CA1219266A - Pseudotropyl halogenobenzoates and their use in migraine treatment - Google Patents

Abstract

PSEUDOTROPYL HALOGENO-BENZOATES AND THEIR USE IN MIGRAINE TREATMENT ABSTRACT OF THE DISCLOSURE Migraine is treated with a novel pseudotropyl benzoate derivative of the following general Formula I:-wherein:-R1 represents halogen preferably chlorine; R2 represents hydrogen or halogen, preferably chlorine; and R3 represents hydrogen or halogen, preferably chlorine, provided that R3 is hydrogen when R2 is hydrogen.

Description

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P~EUDOTROPYL HALOGEN~-BENZOATES ~ND
THEIR USE IN MIGRAINE TREATMENT
FIELD OF THE INYENTION
'rhe lnvention relates to the treatment of 05 migraine with certain novel pseudotropyl halogeno-benzoates and provides pharmaceutical compositions comprising said compounds, methods of treating migraine using said compounds, said compounds for use in treating migraine, and said novel compounds per se.
BA~KGROUND OF THE INVBNTION
Acute attacks of migraine are usually treated with a peripheral vasoconstrictor, such as ergotamine, ~hich may be co-administered with caffeine, and dihydroergotamine; an antipyretic analgesic, such as acetylsalicylic acid or p-acetylaminophenol; and/or an anti-eme-tic such as cyclizine, metoclopramide and thiethylperazine. It has also been repor-ted ~J.B.
Hughes; Med. J. Aust. 2, No. 17, 580, 1977) that immediate relief of acute migraine attac~ can be obtained by slow intravenous injec-tion 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 pathophyslology o~ migraine. Increased amounts o~ 5-~lT and its metabolite 5-hydroxyindole-. . .

~ .

~12~L~92~i - 2 -' acetic acid are excre-ted in the urine during most attacks. Further, plasma and platelet 5-HT
concentrations fall rapidly at the onset of an attack and remain low whilst the headache persists.
05 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 19~0) reported in Advances in Neurology, Vol 33, Raven Press, New York 1982).
The known migraine prophylactic drugs methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but are all 5-HT D-recep-tor 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 supra) that blockade of the M-receptor present on afferen-t sensory neurones affords symp-tomatic relief in an acute migraine attack.
The potency as 5-HT M-recep-tor antagonists of (-) cocaine and some related compounds, including pseudo-tropyl benzoate (i.e. benzoylpseudotropine), has been reported (J.R. Fozard et al, Eur. J. Pharmacol., 59(1979), 195-210) but, with -the excep-tions of . - .

nor(-)cocaine and benzoyltropine, none are as potent as me-toclopramide. The PA2 values reported for pseudotropyl benzoate, nor(-)cocaine and benzoyl-tropine are 7.0, 7.7 and 7.2 respec-tively whilst the 05 PA2 5-~T value determined tor 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 Paten-t Application No. 404222 (as yet unpublished) that substitution of tropylbenzoate (i.e. benzoyltropine) with alkyl, al~oxy or halogen in the 3, 4 and 5, or 3, 4 and 5 positions of the benzene ring surprisingly substantially enhances its potency as a 5-HT
M-receptor antagonist. Tests conducted with pseudotropyl-3,5-dimethoxybenzoate (PA2 6.6) and pseudotropyl-3,4,5-trimethoxybenzoate (PA2 5-7) indicated that corresponding substitutions in the benzene ring of pseudotropyl benzoate would reduce its potency as a 5-HT M-receptor antagonist. However, it has now surprisingly been found that substitution oi pseudotropyl benzoate by halogen in the 3, 3 and 5, or

3, 4 and 5 positions of the benzene ring does substantially enhance its potency. Said derivatives are believed to be novel.
SUMMARY OF ~HE INVENTION
According to a first aspect ot the inven-tion, . . .

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there are provided pseudotropyl benzoate derivatives of the following general Formula I:-¦ NCH3 CH2 C ~\ ~ R3 wherein:-R1 represents halogen;
R2 represents hydrogen or halogen; and R3 represents hydrogen or halogen provided that R3 is hydrogen when R2 is hydrogen, or a pharmaceu-tically acceptable salt -thereof.
According to a second aspec-t 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 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 third aspect of the inven-tion, there are provided compounds of Formula I for use in the treatment of migraine and other vascular headaches.

6~ii ~ ccording to a fourth aspect oe the invention, there is provided a method o~ treating migraine which comprises administering to a patient suffering migraine, an effective migraine-relieving amount of a 05 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 tha-t 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
The compounds of general Formula I have the benzoyloxy moiety substituted in that R1 represents halogen; R2 can represent halogen instead of hydrogen; and R3 is hydrogen except when R2 is halogen, in which case R3 can represent halogen instead of hydrogen.
The halogens ~vhich can be represented by R1, R2 and R3 are bromine, chlorine, fluorine and iodine with bromine, fluorine and, especially, chlorine being preferred.
One preferred compound of Formula I is that in which R1 represents chlorine, R2 represents hydrogen, and R3 represents hydrogen, i.e. pseudo~
tropyl-3-chlorobenzoate.

~nother pre~'erred compound of Formula I is that in which Rl and ~2 are the same and each represents chlorine, and R3 represents hydrogen, i.e. pseudotropyl-3,5-dichlorob.enzoate.
05 Yet another pre~'erred compound of Formula I is that in which Rl, R2 and R3 are all the same and each represents chlorine, i.e. pseudotropyl-3,4,5-trichlorobenzoate.
In addition to the pref'erred chloro compounds specified above, the following are compounds of Formula I:-pseudotropyl 3-bromobenzoate;
pseudotropyl 3-iodobenzoate;
pseudotropyl 3-~luorobenzo&te;
pseudotropyl 3,5-dibromobenzoate;
pseudotropyl 3,5-diiodobenzoate;
pseudotropyl 3,5-difluorobenzoate;
pseudotropyl 3, ,5-tribromobenzoate;
pseudotropyl 3,4,5-triiodobenzoate;
pseudotropyl 3,4,5-trifluorobenzoa-te;

The compounds oi Formula I block the M-receptors ior 5-hydroxytryptamine (5-HT) on af~'erent sensory neurones, certain of which subserve the transmission o~ pain. As explained above, the blocking of such . . .. . ~ . .. . .. .

~l~recep-tors is believed to be a mechanism by which the symptoms ot' migraine can be relieved. Accordingly, the compounds of Formula I are useful in the treatment of migraine when administered in amounts sufficient to 05 effectively block the said M receptors.
The activity of the compounds against 5-HT can be assessed by determining their PA2 values ln 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 antagonlst 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 compound.
The activity of -the compounds against 5-HT can be assessed in vivo by measurement oi the effect oi the compound on the Von Bezold-Jarisch Reflex induced by 5-HT injected intravenously into the rat (see Paintal A.S., 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.
- 25 The cornpounds of Eormula I are believed to be highly selective in thei L' action against 5-llT

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~Z~ 6 ~I-receptor. Their po-tency against other 5-~lT recepors and other spasmogens, in particular oxytocin, acetylcholine, histamine and calcium, is believed to be at least two orders lower than that against 5-HT
05 ~-receptors. Accordingly, their use in the treatment of migraine should be without any side effec-ts.
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 treated either orally or parenterally, for egample, 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 quantity of compound administered may vary over a ~ide range to provide f'rom 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 thesé compounds can contain, for example, from about 0.5 mg to 100 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 ~5 mean a single or multiple dose f'orm containing a quantity o~' the active ingredient in admi~ture with or 6~

otherwise in association with -the diluen-t 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 ~5 dose iorms such as liquids or scored tablets, said predetermined unit will be one fraction, such as a 5 ml (teaspoon) quantity of a liquid or a half or quarter oi a scored tablet, oi the multiple dose form.
In the composition aspect of the invention there are provided pharmaceutical formulations in which form the active compou'nds 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 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 diluen-t, 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 ac-tive ingredient. Suitable carriers or diluents are well known ~ se.

;26~ii -- 1 o The formulations of -the invention may be adapted for enteral or paren-teral use and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like.
05 In the specific examples included hereinbelow illustrative examples of sui-table pharmaceutical formulations are described.
The pseudotropyl benzoate 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, 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/anti-inflammatory 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, 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.

.. . . . . . . .. . .

~g~6 The compounds ot` general Formula I can be prepared in manner known per _ from tropine and an acid halide of the following general Formula IV:-05 XOC ~ 2 Formula IV

~3 wherein:-R1, R2 and R3 are as defined in connection with Formula I, and X represents halogen, especially chlorine.
The reac-tion usually will be carried out by stirring the acid halide and pseudotropine in an aprotic solvent, preferably methylene chloride or acetonitrile, at ambient temperàture. The solvent is evaporated off, usually under reduced pressure, after 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 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 organi.c solvent is evaporated off and the free base recrystallized , 3~2~

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 05 recrystalllzed 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 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, sulPuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, malic, -tartaric, citric, salicylic, o-acetyloxybenzoic, nicotinic or isonicotinic, or organic sulphonic acids, for example methane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acids.
Apart ~rom pharmaceutically acceptable acid addi-tion salts, o-ther 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, :~2~L~26~

pharmaceutlcally nccep-table, acid addition salts, or are useful tor iden-tification or characterisation of the bases.
An acid addition salt may be converted into the 05 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 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.
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, 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 exchange preparation.
The invention is illustrated in -the tollowing non-limiting Examples.

~2~2~6 PSEU~OTROPYL 3,5-DIC~LOROBENZOATE (i.e. 3,5-DICHLOE~O-BENZOIC ACI~ EXO-8-METHYL-8-AZABICYCLO[3,2,1]0CT-3-YL
. . _ _ _ _ _ _ _ _ _ _ ESTER) (FORMULA I, R1=R2=Cl, R3=H) 05 Pseudotropine (1.41 g) and 3,5 dichlorobenzoyl-chloride (2.0~ g) in acetonitrile (50 ml) is stirred at ambient temperature tor 16 hours. The solvent is evaporated off under reduced pressure and the residue treated with water (50 ml) and saturated aqueous potassium carbonate solution (5 ml) is added. The mixture is extracted with diethylether, the ethereal solution washed several times wi-th water, dried and evaporated. The crystalline residue is recrystallized from aqueous methanol to give pseudotropyl 3,5 dichlorobenzoate m.p. 89~C. PA2 8.6.
In -the eollowing Examples relating to pharma-ceutical compositions, the term "active compound" is used to indicate the compound pseudotropyl-3,5-di-chlorobenzoate. This compound may be replaced in these compositions by any other compound of Formula I, for example by pseudo-tropyl-3,4,5-trichlorobenzoate.
Adjustments in the amount of medicament may be necessary or desirable de~ending upon the degree of activity ot the medicament as is well known in the art.

~21~9Z~;6 An illustrative composition for hard gelatln capsules is as follows:-05 (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 hardgelatin capsules at a net fill of 100 mg per capsule.

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 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 mI ampule for an ~, ~

~Z~g2~6 intramuscular injection:-Weight per cent (a) active compound 0.01 (b) polyvlnylpyrrolidone 0.5 05 (c) leci-thin 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 121C. Each ampule contains 1.0 mg per ml of compound (a).

mg/suppository Active Compound 5 Oil of Theobroma (cocoa butter) 995 15 The medicament is powdered and passed through a B~S. No. 100 Sieve and triturated 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 suppositories.

Claims (9)

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 pseudotropyl benzoate derivative of the following general Formula I:- wherein:-R1 represents halogen;
R2 represents hydrogen or halogen; and R3 represents hydrogen or halogen provided that R3 is hydrogen when R2 is hydrogen or a pharmaceutically acceptable salt thereof which comprises the reaction of pseudotropine and the cor-responding acid halide of the following general For-mula IV
Formula IV

wherein R1, R2 and R3 are as defined above and X
represents halogen.

2. A process as claimed in Claim 1 wherein a pseudotropine is stirred with the acid halide in an aprotic solvent at ambient temperature.

3. A method as claimed in Claim 1 wherein R1 represents chlorine, R2 represents hydrogen, and R3 represents hydrogen.

4. A method as claimed in Claim 1 wherein R1 and R2 each represents chlorine and R3 represents hydrogen.

5. A method as claimed in Claim 1 wherein R1, R2 and R3 each represents chlorine.

6. A pseudotropyl benzoate derivative of the following general Formula I:- wherein:-R1 represents halogen;
R2 represents hydrogen or halogen; and R3 represents hydrogen or halogen provided that R3 is hydrogen when R2 is hydrogen or a pharmaceutically acceptable salt thereof whenever prepared by the method of Claim 1 or an obvious chemical equivalent thereof

7. Pseudotropyl-3-chlorobenzoate or a pharmaceutically acceptable salt thereof whenever prepared by the method of Claim 3 or an obvious chemical equivalent thereof.

8. Pseudotropyl-3,5-dichlorobenzoate or a pharmaceutically acceptable salt thereof whenever prepared by the method of Claim 4 or an obvious chemical equivalent thereof.

9. Pseudotropyl-3,4,5-trichlorobenzoate or a pharmaceutically acceptable salt thereof whenever prepared by the method of Claim 5 or an obvious chemical equivalent thereof.