

I I NCH„ CH 02C-Ar CH CH2 wherein:- Ar represents R 1 1 R 3 202724 n represents 0 or an integer from 1 to 3; Rl represents C1-C4 alkyl; R2 represents C1-C4 alkyl, halogen or C1-C4 alkoxy, provided that R2 is the same as 05 R^ when n is 2 or 3; and R3 and R4 independently represent hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halogen provided that for tropyl derivatives R3 is alkyl and R4 is hydrogen, or a pharmaceutically acceptable salt thereof.

According to a second aspect of the invention there are provided pharmaceutical compositions in unit dose form for the effective relief of migraine comprising a compound of general Formula I 15 with a pharma ceutically acceptable diluent or carrier and containing 0.5 to 100 mg per unit dose. Usually, said compositions will contain 1 to 50 mg, especially 3 to 30 mg, per unit dose.

According to a third aspect of the invention, there are provided per se all compounds of Formula I except tropyl-2-methylbenzoate.

According to a fourth aspect of the invention, there is provided a method of treating migraine which 25 comprises administering to a patient suffering migraine, an effective migraine relieving amount of a compound of Formula I. Said amount usually will be in T OCT 1984 202724 the range 0.01 mg/kg to 10 mg/kg, especially 0.03 mg/kg to 3.0 mg/kg. Lt is also contemplated that the compounds of Formula I can be used in the prophylaxis of migraine by administering to a patient at risk 05 of migraine an effective migraine-prophylatic amount of the compound.

DETAILED DESCRIPTION OF THE INVENTION When the bicylic ring of a compound of Formula I is in the endo configuration, the compound is a tropyl 10 benzoate and, when it is in the exo configuration, the compound is a pseudotropyl benzoate. Presently, the tropyl benzoates are preferred over the pseudotropyl benzoates.

The compounds of general Formula I have the 15 benzoyloxy moiety substituted by C^-C^ alkyl in at least the 2 or 3 position and optionally in other positions. In particular R^ represents C^-C4 alkyl; R2 represents C1-C4 alkyl, C^-C4 alkoxy or halogen but is the same as R-]_ when there 20 are two or three R2 substituents; R3 can represent C^-C4 alkyl, C1-C4 alkoxy or halogen instead of hydrogen; R4 can represent C1-C4 alkyl, C1-C4 alkoxy or halogen instead of hydrogen; and n is 0 or an integer up to 3 preferably 0, 1 or 2. The 25 tropyl benzoates (but not pseudotropyl benzoates) of Formula I substituted at the 3-position alone, the 3 and 5 positions only, or the 3,4 and 5 positions only 20272* are excluded because they are already the subject of the previously acknowledged co-pending application.

In general Formula I, Ar can represent phenyl substituted as shown in the following Table I:-05 TABLE I Position 2 3 4 5 6 R-L H H H H R± R2 H H H R1 H R2 H H R1 H H R2 H R1 H H H R2 Rl Ri Rx U H Rx R^ H Rx H Rx Rl H H Rx Rx H R-l Rx H Rx H Rx H Rjl R]_ R1 Rx R1 H R^ R]_ R^ H R-^ Ri Ri H Ri R1 * H R1 H H H H R1 R3 H H * H Ri H R4 H 25 * H Ri R3 R4 H * pseudotropyl benzoate only 202724 8 In the table above , R2, R3 and R4 are as defined in connection with Formula I except that neither R3 nor R4 represents hydrogen.

Examples of <^-04 alkyl groups which are 05 represented by R^ and can be represented by R2, R3 and R4 are methyl, ethyl, n-propyl, n-butyl and iso-propyl with methyl and ethyl being preferred.

Examples of C1-C4 alkoxy groups which can be represented by R2, R3 and R4 are methoxy, ethoxy, n-propoxy, n-butoxy and iso-propoxy, with ethoxy and especially, methoxy being preferred.

The halogens which can be represented by R2, R3 and R4 are bromine, chlorine, fluorine and iodine with bromine, fluorine and, especially, 15 chlorine being preferred.

One preferred class of compounds of the invention are those pseudotropyl benzoates and tropyl benzoates of Formula I in which Ar represents wherein n is 0 or an integer from 1 to 3, R-^ represents Ci-C4 alkyl, and R21 represents 25 C^-C4 alkyl or chlorine provided that R21 is the same as R-^ when n is 2 or 3 . 202724 9 Another preferred class of compounds of the invention are those pseudotropyl benzoates and tropyl benzoates of Formula I in which Ar represents wherein and R3' independently represent C1-C4 alkyl.

Yet another preferred class of compounds are 10 those pseudotropyl benzoates of Formula I in which Ar represents wherein R^ represents C^-C^. alkyl and R3' and R41 independently represent hydrogen or 20 Ci-04 alkyl.

In a presently particularly preferred embodiment of the invention, the compounds are those pseudotropyl benzoates and, preferably, tropyl benzoates of Formula I in which Ar presents phenyl substituted only by 25 C1-C4 alkyl, especially methyl, at the 2; 2, 3; 2, 4; 2, 5; or 3, 4 positions. The said especially 05 20272 preferred methyl-substituted compounds are the following:- tropy1-2-methylbenzoate, tropyl-2,3-dimethylbenzoate, 05 tropyl-2,4-dimethylbenzoate, tropy1-2,5-dimethylbenzoate, tropyl-3,4-dimethylbenzoate, pseudotropyl-2-methylbenzoate, pseudotropy1-2,3-dimethylbenzoate, 10 pseudotropy1-2,4-dimethylbenzoate, pseudotropy1-2,5-dimethylbenzoate, pseudotropy1-3,4-dimethylbenzoate.

In another presently especially preferred embodiment of the invention, the compounds are those 15 pseudotropyl benzoates of Formula I in which Ar represents phenyl substituted only by C1-C4 alkyl, especially methyl, at the 3; 3, 5; or 3, 4, 5 positions. The said especially preferred methyl-substituted compounds are the following:-20 pseudotropyl-3-methylbenzoate, pseudotropyl-3,5-dimethylbenzoate, pseudotropyl-3,4,5-dimethylbenzoate.

In addition to the preferred compounds specified above, the following are illustrative compounds of 25 Formula I:- 202724 - n - tropyl 2-methy1-3-chlorobenzoate; tropyl 2-methy1-4-chlorobenzoate; tropyl 2-methy1-5-chlorobenzoate; tropyl 2,3,5-trimethylbenzoate; 05 tropyl 2,3,4,5-tetramethylbenzoate; tropyl 2-ethylbenzoate; tropyl 3,4-diethylbenzoate; tropyl 2-methy1-4-methoxybenzoate; pseudotropyl 2, 3,5-trimethylbenzoate; 10 pseudotropyl 2-methyl-4-chlorobenzoate; The compounds of Formula I block the M-receptors for 5-hydroxytryptamine (5-HT) on afferent sensory neurones, certain of which subserve the transmission of pain. As explained above, the blocking of such • 15 M-receptors is believed to be a mechanism by which the symptoms of migraine can be relieved.

Accordingly, the compounds of Formula I are useful in the treatment of migraine when administered in amounts sufficient to effectively block the said M-receptors. 20 The activity of the compounds against 5-HT can be assessed by determining their pA2 values in the isolated rabbit heart as described by Fozard et_ a/t Europ. J. Pharmacol. E59, 195-210 (1979). In the method described the molar concentration of antagonist 25 which reduces the effects of twice the ED50 of 5-HT to that of the ED50 in the absence of antagonist is determined. The pA2 value is the negative logarithm 2 02724 of said molar concentrations. In general terms, the higher the pA2 value the more potent is the compound.

The pA2 values of some representative compounds 05 of Formula I are given in the following Table II:- TABLE II Compound pA? 5-HT tropyl 2-methylbenzoate 8.1. tropyl 3,4-dimethylbenzoate 8.2 tropyl 2,5-dimethylbenzoate 8.6 tropyl 2,4-dimethylbenzoate 8.8 pseudotropyl 3,5-dimethylbenzoate 8.9 The pA2 values of some related compounds to those of the invention are given in the following 15 Table III for comparative purposes.

TABLE III Compound pA<? 5-HT pseudotropyl-3,4,5-trimethoxybenzoate 5.7 pseudotropyl-3,5-dimethoxybenzoate 6.6 pseudotropyl-4-chlorobenzoate 6.7 pseudotropyl benzoate 7.0 tropyl 4-chlorobenzoate 7.0 tropyl 3,4-dimethoxybenzoate 7.2 tropyl benzoate 7.2 pseudotropyl-3,4-dichlorobenzoate 7.5 tropyl 4-methylbenzoate 7.8 tropyl 3-methylbenzoate 8.1 202724 tropyl 3,5-dimethoxybenzoate 8.4 tropyl 3,4,5-trimethoxybenzoate 8.5 tropyl 3-chlorobenzoate 8.6 tropyl 3,5-dimethylbenzoate 9.0 05 tropyl 3,5-dichlorobenzoate 9.3 It will be noted inter alia from Tables II and III that the compounds of Formula I show in this test a potency as 5-HT M-receptor antagonists at least an order greater than that of tropylbenzoate or pseudo-10 tropyl benzoate.

The activity of the compounds against 5-HT can be assessed in vivo by measurement of the effect of the compound on the Von Bezold-Jarisch Reflex induced by 5-HT injected intravenously into the rat (see Paintal 15 A.S., Physiol. Rev. ^3 159-227, 1973). The transient cardiac slowing arises from'an increased efferent vagus activity arising from stimulation by 5-HT of sensory afferent fibres in and around the heart.

The compounds of Formula I are believed to be 20 highly selective in their action against 5-HT M-receptor. Their potency against other 5-HT receptors and other spasmogens, in particular oxytocin, acetylcholine, histamine and calcium, is believed to be at least two orders lower than that 25 against 5-HT M-receptors.

Accordingly, their use in the treatment of migraine should be without any side effects. 2027 The compounds of Formula I can be administered in various manners to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient being 05 treated either orally or parenterally, for example, subcutaneously or intravenously. The amount of compound administered will vary and can be any effective migraine-relieving amount. Depending upon the patient and the mode of administration, the 10 quantity of compound administered may vary over a wide range to provide from about 0.01 mg/kg to about 10 mg/kg, usually 0.03 to 3.0 mg/kg, of body weight of the patient per dose. Unit doses of these compounds can contain, for example, from about 0.5 mg to 100 mg, 15 usually 1 to 50 mg and preferably 3 to 30 mg, of the compound and may be administered, for example, from 1 to 4 times daily.

The term "unit dosage form" is used herein to mean a single or multiple dose form containing a 20 quantity of the active ingredient in admixture with or otherwise in association with the diluent or carrier, said quantity being such that one or more predetermined units are normally required for a single therapeutic administration. In the case of multiple 25 dose forms such as liquids or scored tablets, said predetermined unit will be one fraction, such as a 5 2 027 24' ml (teaspoon) quantity of a liquid or a half or quarter of a scored tablet, of the multiple dose form.

In the composition aspect of the invention there 05 are provided pharmaceutical formulations in which form the active compounds of the invention will normally be utilized. Such formulations are prepared in a manner well known per se in the pharmaceutical art and usually comprise at least one active compound of the 10 invention in admixture or otherwise in association with a pharmaceutically acceptable carrier or diluent therefor. For making those formulations the active ingredient will usually be mixed with a carrier, or diluted by a diluent, or enclosed or 15 encapsulated in a capsule, sachet, cachet, paper or other container. A carrier or diluent may be solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the active ingredient. Suitable carriers or diluents are well 20 known per se.

The formulations of the invention may be adapted for enteral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like. 25 In the specific examples included hereinbelow illustrative examples of suitable pharmaceutical formulations are described. 2027 The derivatives of Formula I can be used in migraine therapy with antimigraine drugs having different modes of action. Such drugs include those used prophylactically, such as barbiturates, diazepam, 05 chlorpromazine, amitriptyline, propranolol, methysergide, pizotifen, cyproheptadine, dihydroergotamine, and clonidine, and those used in the acute attack, such as vasoconstrictor agents, e.g. ergotamine and dihydroergotamine, analgaesic/ 10 antiinflammatory agents, e.g. aspirin, paracetamol and indomethacin, or anti-nauseants, e.g. cyclizine, metoclopramide, and triethylperazine (see Fozard, J.R. J. Pharm. Pharmacol. 27_, 297-321 (1975); Saper, J.R., J. Amer. Med. Assoc. 239, 480-484 (1978); Fozard, 15 J.R., supra.) As an example, compounds of general Formula 1 would be beneficial in combination with aspirin 300-1200 mg or methysergide, 2-6 mg given daily.

The compounds of general Formula I can be 20 prepared in manner known per se from tropine or pseudotropine and an acid halide of the following general Formula IV:- XOC-Ar Formula IV wherein Ar is as defined in connection with Formula I, 25 and X represents halogen, especially chlorine. 202724 When preparing tropyl benzoate derivatives, the reaction usually will be carried out in the absence of a solvent by heating, at for example a temperature in the range 140° to 160°C, the acid halide with a 05 hydrohalide salt of tropine whilst stirring. Hydrogen halide is evolved and the mixture first becomes liquid but subsequently becomes solid. Heating is continued for about 15 mins after solidification and the mixture is then cooled and added to water. The product is the 10 hydrohalide of the compound of Formula I and the free base can be obtained by addition of aqueous base, such as sodium or potassium carbonate, which does not hydrolyse the ester, to render the aqueous product solution alkaline and subsequent extraction of the 15 free base with a suitable organic solvent such as, for example, diethylether, ethylacetate and methylene chloride. The organic solution is subsequently evaporated and the residue recrystallized from, for example, aqueous methanol.

When preparing pseudotropyl benzoate derivatives, the reaction usually will be carried out by.stirring the acid halide and pseudotropine in an aprotic solvent, preferably methylene chloride or acetonitrile, at ambient temperature. The solvent is 25 evaporated off, usually under reduced pressure, after 2 027 2 about 2 to 16 hours and water added to the residue, followed by aqueous base, such as sodium or potassium carbonate, which does not hydrolyse the ester, to render the aqueous product solution 05 alkaline. Subsequently desired free base is extracted with a suitable organic solvent such as, for example, diethyl ether, ethylacetate and methylene chloride. The organic solution is then washed with water to remove excess pseudotropine and dried. The organic 10 solvent is evaporated off and the free base recrystallized from, for example, aqueous methanol. Alternatively, the crude free base can be converted into an acid addition salt, preferably hydrochloride, by addition of an ethereal solution of the acid. The 15 acid salt is recrystallized from, for example ethanol or isopropanol.

As mentioned previously, the compounds of Formula I can be used in the form of their pharmaceutically acceptable acid addition salts. 20 The pharmaceutically acceptable acid addition salts can be non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic acids, such as 25 organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, malic, tartaric, citric, 2027 salicylic, o-acetyloxybenzoic, nicotinic or isonicotinic, or organic sulphonic acids, for example methane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-£-sulphonic, or naphthalene-2-05 sulphonic acids.

Apart from pharmaceutically acceptable acid addition salts, other acid addition salts, such as for example, those with picric or oxalic acid, may be serve as intermediates in the purification of the 10 compounds or in the preparation of other, for example, pharmaceutically acceptable, acid addition salts, or are useful for identification or characterisation of the bases.

An acid addition salt may be converted into the 15 free compound according to known methods, for example, by treating it with a base, such as with a metal hydroxide or alkoxide, for example an alkali or alkaline earth metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or 20 calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example, sodium, potassium or calcium carbonate or hydrogen carbonate; with trialkylamine; or with an anion exchange resin. 25 An acid addition salt may also be converted into another acid addition salt according to known methods; 202724 for example, a salt with an inorganic acid may be treated with a metal salt, for example a sodium, barium or silver salt, or an acid in a suitable diluent, in which a resulting inorganic salt is 05 insoluble and is thus removed from the reaction medium. Acid addition salt may also be converted into another acid addition salt by treatment with an anion exchange preparation.

The invention is illustrated in the following 10 non-limiting Examples.

EXAMPLE 1 TROPYL-3,4-DIMETHYLBENZOATE (i.e. 3,4-DIMETHYLBENZOIC ACID ENDO-8-METHYL-8-AZABICYCLO[3,2,110CT-3-YL ESTER (FORMULA I, ENDO, Ar= 3,4-dimethylphenyl) 15 A stirred mixture of tropine hydrochloride (1.76 g) and 3,4-dimethyl benzoyl chloride (1.65 g) is heated at 130-140"C for 30 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and resolidifies. A solution of the cooled solid in 20 water is basified with a solution of potassium carbonate and the base extracted with ethyl acetate. The ethyl acetate solution is washed several times with water, dried over magnesium sulphate, and evaporated to give the free base which is converted to 25 the hydrochloride by the addition of ethereal hydrogen chloride. Recrystallization of the precipitated solid 20272 from ethanol gives crystals of tropyl 3,4-dimethylbenzoate hydrochloride mp. 270-271°C.

The following compounds are prepared by the same method:- 05 tropyl 2-methylbenzoate hydrochloride m.p. 262-3°C; tropyl 2,4-dimethylbenzoate hydrochloride m.p. 256°C; tropyl 2,5-dimethylbenzoate hydrochloride 10 m.p. 269.5-27 0 ° C.

EXAMPLE 2 PSEUDOTROPYL 3,5-DIMETHYLBENZOATE (i.e. 3,5-DIMETHYL-BENZOIC ACID EX0-8-METHYL-8-AZABICYCL0[3,2,1]OCT-3-YL ESTER) 15 (FORMULA I, EXO, Ar = 3,5-dimethylpheny1) Pseudotropine (1.41 g) and 3,5 dimethylbenzoy1-chloride (1.65 g) in methylene chloride (50 ml) is stirred at ambient temperature for 3 hours. The solvent is evaporated off under reduced pressure and 20 the residue treated with water (50 ml) and saturated aqueous potassium carbonate solution (5 ml) is added. The liberated oil is extracted into diethylether, the ethereal solution washed several times with water and then dried over anhydrous magnesium sulfate. 25 Distillation of the dried ethereal solution gives a residue which is treated with anhydrous 'diethyl ether 20272 and ethereal hydrogen chloride. Crystallization of the precipitate from ethanol affords pseudotropy1-3,5-diraethylbenzoate hydrochloride mp 245°C. 05 In the following Examples relating to pharma ceutical compositions, the term "active compound" is used to indicate the compound tropy1-2,4-dimethy1-benzoate. This compound may be replaced in these compositions by any other compound of Formula I, for 10 example by pseudotropy1-3,5-dimethylbenzoate. Adjustments in the amount of medicament may be necessary or desirable depending upon the degree of activity of the medicament as is well known in the ar t.

EXAMPLE 3 An illustrative composition for hard gelatin capsules is as follows:- (a) active compound 5 mg (b) talc 5 mg (c) lactose 90 mg The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into hard 25 gelatin capsules at a net fill of 100 mg per capsule. 2027 2 EXAMPLE 4 An illustrative composition for tablets is as follows:- (a) active compound mg 05 (b) starch 43 mg (c) lactose 50 mg (d) magnesium stearate 2 mg The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and 10 granulating with starch paste is dried, screened, and mixed with the magnesium stearate. The mixture is compressed into tables weighing 100 mg each.

EXAMPLE 5 An illustrative composition for an injectable 15 suspension is the following 1 ml ampule for an intramuscular injection:- Weight per cent (a) active compound 0.01 (b) polyvinylpyrrolidone 0.5 20 (c) lecithin 0.25 (d) water for injection to make 100.0 The material (a) - (d) are mixed, homogenized, and filled into 1 ml ampules which are sealed and autoclaved 20 minutes at 121°C. Each ampule contains 25 1.0 mg per ml of compound (a).

Claims (14)

2027 - 24 - EXAMPLE 6 mg/suppository Active Compound 5 Oil of Theobroma (cocoa butter) 995 05 The medicament is powdered and passed through a B.S. No. 100 Sieve and tritorated with molten oil of theobroma at 45°C to form a smooth suspension. The mixture is well stirred and poured into moulds each of 10 nominal 1G capacity, to produce suppositories. 202724 - 25 - WHATi/Wf is."

1. A pharmaceutical composition in unit dose form for th$ treatment of-migraine comprising, with a pharmaceutically 05 acceptable diluent or carrier, an amount of 0.5 to 100 mg per unit dose of a tropyl or pseudotropyl benzoate derivative of the following general Formula I : - 10 H2C _ CH CHa NCHrt CH 0oC-Ar I I H2C CH — CH2 wherein:- Ar represents 15 ""O" R, <R2>n \ ri represents 0 or an integer from 1 to 3 Rl represents C^-C^ alkyl; 20 R2 represents C^-C4 alkyl, C1-C4 alkoxy or halogen provided that R2 is the same as Ri when n is 2 or 3; and R3 and R4 independently represent hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or halogen provided 25 that for tropyl derivatives R3 is alkyl and R4 is hydrogen; or a pharmaceutically acceptable salt thereof. 202724 - 26 -

2. , A tropyl or pseudotropyl benzoate derivative of the following general Formula I:-— CH CH„ 05 h2c .-H2c I I NCH., CH I I CH CH, 02C-Ar' wherein:- Ar' represents R^ 10 or <R2>n f R1 R „ R, n_ represents 0 or an integer from 1 to 3 R]_ represents C1-C4 alkyl provided that is not methyl when 11 is 0; R2 represents C1-C4 alkyl, C1-C4 alkoxy 15 or halogen, provided that R2 is the same as R^ when n is 2 or 3; and R3 and R4 independently represent hydrogen, C1-C4 alkyl, C^-C4 alkoxy, or halogen, provided that for tropyl derivatives R3 is alkyl and R4 is 20 hydrogen; or a pharmaceutically acceptable salt thereof.

3. A compound as claimed in Claim 2 wherein Ar' represents: - 25 R ■> \s OCT 1984 2 n 2027 27 wherein n is 0 or an integer from 1 to 3, represents C^-04 alkyl and R2 represents C1-C4 alkyl or chlorine, provided that Ri is not methyl^when n is 0 and that R21 is the same as Ri 05 when n is 2 or 3, or a pharmaceutically acceptable salt thereof.

4. A compound as claimed in Claim 3 wherein R^ and

R21 both represent methyl, or a pharmaceutically acceptable salt thereof. 10 5. A compound as claimed in Claim 3 wherein n is 1 and the phenyl group is substituted in the 2,3; 2,4; or 2,5 positions, or a pharmaceutically acceptable salt thereof.

6. A compound as claimed in Claim 3 which is a 15 tropyl benzoate derivative, or a pharmaceutically acceptable salt thereof.

7. A compound as claimed in Claim 3 which is tropyl 2 ,4-dimethylbenzoate, tropyl 2,5-dimethylbenzoate, or a pharmaceutically acceptable salt thereof. 20

8. A compound as claimed in Claim 2 which is a tropyl benzoate derivative of Formula I in which Ar' represents:- R 25 wherein R^ and R3' independently represent C1-C4 alkyl groups, or a pharmaceutically acceptable salt thereof. 202724 2 8

9. A compound as claimed in Claim 8 which is tropyl-3,4-dimethylbenzoate, or a pharmaceutically acceptable salt thereof.

10. A compound as claimed in Claim 2 which is a 05 pseudotropyl benzoate of Formula I in which Ar' wherein represents C1-C4 alkyl, and R31 and R4' independently represent hydrogen or C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. 15

11. A compound as claimed in Claim 10 wherein R^ represents methyl, and R31 and R41 independently represent hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

12. A compound as claimed in Claim 11 which is 20 pseudotropyl 3,5-dimethyl benzoate, or a pharmaceutically acceptable salt thereof.

13. A composition as claimed in Claim 1 wherein the compound of general Formula I is as claimed in any one of Claims 2 to 12. 25

14. A composition as claimed in Claim 1 wherein the compound of general Formula I is tropy1-2-methy1-benzoate. represents:- 10 . ftr^l * a. /TUnlf mithnrrsed Ag©"*8,