NO157932B - ANALOGUE PROCEDURE FOR THE POSITION OF THERAPEUTICALLY ACTIVE TROPYL AND PSEUDOTROPYL ALKYL BENZOATES. - Google Patents

Description

The present invention relates to the production of certain tropyl and pseudotropyl alkyl benzoates which are used for the treatment of migraine.

Acute attacks of migraine are usually treated with a peripheral vasoconstrictor such as ergotamine, which can be administered with caffeine, and dihydroergotamine; an antipyretic analgesic agent such as acetylsalicylic acid or p-acetyl-aminophenol; and/or an antiemetic such as cyclizine, metoclopramide and thiethylperazine. It has also been reported (J.B. Hughes; Med. J. Aust. 2, No. 17, 580, 1977) that the immediate relief of an 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 that most likely plays a 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. Furthermore, plasma and platelet 5-HT concentrations fall rapidly at the onset of an attack and remain low while the headache persists. Furthermore, attacks of migraine have clearly been associated with periods of thrombocytopenia in certain patients. It has been suggested that compounds which block the activity of 5-HT would be useful in the treatment of migraine (J.R. Fozard, International Headache Congress 1980) as reported in Advances in Neurology, vol. 33, Raven Press, New York 1982).

The known migraine prophylactic drugs methysergide, propranolol, amitriptyline and chlorpromazine have very 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 suggested (J.R. Fozard supra) that the blockade of the M receptor present on afferent sensory neurons provides symptomatic relief in an acute migraine attack.

The 5-HT M receptor antagonist potency of (-)-cocaine and some related compounds, including benzoylpseudotropine (ie, pseudotropylbenzoate) and benzoyltropine (ie, tropylbenzoate) has been reported (J.R. Fozard et al., Eur. J. Pharmacol., 59 (1979), 195-210), but with the exception of nor(-)-cocaine and benzoyltropine, none are as potent as metoclopramide. The pA2 values reported for nor(-)-cocaine, benzoyltropine and benzoylpseudotropin are 7.7, 7.2 and 7.0, while 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 is stated in Norwegian patent application 822561 that substitution of tropyl benzoate with alkyl, alkoxy or halogen in 3,4-

and the 5- or 3,4- and 5-positions of the benzene ring surprisingly increase its potency as a 5-HT M receptor antagonist. Tests carried out with tropyl-4-chlorobenzoate (PA2 7.0), tropyl-4-methyl-benzoate (pA2 7.8), tropyl-3,4-dichlorobenzoate (pA2 7.8) and tropyl-3,4 -dimethoxybenzoate (pA2 7.2) indicated that corresponding substitutions in the benzene ring would not give the same increase in potency. Furthermore, tests performed 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 pseudotropylbenzoate would actually reduce its potency as a 5-HT M receptor antagonist. However, it is now quite surprisingly found that substitution with methyl

in the 2-position or in the 3,4-position of the benzene ring in tropylbenzoate and pseudotropylbenzoate and in the 3- and 5-, or 3,4-positions of the benzene ring in pseudotropylbenzoate significantly increased its potency as a 5-HT M receptor antagonist.

The invention thus relates to an analog method

for the preparation of therapeutically active tropyl or pseudotropyl benzoate derivatives of general formula I

in which

Ar' denotes

1*2 denotes hydrogen or methyl in the 4- or 5-position of the phenyl ring, and one of and R^ denotes hydrogen, and the other of R^ and R^ denotes methyl, provided that for the tropyl derivatives R^ is methyl and R4 is hydrogen;

or a pharmaceutically acceptable salt thereof.

When the bicyclic 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. Currently, tropyl benzoates are preferred over pseudotropyl benzoates.

In general formula I, Ar can denote phenyl substituted

as shown in the following Table I:

Examples of compounds produced according to the invention are:

tropyl-2-methylbenzoate,

tropyl-2,4-dimethylbenzoate,

tropyl-2,5-dimethylbenzoate,

tropyl-3,4-dimethylbenzoate,

pseudotropyl-2,4-dimethylbenzoate,

pseudotropyl-2,5-dimethylbenzoate,

pseudotropyl-3,4-dimethylbenzoate, and

pseudotropy1-3,5-dimethylbenzoate.

The compounds of formula I block the M-receptors for 5-hydroxytryptamine (5-HT) on afferent sensory neurons, some of which act in 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 alleviated. Accordingly, the compounds of formula I are useful in the treatment of migraine when administered in amounts sufficient to effectively block designated M receptors.

The activity of the compounds towards 5-HT can be determined by determining their pA2 values in isolated rabbit heart as described by Fozard et al., Europ. J. Pharmacol. 5_9,

195-210 (1979). In the described method, the molar concentration of antagonist that reduces the effect of twice the ED5Q of 5-HT to ED5Q in the absence of antagonist is determined. <p>A2~ value is the negative logarithm of specified molar concentrations. The higher the pA2~ value, the stronger the compound.

pA2~ values for some representative compounds of formula I as well as some known, related compounds are given in subsequent tables II and III with tropyl-4-methylbenzoate and tropylbenzoate as standard compounds.

It appears i.a. from Tables II and III that the compounds of formula I exhibit in this test a potency as 5-HT M receptor antagonists at least one order of magnitude higher than that of tropyl benzoate or pseudotropyl benzoate.

The activity of the compounds against 5-HT can be determined in vivo by measuring the effect of the compound on the Von Bezold-Jarisch reflex evoked by 5-HT injected intravenously in rats (see Paintal A.S., Physiol. Rev. 53, 159-227, 1973) .

The transient decrease in cardiac activity arises from an increased efferent vagus activity that occurs when stimulation with 5-HT of sensory fibers in and around the heart.

The compounds of formula I are believed to be highly selective in their action towards the 5-HT M receptor. Their strength against other 5-HT receptors and other spasmogens, in particular oxytocin, acetylcholine, histamine and calcium, seems to be at least two orders of magnitude lower than against 5-HT M receptors.

Consequently, the use of these in the treatment of migraine should be without any side effects.

The analog method according to the invention is characterized by the fact that tropine or pseudotropine is reacted with the corresponding acid halide of general formula IV

in which Ar' is as defined above and X denotes halogen.

When preparing the tropyl benzoate derivatives, the reaction will usually be carried out in the absence of a solvent and under heating/ e.g. to a temperature in the range of 140 to 160°C, of the acid halide with a hydrohalide salt of tropine with stirring. Hydrogen halide is evolved, and the mixture first becomes liquid, but then becomes solid. Heating is continued for 15 minutes 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 base can be obtained by adding an aqueous base such as sodium or potassium carbonate, which does not hydrolyze the ester, to render the aqueous product solution alkaline, after which the free base is then extracted with a suitable organic solvent such as e.g. diethyl ether, ethyl acetate and methylene chloride. The organic solution is then evaporated, and the residue is recrystallized from e.g. methanol.

In the preparation of pseudotropyl benzoate derivatives, the reaction will usually 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, and after 2 to 16 hours water is added to the residue, followed by an aqueous base such as sodium or potassium carbonate, which does not hydrolyze the ester, to render the aqueous product solution alkaline. The desired free base is then extracted with a suitable organic solvent such as e.g. diethyl ether, ethyl acetate and methylene chloride. The organic solution is then washed with water to remove excess pseudotropin and then dried. The organic solvent is evaporated from, and the free base is recrystallized from. e.g. aqueous methanol. Alternatively, the impure free base can be converted into an acid addition salt, preferably hydrochloride, by adding an ethereal solution of the acid. The acid salt is recrystallized from e.g. ethanol or isopropanol.

As previously indicated, the compounds of formula I may be used in the form of their pharmaceutically acceptable acid addition salts.

The pharmaceutically acceptable acid addition salts may be non-toxic addition salts with suitable acids such as those with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acids, or with organic acids such as organic carboxylic acids, e.g. glycolic acid, maleic acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, salicylic acid, o-acetyloxybenzoic acid, nicotinic acid or isonicotinic acid, or organic sulphonic acids, e.g. methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid or naphthalene-2-sulfonic acids.

Apart from pharmaceutically acceptable acid addition salts, other acid addition salts, e.g. those with picric acid or oxalic acid are used as intermediates in the purification of the compounds, or for the preparation of others, e.g. pharmaceutically acceptable acid addition salts, or are useful for identifying or characterizing the bases.

An acid addition salt can be converted to the free compound by known methods, e.g. by treatment with a base such as with a metal hydroxide or alkoxide, e.g. an alkali or alkaline earth metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate such as an alkali metal or alkaline earth metal carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate; with trialkylamine; or with an anion exchange resin.

An acid addition salt can also be converted into another acid addition salt by known methods; for example, a salt with an inorganic acid can be treated with a metal salt, e.g. sodium, barium or silver salt, or an acid in a suitable diluent in which a resulting inorganic salt is insoluble, and which can thus be removed from the reaction medium. The acid addition salt can also be converted into another acid addition salt by treatment with an anion exchange material.

The invention is illustrated in the following examples.

Example 1

Tropyl-3,4-dimethylbenzoate (ie 3,4-dimethylbenzoic acid endo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl ester

(formula I, endo, Ar = 3,4-dimethylphenyl)

A stirred mixture of 1.76 g of tropine hydrochloride and

1.65 g of 3,4-dimethylbenzoyl chloride was heated to 130-140°C for 30 minutes, during which time the mixture went into liquid phase, hydrogen chloride gas was evolved, and the mixture solidified again. A solution of the cooled solid in water was made basic with a solution of potassium carbonate, and the base was extracted with ethyl acetate. The ethyl acetate solution was washed several times with water, dried over magnesium sulfate and evaporated to give the free base, which was converted to the hydrochloride by addition of ethereal hydrogen chloride. Recrystallization of the precipitated solid from ethanol gave crystals of tropyl-3,4-dimethylbenzoate hydrochloride,

m.p. 270-271°C.

The following compounds were prepared by the same method: tropyl-2,4-dimethylbenzoate hydrochloride, m.p. 256°C, tropyl-2,5-dimethylbenzoate hydrochloride, m.p. 269.5-270°C.

Example 2

Pseudotropyl-3,5-dimethylbenzoate

(ie 3,5-dimethylbenzoic acid exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl-ester) (formula I, exo, Ar-3,5-dimethylphenyl)

1.41 g of pseudotropine and 1.65 g of 3,5-ldimethylbenzoyl chloride in 50 ml of methylene chloride were stirred at ambient temperature for 3 hours. The solvent was evaporated from under reduced pressure, and the residue was treated with 50 ml of water, and 5 ml of saturated aqueous potassium carbonate solution was added. The released oil was extracted into diethyl ether, the ether solution was washed several times with water and was then dried over anhydrous magnesium sulfate.

Distillation of the dried ethereal solution gave a residue which was treated with anhydrous diethyl ether and ethereal hydrogen chloride. Crystallization of the precipitate from ethanol gave pseudotropyl-3,5-dimethylbenzoate hydrochloride,

m.p. 245°C.

Claims (1)

Analogous process for the preparation of therapeutically active tropyl or pseudotropyl benzoate derivatives of general formula I 1*2 denotes hydrogen or methyl in the 4- or 5-position of the phenyl ring, and one of R^ and R^ denotes hydrogen, and the other of R^ and R^ denotes methyl, provided that for the tropyl derivatives R^ is methyl and R^ is hydrogen; or a pharmaceutically acceptable salt thereof, characterized in that tropine or pseudotropine is reacted with the corresponding acid halide of general formula IV in which Ar' is as defined above and X denotes halogen.