NZ202723A - Pseudotropyl benzoate derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02723 2 027 23 Priority Date(s)': Complete Specification Filed: 7.^ 1?."."?.? Class: J.. AfcJ. fcv5>A /-4h£....

Publication Date: ... 5! ?, #5? , P.O.

MO No: Date: PSEUDOTROPYL HALOGENOBENZOATES AND THEIR USE IN MIGRAINE TREATMENT 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 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) PATENTS ACT, 1953 AMENDED under Section — of Patents £ct 1953 ?3.:.

A^TANT COMMISSIONER OF PATENTS COMPLETE SPECIFICATION 2027 _ i PSEUDOTROPYL IIALOGENO-DENZOATEO AND ■ -THEIR USE IN MIGRAINE TREAT-MB#^ FIELD OF THE INVENTION The invention 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 10 se.

BACKGROUND OF THE INVENTION Acute attacks of migraine are usually treated with a peripheral vasoconstrictor, such as ergotamine, which may be co-administered with caffeine, and 15 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 20 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 25 role in the pathophysiology of migraine. Increased 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 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 10 Headache Congress 1980) 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 15 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 supra) that blockade of the M-receptor present on 20 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 pseudotropyl benzoate (i.e. benzoylpseudotropine), has been 25 reported (J.R. Fozard ejt a_l, Eur. J. Pharmacol., 59(1979), 195-210) but, with the exceptions of {now f£"£{.-^3\ 202723 nor(-)cocaine and benzoyltropine, none are as potent as metoclopramide. The pA2 values reported for pseudotropyl benzoate, nor(-)cocaine and benzoyl-tropine are 7.0, 7.7 and 7.2 respectively whilst the 05 pA2 5-HT value determined for metoclopramide by the same procedure is 7.2 (J.R. Fozard ejt al^. Eur. J. Pharmacol., 49(1978), 109-112).

It has been reported in New Zealand Patent Specification No. 201397 ' that / substitution of tropylbenzoate (i.e. benzoyltropine) / / with alkyl, alkoxy or halogen in the 3, 4 and 5, or 3, / 4 and 5 positions of the benzeneyring surprisingly / substantially enhances its pote-hcy as a 5-HT / /M-receptor antagonist. Tests' conducted with 15 pseudotropyl-3,5-dimethoxybenzoate (pA2 6.6) and pseudotropyl-3 ,4 , 5-trimet'hoxybenzoate (pA2 5.7) indicated that corresponding substitutions in the benzene ring of pseudotropyl benzoate would reduce its potency as a 5-HTyM-receptor antagonist. However, it 20 has now surprisi/ngly been found that substitution of pseudotropyl benzoate by halogen in the 3, 3 and 5, or 3, 4 and 5 p'ositions of the benzene ring does substantially enhance its potency. Said derivatives are believed to be novel.

/ SUMMARY OF THE INVENTION According to a first aspect of the invention, .4MARW85 202723 nor(-)cocaine and benzoyltropine, none are as potent as metoclopramide. The pA2 values reported for pseudotropyl benzoate, nor(-)cocaine and benzoyltropine are 7.0, 7.7 and 7.2 respectively whilst the 05 pA2 5-HT value determined for metoclopramide by the same procedure is 7.2 (J.R. Fozard et a^. Eur. J. Pharmacol., 49(1978), 109-112).

It has been reported in New Zealand Patent Specification- No. 201397 that substitution of tropylbenzoate (i.e. benzoyltropine) with alkyl, alkoxy or halogen in the 3; 3 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 15 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 20 has now surprisingly been found that substitution of 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 THE INVENTION According to a first aspect of the invention, 202723 there are provided pseudotropyl benzoate derivatives of the following general Formula I:-H2C CH CH2 „ R< I I -o NCH3 CH02 C-^ R3 05 H2C — f CH2 'R (exo) wherein R^ represents halogen; R2 represents hydrogen or halogen; and 10 R3 represents hydrogen or halogen provided that Ry is hydrogen when R2 is hydrogen, or a pharmaceutical^ acceptable salt thereof.

According to a second aspect of the invention there are provided pharmaceutical compositions in unit 15 dose form for the effective relief of migraine comprising a compound of general Formula I with a pharmaceutical^ acceptable diluent or carrier and containing 0.5 to 100 mg per unit dose. Usually, said 20 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 compounds of Formula I for use in the treatment of migraine and other vascular 25 headaches.

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 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 that the compounds of Formula I can be used in the prophylaxis of migraine by administering to a patient at risk 10 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 R^ represents 15 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 which can be represented by R^, 20 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 Ri represents chlorine, R2 represents 25 hydrogen, and R3 represents hydrogen, i.e. pseudotropyl -3-chlorobenzoate.

Another preferred compound of Formula I is that in which and R2 are the same and each represents chlorine, and R3 represents hydrogen, i.e. pseudotropyl-3,5-dichlorobenzoate. 05 Yet another preferred compound of Formula I is that in which R^, R2 and R3 are all the same and each represents chlorine, i.e. pseudotropyl-3,4,5-trichlorobenzoate.

In addition to the preferred chloro compounds 10 specified above, the following are compounds of Formula I:- pseudotropyl 3-bromobenzoate; pseudotropyl 3-iodobenzoate; pseudotropyl 3-fluorobenzoate; 15 pseudotropyl 3,5-dibromobenzoate; pseudotropyl 3 , 5-diiodobenzoate; pseudotropyl 3 ,5-difluorobenzoate; pseudotropyl 3,4,5-tribromobenzoate; pseudotropyl 3,4,5-triiodobenzoate; 20 pseudotropyl 3,4,5-trifluorobenzoate; 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 2 0272 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 05 effectively block the said M-receptors.

The activity of the compounds against 5-HT can be assessed by determining their pA£ values in the isolated rabbit heart as described by Fozard et at^ Europ. J. Pharmacol. 59, 195-210 (1979). In the 10 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 pA£ value is the negative logarithm of said molar concentrations. In general terms, the 15 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 of the effect of the compound on the Von Bezold-Jarisch Reflex induced by 20 5-HT injected intravenously into the rat (see Paintal A.S., Physiol. Rev. 5^3 159-227, 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. 25 The compounds of Formula I are believed to be highly selective in their action against 5-HT 2 i«&. ' »--V M-receptor. Their potency against other 5-HT 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 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 10 pharmaceutical preparations to the patient being 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 15 the patient and the mode of administration, the 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 20 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 25 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 05 dose forms 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 of a scored tablet, of the multiple dose form.

In the composition aspect of the invention there 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 15 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 20 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, excipient or medium for the active 25 ingredient. Suitable carriers or diluents are well known per se. 20272 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. 05 In the specific examples included hereinbelow illustrative examples of suitable pharmaceutical formulations are described.

The pseudotropyl benzoate derivatives of Formula I can be used in migraine therapy with antimigraine 10 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 15 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 20 J. Pharm. Pharmacol. 2^7, 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 25 daily. 202723 ii The compounds of general Formula I can be prepared in manner known per se from tropine and an acid halide of the following general Formula IV:- R 1 05 XOC R Formula IV 3 R 2 wherein:- Rl, R2 and R3 are as defined in connection with Formula I, and X represents halogen, especially chlorine. The reaction usually will be carried out by stirring the acid halide and pseudotropine in an 15 aprotic solvent, preferably methylene chloride or acetonitrile, at ambient temperature. 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 20 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 25 organic solution is then washed with water to remove excess pseudotropine and dried. The organic solvent is evaporated off and the free base recry^tall " 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 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. 10 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 15 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 20 sulphonic, toluene-£-sulphonic, 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 25 serve as intermediates in the purification of the compounds or in the preparation of other, for example, 202723 pharmaceutically acceptable, acid addition salts, or are useful for identification 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 10 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. 15 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 20 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 following non-limiting Examples. ¥ !» 14 EXAMPLE 1 PSEUDOTROPYL 3,5-DICHLQRQBENZQATE (i.e. 3,5-DICHLORO-BENZOIC ACID EXO-8-METHYL-8-AZABICYCLO[3,2,110CT-3-YL ESTER) (FORMULA I, Ri=R?=Cl, R^=H) chloride (2.06 g) in acetonitrile (50 ml) is stirred at ambient temperature for 16 hours. The solvent is evaporated off under reduced pressure and the residue treated with water (50 ml) and saturated aqueous, 10 potassium carbonate solution (5 ml) is added. The mixture is extracted with diethylether, the ethereal solution washed several times with water, dried and evaporated. The crystalline residue is recrystallized from aqueous methanol to give pseudotropyl 3,5 15 dichlorobenzoate m.p. 89°C. pA2 8.6.

In the following Examples relating to pharmaceutical compositions, the term "active compound" is used to indicate the compound pseudotropyl-3,5-di-chlorobenzoate. This compound may be replaced in 20 these compositions by any other compound of Formula I, for example by pseudotropyl-3,4,5-trichlorobenzoate. 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 25 art. 05 Pseudotropine (1.41 g) and 3,5 dichlorobenzoy1- 202723 EXAMPLE 2 An illustrative composition for hard gelatin 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 10 mixing them well. The powder is then filled into hard gelatin capsules at a net fill of 100 mg per capsule.

EXAMPLE 3 An illustrative composition for tablets is as follows:- (a) active compound mg (b) starch 43 mg (c) lactose 50 mg (d) magnesium stearate 2 mg The granulation obtained upon mixing the lactose 20 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.

EXAMPLE 4 An illustrative composition for an injectable suspension is the following 1 ml ampule for an

Claims (9)

202723 - 16 - intramuscular injection:- Weight per cent (a) active compound 0.01 (b) polyvinylpyrrolidone 0.5 05 (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 10 1.0 mg per ml of compound (a). EXAMPLE 5 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 1G capacity, to produce suppositories. 202723 17 clWM " cuwrt-a

1. A pseudotropyl benzoate derivative of the following general Formula I:- CH CHf. R 05 R 3 wherein:- H2C CH — CH2 R^ represents halogen; R2 represents hydrogen or halogen; and (exo) R 2 10 R3 represents hydrogen or halogen provided that R3 is hydrogen when R2 is hydrogen or a pharmaceutically acceptable salt thereof.

2. Pseudotropyl-3-chlorobenzoate or a 15 pharmaceutically acceptable salt thereof.

3. Pseudotropyl-3,5-dichlorobenzoate or a pharmaceutically acceptable salt thereof.

4. Pseudotropyl-3,4,5-trichlorobenzoate or a pharmaceutically acceptable salt thereof. 20

5. A pharmaceutical composition in unit dose form for the treatment of migraine comprising, acceptable diluent or carrier, an amount of 0.5 to lOOmg per unit dose of a pseudotropyl benzoate 25 derivative as claimed in any one of the preceding claims or a pharmaceutically acceptable salt thereof. with a pharmaceutically 202723 - 18 -

6. A composition as claimed in Claim 5 containing 1 to 50 mg of said compound per unit dose.

7. A composition as claimed in Claim 6 containing 3 to 30 mg of said compound per unit dose. 05

8. A process for preparing a compound as claimed in Claim 1 which comprises the reaction in manner known per se of pseudotropine and the corresponding acid halide of the following general Formula IV R. 10 XOC R Formula IV wherein R^, R2 and R3 are as defined in Claim 1 and X represents halogen.

9. A pseudotropyl benzoate derivative as claimed in 15 any one of Claims 1 to 4 or a pharmaceutically acceptable salt thereof for use in the treatment of migraine. 20 zJc Co*\j>iCLy*i£ fef-. 25