CA1215714A - Tropyl and pseudotropyl alkyl-benzoates and their use in migraine treatment - Google Patents

Abstract

TROPYL AND PSEUDOTROPYL ALKYL-BENZOATES

AND THEIR USE IN MIGRAINE TREATMENT

ABSTRACT OF THE DISCLOSURE
Migraine is treated with a pseudotropyl or tropyl benzoate derivative of the following general Formula I:- wherein:-Ar represents n represents O or an integer from 1 to 3 R1 represents C1-C4 alkyl;
R2 represents C1-C4 alkyl, C1-C4 alkoxy or halogen provided that R2 is the same as R1 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.
With the exception of tropyl-2-methylbenzoate, the derivatives of Formula I are novel compounds.

Description

7~4 TROPYL AND PSEUDOTR~PYL ALKYL-BENZOATES
.
AND 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 also provides said compounds for use in treating migraine and, when said compounds are novel, it provides said novel compounds per se.
BACKGROUND OF T~E INVENTION
Acute attacks of migraine are usually treated 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 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 ., . ~

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.

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amounts of 5-HT and i-ts 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 at-tack 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 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 prophylac-tic drugs methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but are all 5-HT ~-receptor antagonists a-t the doses used clinically for the treatmen-t of migraine. Metoclopramide is a potent 5-HT M-receptor antagonist and it has been proposed (J.R. Fozard 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 pseudotropine (i.e. pseudotropyl ~enzoate) and benzoyl tropine (i.e. tropyl benzoa-te), has been reported ~5~4 (J.R. Fozard et al, Fur. J. Pharmacol., 59(1979), 195-210) but, wi-th the exceptions of nor(-)cocaine and benzoyl tropine, none are as potent as metoclopramide.
The PA2 values reported ~or 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 et al. Eur. J. Pharmacol., 49(1978), 109-112).
It has been reported in Canadian Patent Patent Application No. 404222 (as yet unpublished) 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 a 5-HT M-receptor antagonis~. Tests conducted with tropyl-4-chlorobenzoate (PA2 7.0), tropyl-4-methyl-benzoate (PA2 7.8), tropyl-3,4-dichlorobenzoate (PA2 7.8) and tropyl 3,~ dimethoxybenzoate (PA2 7.2), indicated that corresponding substitutions elsewhere in the benzene ring would not provide the same order o~ increase in potency. Further, tests conducted with pseudotropyl-3,5-dimetho~ybenzoate (PA2 ~.6), and pseudotropyl-3,4,5-trimethoxybenzoate (PA2 5-7) indicated that corresponding substitutions 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 - 4 - ~ ~ ~7~

found that substitution by alkyl in a-t least the 2 position or in the 3,4 position of the benzene ring of tropyl benzo-ate and pseudotropyl benzoate and in the 3, 3 and 5, or 3, 4 and 5 positions o~ the benzene ring of pseudotropyl benzoate does substantially enhance potency as a 5-HT M-receptor an-tagonist.
All the tropyl benzoate derivatives of Formula I ex-cept tropyl-2-methylbenzoate, and all the pseudotropyl benzo-ates of Formula I are believed to be novel compounds. Tropyl-

2~methylbenzoate is disclosed in Al-Yahya, et al. (J. Chem.
Soc. Perkins Trans. 1, 1979 (93, 2130-2) but no pharmacologi-cal use has been reported for the compound.
SUMMAR~ 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 deri-vative of the following general Formula I:-H C ~ CH ~ CH2 l I
NCH3 CH ~ O2C-Ar 2 ~CH - CH2 wherein:-Ar represents R~ R

~ { /~
(R2)n R4 ~57~L~

n represents 0 or an integer from 1 to 3;
Rl represents Cl-C~ alkyl;
R2 represents Cl-C4 alkyl, halogen or Cl-C4 alkoxy, provided that R2 is the same as 05 Rl when n is 2 or 3; and R3 and R4 independently represent hydrogen, Cl-C4 alkyl, Cl-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 in admi~ture or otherwise associated 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 comprises administering to a patient suffering migraine, an effective migraine relieving amount of a compound of Formula I. Said amount usually will be in 7~

the range 0.01 mg/kg to 10 mg/kg, especially 0.03 mg/kg to 3.0 mg/kg. It ls also contemplated that the compounds of Formula I can be used ln the prophylaxis of migraine by administering to a patient at risk 05 of migraine an eefective 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 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 benzoyloxy moiety substituted by C1-C4 alkyl in at least the 2 or 3 posi-tion and optionally in other positions. In particular R1 represents C1-C4 alkyl; R2 represents C1-C4 alkyl, C1~C4 alkoxy or halogen but is the same as R1 when there are two or three R2 substituents; R3 can represent C1-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 O or an integer up to 3 preferably 0, 1 or ~. The 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 are e~clucled becau~e they are aLready -the subject oi the previously acknowleclged co-pending applica-tion.
In general Formula I, Ar c~n represent phenyl substituted as shown in the following Table I:-05 TA~3L.E_ Position 2 3 4 5 6 R1 H H R~ H
10R1 H H H R~

* H R1 H H H

* H R1 I-l R4 H
25* H R1 R3 R4 H
* pseudotropyl benzoate only In the table above Rl, R~, R~ and K4 are as defined in connection with Forrnula I except that neither R3 nor R4 represents hydrogen.
Examples of Cl-C4 alkyl groups which are 05 represented by Rl 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 Cl-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, 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:-~

~ (R2 )n wherein n is O or an integer from 1 to 3, Rrepresents Cl-C4 alkyl, and R2' represents Cl-C4 alkyl or chlorine provided -that R2' is the same as Rl when n is 2 or 3.

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Another preferred class of compounds of the invention are those pseudotropyl benzoates and tropyl benzoates of Formula I in which Ar represents:-~ R

05 ~ R3' wherein Rl and R3' independently representCl-C4 alkyl.
Yet another preferred class of compounds are those pseudotropyl benzoates of Formula I in which Ar represents:-~ ~ R3' wherein Rl represents Cl-C4 alkyl and R3' and R4' independently represent hydrogen or Cl-C4 alkyl.
In a presently par-ticularly 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 Cl-C4 alkyl, especially methyl, at the 2; 2, 3;

2, 4; 2, 5; or 3-, 4 positions. The said especially 7~

preferred methyl-substituted compounds are the following:-tropyl-2-methylbenzoate, tropyl-2,3-dimethylbenzoate, 05 tropy1-2,4-dimethylbenzoa-te, tropyl-2,5-dimethylbenzoate, tropyl-3,4-dimethylbenzoate, pseudotropyl-2-methylbenzoate, pseudotropyl-2,3-dimethylbenzoate, pseudotropyl-2,4-dimethylbenzoate, pseudotropyl-2,5-dimethylbenzoate, pseudotropyl-3,4-dimethylbenzoateO
In another presently especially preferred embodiment of the invention, tha compounds are those 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:-pseudotropyl-3-methylbenzoate, pseudotropyl-3,5-dimethylbenzoa-te, pseudotropyl-3,4,5-dimethylbenzoate.
In addition to the preierred compounds specified above, the following are illustrative compounds of ~5 Formula I:-tropyl 2-methyl-3 chlorobenzoate;
tropyl 2-methyl-~-chlorobenzoate;
tropyl 2-methyl-5-chlorobenzoate;
tropyl 2,3,5-trimethylbenzoate;
05 tropyl 2,3,4,5-tetramethylbenzoate;
tropyl 2-ethylbenzoate;
tropyl 3,4-diethylbenzoate;
tropyl 2-methyl-4-metho~ybenzoate;
pseudotropyl 2,3,5-trimethylbenzoate;
pseudotropyl 2-methyl-4-chlorobenzoate;
The compounds of Formula I block the M-receptors for 5-hydroxytryptamine (5-HT) on afferent sensory neurones, cextain of which subserve the transmission of pain. As explained above, the blocking of such 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.
The activity of the compounds against 5-ffT can be assessed by determining their PA2 values in the isolated rabbit heart as described by Fozard et at Europ. J. Pharmacol. 59, 195-210 (1979). In the method described the molar concentration of antagonist 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 . ~; , . .. ...

of said molar concentrations. In general terms, the higher the PA2 value the more po-tent is the compound.
The PA2 values of some representative compounds 05 of Formula I are given in the following Table II:-TABLE II
Compound ~2 5-HT
tropyl 2-methylbenzoate 8.1.
tropyl 3,4-dimethylbenzoate 8.2 tropyl 2,5-dimethylbenzoate 8.6 tropyl 2,4-dime-thylbenzoate 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 5 Table III for comparative purposes.
TABLE III
Compound ~2 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,~-dimethoxybenzoate 7.2 tropyl benzoate 7.2 pseudotropyl-3,4-dichlorobenzoate 7.5 tropyl 4-methylbenzoate 7.8 tropyl 3-methylbenzoate 8.1 tropyl 3,5-dimetho~ybenzoate 8.4 -tropyl 3,4,5-trimetho~ybenzoate 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-tropyl benzoate.
The activity of the compounds against 5-HT can be assessed in vivo by measurement oi the effect of the compound on the Von Bezold-Jarisch Refle~ induced by 5-HT injected intravenously into the rat (see Paintal A.~., Physiol. Rev. 53 159-227, 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 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 against 5-HT M-receptors.
- Accordingly, their use in the treatment of migraine should be without any side effects.

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 prepara-tions 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 amountO Depending upon the patient and the mode of administration, the quantity of compound administered may vary over a wide range to provide from about 0.01 mK/kg to about 10 mg/kg, usually 0.03 to 3.0 mg/kg, o~ body weight of the patient per doseO Unit doses of these compounds can contain, for example, from about 0.5 mg to lO0 mg, 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 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 dose forms such as liquids or scored tablets, said predetermined unit will be one fraction, such as a 5 ml (teaspoon) quantity OI' a liquid or a half or quarter OI 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 invention in admix-ture or otherwise in association with a pharmaceutically acceptable carrier or diluent therefor. For making those formulations the active ing~edient will usually be mixed with a carrier, or diluted by a diluent, or enclosed or 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, e~cipient or medium for the active ingredient~ ~uitable carriers or diluents are well known ~ 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.
In the specific examples included hereinbelow illustrative examples of suitable pharmaceutical formulations are described.

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Tlle derivatlves o~ 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/
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-~84 (1978); Fozard, 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 prepared in manner ~nown ~ 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, and X represents halogen, especially chlorine.

7~

When preparing tropyl benzoate derivatives, the reaction usually will be carried out in the absence o~
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 mi~ture first becomes liquid but subsequently becomes solid. Heating is continued for about 15 mins after solidification and the mi~ture is then cooled and added to water. The product is the 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 free base with a suitable organic solvent such as, for e~ample, 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 evaporated off, usually under reduced pressure, after ~2~

about 2 to 1~ 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, e-thylaceta-te and methylene chloride.
The organic solution is then washed with wa-ter to remove excess pseudotropine and dried. The organic solvent is evaporated off and the eree 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 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.
The pharmaceutica]ly 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 organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, malic, tartaric, citric, ~Zl~i7~ ~

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 acidaddition 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 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 free compound according to known methods, for example, by treating it with a base, such as with a ~etal hydroxide or alkoxide, for e~ample an alkali or alkaline earth metal hydroxide, for e~ample, lithium hydroxide, sodium hydro~ide, potassium hydroxide or calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example, sodium, potasslum or calcium carbonate or hydrogen carbonate; with trialkylamine; or with an anion exchange resin.
An acid addition salt may also be converted into another acid addition salt according to known ~ethods;

... ..

~%~7~
~o --for example, a s~lt with an inorganic acid rnay be treated with a metal salt, tor example a sodium, barium or silver salt, or an acid in a suitable diluen-t, in which a resulting inorganic salt is 05 insoluble and is thus removed trom the reaction medium. Acid addition salt may also be converted into another acid addition salt by trea-tment with an anion exchange preparation.
The invention is illustrated in the following non-limiting Examples.

TROPYL-3,4-DIMETHYLBENZOATE (i.e. 3,4-DIMETHYLBENZOIC
ACID ENDO-~-METHYL-8-AZABICYCL0~3,2,1]OCT-3-YL E~TER
(FORMULA I, ENDO, Ar= 3,4-dimethylphenyl) A stirred mixture of tropine hydrochloride (1.76 g) and 3,4-dimethyl benzoyl chloride (1.65 g) is heated at 130-140C for 30 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and resolidifies. A solution of the cooled solid in 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 the hydrochloride by the addition of ethereal hydrogen chloride. Recrystallization ot the precipitatecl solid ~%~57~L4 ~`rom ethanol gives crystals of tropyl 3,4-dimethyl-benzoate hydrochloride mp. 270-271'C.
The following compounds are prepared by the same method:-05 tropyl 2-methylbenzoate hydrochloride m.p. 262-3C;
tropyl 2,4-dimethylbenzoate hydrochloride m.p. 256-C;
tropyl 2,5-dimethylbenzoate hydrochloride m.p. 269.5-270~C.

PSEUDOTROPYL 3,5-DIMETHYLBENZOATE
-(i.e. 3,5-DIMETHYL-BENZOIC ACID
EXO-8-METHYL-8-AZABICYCLO[3,2,1]OCT-3-YL ESTER) (FORMULA I, EXO, Ar = 3,5-dimethylphenyl) Pseudotropine (1.41 g) and 3,5 dimethylbenzoyl-chloride (1.65 g) in methylene chloride (50 ml) is stirred at ambient temperature for 3 hours. The solvent is evaporated of~ under reduced pressure and 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 sul~`ate.
Distillation of the dried ethereal solution gives a residue which is treated with anhydrous diethyl ether , . '1 `"

and etllereal hydrogen chloride. Crystallization ol -the precipitate t`rom ethanol afords pseudotropyl 3,5-dlmethylbenzoate hydrochloride mp 245 C.

05 In the following Examples relating to pharma-ceutical compositions, the term "active compound" is used to indicate the compound tropyl-2,4-dimethyl-benzoate. This compound may be replaced in these compositions by any other compound of Formula I, for example by pseudotropyl-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 art.
_XAMPLE 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 gelatin capsules at a net eill of 100 mg per capsule.

'7:~
- ~3 -An illustrative composition for table-ts is as follows:-(a) active compound 5 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 granulating with starch paste is dried, screened, and mixed with the magnesium stearate. The mixture is compressed into tables weighing 100 mg each.

An illustrative composition for an injectable suspension is the following 1 ml ampule for an intramuscular injection:-Weight per cent (a) active compound 0.01 (b) polyvinylpyrrolidone 0.5 (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 1~1C. Each ampule contains 1.0 mg per ml of compound (a).

, ~; , - ~4 -EXAMPL--h-1 ~
mg/suppository Ac-tive Compound 5 Oil of Theobroma (cocoa butter) 995 The medicament is powdered and passed through a B.S. No. 100 Sieve and tri-turated with molten oil of theobroma at 45~C -to form a smooth suspension. The mixture is well stirred and poured into moulds each of nominal lG capacity, to produce supposi-tories.

Claims (18)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. An analogous process for preparing a tropyl or pseudotropyl benzoate derivative of the following general Formula I:- wherein:-Ar' represents n represents O or an integer from 1 to 3 R1 represents C1-C4 alkyl provided that R1 is not methyl when n is O;
R2 represents C1-C4 alkyl, C1-C4 alkoxy 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, C1-C4 alkoxy, or halogen, provided that for tropyl derivatives R3 is alkyl and R4 is hydrogen;
or a pharmaceutically acceptable salt thereof, which comprises the reaction of tropine or pseudo-tropine and the corresponding acid halide of the fol-lowing general Formula IV:-XOC - Ar' Formula IV

wherein Ar' is as defined above and X represents halogen.

2. A process as claimed in Claim 1 wherein Ar' represents:- wherein n is O or an integer from 1 to 3, R1 represents C1-C4 alkyl and R2' represents C1-C4 alkyl or chlorine, provided that R1 is not methyl when n is O and that R2' is the same as R1 when n is 2 or 3,

3. A process as claimed in Claim 2 wherein R1 and R2' both represent methyl.

4. A process as claimed in Claim 2 wherein n is 1 and Ar' is phenyl substituted in the 2,3; 2,4; or 2,5 positions.

5. A process as claimed in Claim 2 wherein tropine is reacted with the acid halide to give the corresponding tropyl benzoate of Formula I.

6. A process as claimed in Claim 1 wherein tropine is reacted with an acid halide of the following Formula IVa:- wherein R1 and R3' independently represent C1-C4 alkyl groups and X represents halogen, to give the corresponding tropyl benzoate of Formula I.

7. A process as claimed in Claim 6 wherein R1 and R3' are both methyl.

8. A process as claimed in Claim 1 wherein pseudo-tropine is reacted with an acid halide of the following Formula IVb:- wherein R1 represents C1-C4 alkyl, R3' and R4' independently represent hydrogen or C1-C4 alkyl, and X represents halogen to give the corresponding pseudotropyl benzoate of Formula I.

9. A process as claimed in Claim X wherein R1 represents methyl, and R3' and R4' independently represent hydrogen or methyl.

10. A tropyl or pseudotropyl benzoate derivative of the following general Formula I:- wherein:-Ar' represents n represents O or an integer from 1 to 3 R1 represents C1-C4 alkyl provided that R1 is not methyl when n is 0;
R2 represents C1-C4 alkyl, C1-C4 alkoxy 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, C1-C4 alkoxy, or halogen, provided that for tropyl derivatives R3 is alkyl and R4 is hydrogen;
or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.

11. A compound as claimed in Claim 10 wherein Ar' represents:- wherein n is O or an integer from 1 to 3, R1 represents C1-C4 alkyl and R2 represents C1-C4 alkyl or chlorine, provided that R1 is not methyl when n is O and that R2' is the same as R
when n is 2 or 3, or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 2 or an obvious chemical equivalent thereof.

12. A compound as claimed in Claim 10 wherein R1 and R2' both represent methyl, or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 3 or an obvious chemical equivalent thereof.

13. A compound as claimed in Claim 25 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 whenever prepared by the process of Claim 4 or an obvious chemical equivalent thereof.

14. A compound as claimed in Claim 23 which is a tropyl benzoate derivative, or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 5 or an obvious chemical equivalent thereof.

15. A compound as claimed in Claim 10 which is a tropyl benzoate derivative of Formula I in which Ar' represents:- wherein R1 and R3' independently represent C1-C4 alkyl groups, or a pharmaceutically acceptable salt thereof whenever prepared by -the process of Claim 6 or an obvious chemical equivalent thereof.

16. Tropyl-3,4-dimethylbenzoate, or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 7 or an obvious chemical equivalent thereof.

17. A compound as claimed in Claim 10 which is a pseudotropyl benzoate of Formula I in which Ar' represents:- wherein R1 represents C1-C4 alkyl, and R3' and R4' independently represent hydrogen or C1-C4 alkyl, or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 8 or an obvious chemical equivalent thereof.

18. A compound as claimed in Claim 17 wherein R
represents methyl, and R3' and R4' independently represent hydrogen or methyl, or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 9 or an obvious chemical equivalent thereof.