NZ201397A - Pharmaceutical compositions based on tropyl benzoates and certain of these tropyl benzoates - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £01 397 201397 Priority Date(s): 0 "7 2 Complete Specification Filed: .v........

Class: Publication Date: P.O. Journal, No: .....

NO ' NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION "PHARMACEUTICAL COMPOSITIONS CONTAINING TROPYL BENZOATE DERIVATIVES" Ck/Wc, MERRELL TORAUDE ET COMPAGNIE, a French company, of 16 Rue d'Ankara, Strasbourg 67084, France, hereby declare the invention for which <£-/ we pray that a patent may be granted to rae^/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page la) 201597 -la- FIELD OF THE INVENTION The invention relates to the treatment of migraine with certain tropyl benzoate derivatives and provides pharmaceutical compositions comprising said compounds and, when said compounds are novel, it provides said novel compounds per se.

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-acetylarainophenol; and/or an anti-emetic such as cyclizine, raetoclopramide 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 occuring substance most likely to play a role in the pathophysiology of migraine. Increased BACKGROUND OF THE INVENTION #'V 201 amounts of 5-HT and its metabolite 5-hydroxyindole-aqetic 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.

It is an object of the present invention to provide compounds which are more potent and selective 25 5-HT M-receptor antagonists than metoclopramide and hence indicated for use in the treatment of migraine. 201397 The potency as 5-HT M-receptor antagonists of (-) cocaine and some related compounds has been reported (J.R. Fozard et jQ, Eur. J. Pharmacol., 59(1979), 195-210) but, with the exceptions of nor(-)cocaine and 05 benzoyltropine, none are as potent as metoclopramide. The pA2 values reported for nor(-)cocaine and benzoyltropine are 7.7 and 7.12 respectively whilst the pA£ 5-HT value determined for metoclopramide by the same procedure is 7.2 (J.R. Fozard ejt al. Eur. J. 10 Pharmacol., 49(1978), 109-112).

Surprisingly, it has been found that substitution of benzoyltropine by alkyl, alkoxy or halogen in the 3, 3 and 5, or 3, 4 and 5 positions of the benzene ring substantially enhances its potency as a 5-HT 15 M-receptor antagonist.

The tropyl benzoate derivatives of Formula I set forth in the following Table I are known compounds.

TABLE I KNOWN TROPYLBENZOATES OF FORMULA I «i «2 R3 Reference 0CH3 H H ) ) ) 0CH3 0CH3 0CH3 e.g.C.A. 59, 0CH3 0CH3 0C4H9 C. A. 67.

CI CI H CI H H ) ) e.g.C.A. 78, 201397 Some of the said known tropyl benzoate derivatives and certain known positional isomers thereof have been reported to have pharmacological activity, specifically local anesthetic, central nervous system stimulant, cholinolytic and/or spasmolytic activity. However no pharmacological activity indicating use in the treatment of migraine has been reported.

GB 1,012,622 discloses quaternary tropeines having long-acting hypertensive action but low anti-ganglionic and anti-acetylcholinic activity. These quaternary tropeines can be prepared by quaternizing the corresponding tropeine (i.e. 3-ol-ester of tropine). No reference is made to these tropeine intermediates having any pharmacological activity. A number of tropyl benzoates substituted in the benzoyl moiety are amongst the tropeines disclosed. In particular, there are disclosed the following compounds of Formula/T herein: TrojDjyl-vy-methylbenzoate Tropyl 3-chlorobenzoate Tropyl 3,5-dimethylbenzoate Tropyl 3,4,5-Trimethoxybenzoate.

The compounds of Formula I can be effectively administered in the treatment of migraine at dose levels well below those at which pharmacological activity has previously been reported for any of the said known compounds or their known isomers.

SUMMARY OF THE INVENTION According to a first aspect of the invention, there are provided pharmaceutical compositions in unit dosage form for use in the treatment of migraine said compositions comprising a tropyl benzoate derivative of the following general Formula I:- ' wherein: - RjL represents C1-C4 alkyl; C1-C4 alkoxy; or halogen; R2 represents hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halogen; and R3 represents hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or halogen provided that R3 is hydrogen when R2 is hydrogen, or a pharmaceutically acceptable salt thereof in admixture 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~second aspect of the invention, there are provided per se compounds of Formula I excluding those listed in Table I, tropyl 3-methyl benzoate and tropyl 3,5-dimethyl benzoate.

The compounds and compositions of the invention are suitable for use in the treatment of migraine by administering to a patient suffering migraine, an effective migraine relieving amount of a compound of Formula I. Said amount usually will be in the range 0.01 mg/kg to 10 mg/kg, especially 0.03 mg/kg to 3.0 mg/kg. It is also contemplated that the compounds of Formula I can be used in the prophylaxis of migraine by administering to a patient at risk of migraine an effective migraine-prophylatic amount of "the compound.

DETAILED DESCRIPTION OF THE INVENTION 05 The compounds of general Formula I have the benzoyloxy moiety substituted in that R^ represents . C1-C4 alkyl, C1-C4 alkoxy or halogen; R2 can represent C1-C4 alkyl, C1-C4 alkoxy or halogen instead of hydrogen; and R3 is hydrogen except when 10 R2 is other than hydrogen, in which case R3 can represent C1-C4 alkyl, C1-C4 alkoxy or halogen instead of hydrogen.

Examples of C1-C4 alkyl groups which can be represented by R2, R3 and R4 are methyl, ethyl, 15 n-propyl, N-butoxy 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 20 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 are those of Formula I in which represents methyl, methoxy or 20139 chlorine, R2 represents hydrogen, and R3 represents hydrogen.

Another preferred class of compounds are those of Formula I in which R^ and R2 are the same and each 05 represents methyl, methoxy or chlorine, and R3 represents hydrogen.

Yet another preferred class of compounds are those of Formula I in which R^, R2 and R3 are all the same and each represents methyl, methoxy or 10 chlorine.

In one presently particularly preferred embodiment of the invention, the compounds are those of Formula I in which (a) R^ represents methoxy and R2 and R3 represent hydrogen, (b) R^ and R2 15 both represents methoxy and R3 represents hydrogen, or (c) Rj_, R2 and R3 each represent methoxy.

Said compounds are:- tropyl-3-methoxybenzoate tropy1-3,5-dimethoxybenzoate, and 20 tropyl-3,4,5-trimethoxybenzoate The di- and tri-methoxy compounds are preferred over the monomethoxy compound.

In another presently particularly preferred embodiment of the invention, the compounds are those 25 of Formula I in which (a) R^ represents chlorine and R2 and R3 represent hydrogen, (b) R]_ and R2 both represent chlorine and R3 represents hydrogen, or (c) R]_, R2 and R3 each represent chlorine. Said compounds are:-tropy1-3-chlorobenzoate 05 tropyl-3,5-dichlorobenzoate tropyl-3,4,5-trichlorobenzoate The dichloro compound is presently preferred to the mono-or tri-chloro compounds.

In addition to the preferred methoxy and chloro 10 compounds specified above, the following are illustrative compounds of Formula I:-tropyl 3,5-dibromobenzoate; tropyl 3,5-diiodobenzoate; tropyl 3,5-difluorobenzoate; tropyl 3,5-diethoxybenzoate; tropyl 3-methoxy-5-chlorobenzoate; tropyl 3-methyl-benzoate; tropyl 3,5-dimethylbenzoate; tropyl 3,4,5-trimethylbenzoate; tropyl 3,5-diethylbenzoate; tropyl 3,5-di n-butoxybenzoate; The compounds of Formula I block the M-receptors for 5-hydroxytryptamine (5-HT) on afferent sensory neurones, certain of which subserve the transmission 25 of pain. As explained above, the blocking of such M-receptors is believed to be a mechanism by which the 201397 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. 05 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 e_t a_t Europ. J. Pharmacol. 59, 195-210 (1979). In the method described the molar concentration of antagonist 10 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 potent is the 15 compound.

The pA2 values of some representative compounds of Formula I are given in the following Table II:— TABLE II Compound pA? 5-HT tropyl 3- methylbenzoate 8.2 tropyl 3,5-dimethoxybenzoate 8.4 tropyl 3,4,5-trimethoxybenzoate 8.5 tropyl 3-chlorobenzoate 8.6 tropyl 3,5-dimethylbenzoate 9.0 tropyl 3,5-dichlorobenzoate 9.3 The pA£ values of some closely structurally related compounds to those of the invention are given 2013 in the following Table III for comparative purposes.

TABLE III Compound pAs 5-HT 05 tropyl 4-chlorobenzoate 7.0 tropyl 3,4-dimethoxybenzoate 7.2 tropyl benzoate 7.2 tropyl 4-methylbenzoate 7.8 nortropyl 3,5-dichlorobenzoate 7.8 It will be noted 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.

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 A.S. , Physiol. Rev. f>3 159-227, 1973). The transient 20 cardiac slowing arises from an increased efferent vagus activity arising from stimulation by 5-HT of sensory afferent fibres in and around the heart (see Example 3).

The compounds of Formula I are highly selective 25 in their action against 5-HT M-receptor. Their potency against other 5-HT receptors and other 2 013 - n - spasmogens, in particular oxytocin, acetylcholine, histamine and calcium, appears to be at least two orders lower than that against 5-HT M-receptors (see Example 4). Accordingly, their use in the treatment 05 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 preparations to the patient being 10 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 15 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, 20 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.

It will be appreciated that the dosage levels referred to above are substantially less than those 25 which would be required for medical treatment based on any known pharmacological activity of any of the known 139 compounds of Formula I. In the particular case ofj for example, tropine-3,5-dichlorobenzoate, in vitro data (see Table VI) indicate that the dose levels for treating migraine are between 4,500 and at 05 least 62,000 times less than that required to produce spasmolytic effects.

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 10 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 15 predetermined unit will be one fraction, such as a 5 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 20 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 25 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 encapsulated in a capsule, sachet, cachet, paper or 05 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 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.

In the specific examples included hereinbelow 15 illustrative examples of suitable pharmaceutical formulations are described.

The tropyl benzoate derivatives of Formula I can be used in migraine therapy with antimigraine drugs having different modes of action. Such drugs include 20 those used prophylactically, such as barbiturates, diazepam, chlorpromazine, amitriptyline, propranolol, methysergide, pizotifen, cyproheptadine, dihydroergotamine, and clonidine, and those used in the acute attack, such as vasoconstrictor agents, e.g. 25 ergotamine and dihydroergotamine, analgaesic/anti-inflammatory agents, e.g. aspirin, paracetamol and 20139 14 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, 05 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.

Formula I are known compounds and hence their preparation or, in the case of naturally occurring literature.

The compounds of general Formula I can be 15 prepared in manner known per se from tropine and an acid halide of the following general Formula IV:- As mentioned above, certain of the compounds of compounds, their isolation is described in the R XOC R 3 Formula IV wherein R^, R2 and R3 are as defined in connection with Formula I, and X represents halogen, especially chlorine. 20139 The reaction can 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 hydrohalide salt of tropine whilst stirring. Hydrogen 05 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 hydrohalide of the compound of Formula I and the free 10 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 15 "example, diethyl ether, ethylacetate and methylene chloride. The organic solution is subsequently evaporated and the residue recrystallized from, for example, aqueous methanol.

As mentioned previously, the compounds of Formula 20 I can be used in the form of their pharmaceutically acceptable acid addition salts.

The pharmaceutically acceptable acid addition salts can be non-toxic addition salts with suitable acids, such as those with inorganic acids, for example 25 hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic acids, such as 201 organic carboxylic acids, for example, glycollic, marleic, hydroxymaleic, malic, tartaric, citric, salicylic, o-acetyloxybenzoic, nicotinic or isonicotinic, or organic sulphonic acids, for example 05 methane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-£-sulphonc, or naphthalene-2-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 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 metal hydroxide or alkoxide, for example an alkali or 20 alkaline earth metal hydroxide, for example, lithium hydroxide, sodium hydroxide, 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, potassium or 25 calcium carbonate or hydrogen carbonate; with trialkylamine; or with an anion exchange resin. 201 An acid addition salt may also be converted into another acid addition salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, for example a sodium, 05 barium or silver salt, or an acid in a suitable diluent, in which a resulting inorganic salt is 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 10 exchange preparation.

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

EXAMPLE 1 TROPYL 3,5-DICHLORQBENZOATE 15 (FORMULA I, RI=RQ=C1, Rq=H) Tropine (34.24 g) is treated with anhydrous diethyl ether and ethereal hydrogen chloride and the precipitated hydrochloride is isolated by evaporation of the solvent. 3,5 Dichlorobenzoylchloride (51.7 g) 20 is added and the mixture stirred at 140*C for 15 mins during which time the mixture liquefies, evolves hydrogen chloride gas and resolidifies. After heating for a further 15 mins the cooled solid is dissolved in water, an excess of an aqueous solution of potassium 25 carbonate is added, and the base is extracted with ethyl acetate. Evaporation of the dried ethyl acetate solution gives a solid which is recrystallised from aqueous methanol to give tropyl 3,5 dichlorobenzoate m.p. 95*C (51.8 g). c15 H17N02cl-2 05 Calculated C, 57.33 H, 5.46 N, 4.46% Found C, 57.55 H, 5.53 N, 4.47% The following compounds are prepared by the same method. tropyl 3,5 dimethoxybenzoate m.p. 200°C 10 tropyl 3-chlorobenzoate hydrochloride m.p. 235-6 * C tropyl 3,4,5 trimethoxybenzoate m.p. 118°C EXAMPLE 2 TROPYL 3,5« DIMETHYLBENZOATE HYDROCHLORIDE 15 (FORMULA I, R1 = R9=CHct, R^=H) A stirred mixture of tropine hydrochloride (5.27 g) and 3,5-dimethyl benzoyl chloride (5g) is heated at 130^140* for 30 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and 20 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 25 the free base which is converted to the hydrochloride by the addition of ethereal hydrogen chloride. 2 013 9 7 Recrystallization of the precipitated solid from ethanol gives crystal of tropyl 3,5,-dimethylbenzoate hydrochloride (5.4 g) mp 260°.

C17H24N02C1 05 Calculated C 65.88 H 7.75 N 4.52% Found C 65.92 H 7.67 N 4.34% EXAMPLE 3 Antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat was measured 10 for tropyl-3,5-dimethoxybenzoate (A) tropyl-3,5- dimethylbenzoate (B) and tropyl-3,5-dichlorobenzoate (C) using the following method.

Male Sprague-Dawley rats weighing 250-300 g are anaesthetized with urethane, 1.25 g/kg injected 15 intraperitoneally and set up for recording blood pressure and heart rate as described in Fozard JR et^ al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dose of 5-HT (2jig/kg) is given repeatedly into the cannulated jugular vein and changes in heart 20 rate quantified. Antagonists are given intravenously and the doses required to just inhibit the response to 5-HT (threshold dose) or to inhibit the response to 5-HT by 50% (ED50) are determined.

The results obtained are set forth in Table IV 25 below in which the compounds are identified by the reference letters used above. - 20 -TABLE IV VON BEZOLD-JARISCH REFLEX ANTAGONISM COMPOUND THRESHOLD DOSE ED50 (^•g/kg) 9*g/kg) 05 A 6.96+0.90 13.7+1.20 B 3.57+0.33 6.07+0.72 C 7.72+0.63 22.0+3.2 In a comparative test metoclopramide gave a threshold dose of 233.4+ 66.3y/.g/kg and an ED50 of 10 408.4+80.9^g/kg.

This comparative test shows that compounds A, B and C are many times more potent than metoclopramide j.n this particular test indicating a corresponding reduction in dosage levels in the treatment of 15 migraine.

Compounds A, B and C are also relatively non-toxic as shown by their respective LD50 values in the mouse and rat (see Table V).

TABLE V LD50 IN THE MOUSE AND RAT (mg/kg) ROUTE MOUSE RAT A C B A C B i .p. 28 32 47 NT NT NT s. c. 17 NT NT NT NT NT i. v. 29 24 17 13 14 9 oral 160 90 116 NT NT NT (NT = not tested) 201397 - 21 -EXAMPLE 4 SELECTIVITY OF ACTION A selection of classical in vitro pharmacological test preparations (rat uterus; rat fundus; guinea-pig 05 ileum; guinea-pig taenia caeci) were set up according to well-established procedures (see "Pharmacological . experiments on isolated preparations" Staff of the Department of Pharmacology, University of Edinburgh, Livingstone, Edinburgh 1970). Various spasmogens were 10 used to elicit contraction of these tissues though mechanisms other than the 5-HT "M" receptor. The concentrations of tropyl-3,5-dimethoxybenzoate (A) tropyl-3,5-dimethylbenzoate (B) and tropyl-3,5-dichlorobenzoate (C) which reduced the 15 effects of a submaximal dose of agonist by 50% were determed (IC50). The results are set forth in Table VI below in which the compounds are identified by the reference letters used above.

From Table VI it is clear that A, B and C were at 20 least 700 times and in several instances greater than 50,000 times more potent as blockers of the 5-HT M receptor than of responses elicited through other means.

TABLE VI (CONCENTRATION IN NM TO INHIBIT STANDARD RESPONSE TO STIMULANTS BY 50% AGONIST RABBIT HEART RAT UTERUS RAT FUNDUS GUINEA-PIG ILEUM GUINEA-PIG CAECI* TAENIA A B C A A A B C A B C 5HT 9.4 1.03 0.82 >52480 40016 OXYTOCIN >52480 ACETYLCHOLINE 13120 9565 9590** 8055 HISTAMINE 6613 NT 3676 CALCIUM * 36080 34230 28620 * In potassium-depolarised Tyrode solution ** Carbachol agonist instead of Acetylcholine NT Not Tested f\J O \Q -^4 20l3<*7 23 EXAMPLE 5 PILOT STUDY OF TOLERANCE TO INTRAVENOUS TROPYL-3,5-DICHLOROBENZOATE IN PATIENTS WITH MIGRAINE OR CLUSTER HEADACHES 05 This study was designed to evaluate tolerance and, if possible, efficacy of intravenous tropyl-3,5-• dichlorobenzoate In patients with migraine or cluster headaches.

Eight patients (4 males), aged 27 - 47 with known 10 headache disorders of 5 - 27 years duration (see Table VII) took part in the study but Patient Nos. 2 and 4 had cluster not migraine headaches and the cause of headaches in Patient No. 6 was unknown. sterile solution, 1 mg/ml; the desired dose to be diluted in 10 ml normal saline for intravenous infusion over a 2 minute period. No other therapy was taken for at least 24 hours before treatment or during the course of therapy.

The initial dose of 1 mg, when shown to be well tolerated, was increased gradually in subsequent patients. (Table VII]). Doses as high as 14 mg/day and 9 mg single dose were administered without any signs of intolerance. Cumulative doses as high as 177 mg 25 over 18 days were also well tolerated.

Tropyl-3,5-dichlorobenzoate was provided as a 2013<W In 2 of the 3 patients treated with repeated doses of tropyl-3,5-dichlorobenzoate (patients 6 and 8)," a marked diminution of headache and associated symptoms occurred. Thus, Patient No. 6, refractory to 05 standard migraine therapies, had a slight reduction in her bilateral headache with 3 mg single doses and a further amelioration with 4 mg bid. This reduction in headache intensity lasted over a 2\ week period. Patient No. 8, an abuser of analgesics with daily 10 bilateral headaches accompanied by nausea, vomiting, vertigo and photophobia, had a decrease in all symptoms with the first dose of 3 mg. This amelioration continued with subsequent increases in doses, except for a single episode of symptom return 15 on first day of 9 mg. Within 6-7 days of stopping t therapy, headache returned to pre-treatment intensity.

It can be seen from Table VIII that single intravenous doses of tropyl-3,5-dichlorobenzoate up to 20 9 mg or repeated doses up to 7 mg bid were well tolerated in patients with headaches. In some patients treated with doses of 3 mg or greater, pain intensity and associated symptoms were ameliorated.

VL-.\;;VC.

Patient Sex Age Weight Type of Headache History of Headache Usual Freq.

Usual Duration 1 M 45 65 Chronic with exacerbations 19 years 2 - 3/ wk 18 - 24 hours 2 M 27 70 Cluster years daily - 45 min 3 F 31 67.4 Continuous with exacerbations years daily continuous 4 M 47 66 Cluster 11 years 2-3/ day 1-2 hours U 43 84.7 Chronic with daily crises, "Horton-like" years daily 3-4 hours 6 F 45 74 ? 27 years daily ? 7 F 34 53 Continuous with exacerbations, and extracranial pain 11 years 3-4/ week 3-5 hours 8 F 36 51.2 Chronic with daily exacerbations 7 years daily 4-6 hours ro o 04 Patient Posology (intravenous) Response .

Tolerance 1 1 mg, then 1 hour later 2 mg no effect on headache or nausea good 2 1 mg no effect good 3 3 mg no effect good 4 3 mg no effect good mg no effect good 6 3 mg single doses x 3 days, then 4 mg bid x 2 days, then 5 mg bid x 2 days then 6 mg bid x 11 days. reduction of pain intensity by 70-80% within 30 minutes after 4 mg dose and lasting 4-8 hours; no greater effect with increased doses. good 7 3 mg x 1 day, then 5 mg x 2 days then 7 mg x 1 day. no effect good 8 3 mg x 2 days, then 6 mg x 1 day, 7 mg x 2 days and 9 mg x 1 day. reduction of pain by about 30% with 3 mg, and maintained during increasing doses except for single episode of pain, nausea, vomiting and photophobia on first day of 9 mg. good 2 013 9 7 In the following Examples relating to pharmaceutical compositions, the term "active compound" is used to indicate the compound tropyl-3,5-dichlorobenzoate. This compound may be replaced in these 05 compositions by any other compound of Formula I, for example by tropyl-3,5-dimethoxybenzoate. 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. 10 EXAMPLE 6 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 20 gelatin capsules at a net fill of 100 mg per capsule.

EXAMPLE 7 An illustrative composition for tablets is as follows:- (a) active compound 5 mg (b) starch 43 mg (c) lactose 50 mg (d) magnesium stearate 2 mg

Claims (16)

201397 - 28 - The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated with starch paste is dried, screened, and mixed with the magnesium stearate. the mixture is 05 compressed into tables weighing 100 mg each. EXAMPLE 8 An illustrative composition for an injectable suspension is the following 1 ml ,ampul for an intramuscular injection:-10 Weight per cent (a) active compound 0. 01 (b) polyvinylpyrrolidone 0. 5 (c) lecithin 0. 25 (d) water for injection to make 100. 0 15 The material (a) - (d) are mixed, homogenized, and filled into 1 ml ampuls which are sealed and autoclaved 20 minutes at 121°C. Each ampul contains

1.0 mg per ml of compound (a).

EXAMPLE 9 20 mg/suppository

Active Compound 5

Oil of Theobroma (cocoa butter) 995

The medicament is powdered and passed through a B.S. No. 100 Sieve and triturated with molten oil of 25 Theobroma at 45*C to form a smooth suspension. The mixture is well stirred and poured into moulds each of nominal 1G capacity, to produce suppositories.;201 in;- 29 -;>J/VVJAW.WE CLAp J||;1. A pharmaceutical composition in unit dose form suitable for the treatment of migraine comprising, in admixture or otherwise associated with a pharmaceutically 05 acceptable diluent or carrier, an amount of 0.5 to lOOmg per unit dose of a tropyl benzoate derivative of the following general Formula I:-iLc CH CH;I;NCH;I;10 HQ CH;(endo);wherein:-;represents C1-C4 alkyl, C1-C4 ^ 15 alkoxy^ or halogen;;R2 represents hydrogen, C1-C4 alkyl,;C1-C4 alkoxy or halogen; and;R3 represents hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or halogen provided that R3 is 20 hydrogen when R2 is hydrogen;;or a pharmaceutically acceptable salt thereof.;2. A composition as claimed in Claim 1 containing 1 to 50 mg of said compound per unit dose.;3. A composition as claimed in Claim 2 containing 3 25 to 30 mg of said compound per unit dose.;013;- 30 -;4. A composition as claimed in any one of the preceding Claims wherein R^ represents methyl,;methoxy or chlorine, R2 represents hydrogen, and R3 represents hydrogen.;05 5. A composition as claimed in any one of Claims 1 to 3 wherein R^ and R2 are the same and each represents methyl, methoxy or chlorine, and R3 represents hydrogen.;

6. A composition as claimed in any one of Claims 1 10 to 3 wherein R^, R2 and R3 are all the same and each represents methyl, methoxy or chlorine.;,

7. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropyl)^ 3-methoxybenzoate or a pharmaceutically acceptable 15 salt thereof.;'

8. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropy],^* 3,5-dimethoxybenzoate or a pharmaceutically acceptable salt thereof. 20

9. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropylX 3,4,5-trimethoxybenzoate or a pharmaceutically I/ acceptable salt thereof.

,,"10. A composition as claimed in any one of Claims 1 25 to 3 wherein the tropylbenzoate derivative is tropyl^ 3-chlorobenzoate or a pharmaceutically acceptable salt thereof. 201397 / 05 10 / 15 20

-Sill. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropyl)(3 ,5 -dichlorobenzoate or a pharmaceutically acceptable salt thereof.

12. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropy 1)(3,4 ,5-trichlorobenzoate or a pharmaceutically acceptable salt thereof.

13. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropyl^ 3-methylbenzoate or a pharmaceutically acceptable salt thereof.

14. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropyl^ 3,5-dimethylbenzoate or a pharmaceutically acceptable salt thereof.

15. A composition as claimed in any one of Claims 1 to 3 wherein the tropylbenzoate derivative is tropyl^ 3,4,5-trimethylbenzoate or a pharmaceutically acceptable salt thereof.

16. A tropyl benzoate derivative of the following general Formula I:- H2C 25 h2c CH - I NCH, I ' CH - (endc) CH I 2 CHO -C l CH_