IE57090B1 - Indolyl carboxylic acid azabicyclooctyl piperidyl ester - Google Patents

Description

; 1' « 0 The present invention relates to indol-3-yl carboxylic acid endo-8-methyl- 8 - aza-bicyclo[3.2.1]oct-3-yl ester, in free base form or in acid addition salt form, hereinafter referred to as the compound of the invention.

Attention is directed to our Patent Specification No. 5^05^ which describes and claims a related class of compounds.

The compound of the invention may be produced by condensing indol-3-yl carboxylic acid or a reactive derivative thereof, with endo-8-methyl- 8-aza-bicyclo[3.2.1]oct-3-ol, and recovering the resultant ester in free base form or in acid addition form.

The condensation process may be effected in conventional manner for analogous compounds.

For example the carboxylic acid group may be activated in the form of a reactiva acid derivative.

Suitable reactive acid derivatives may be formed by reaction vith 25 N,N'-carbonyl-diimidazol® producing an intermediate carboxylic acid imidazolide, or with N-hydroxy-succinimide. Alternatively an acid chloride may be used, e.g. produced by reaction vith oxalyl chloride.

For production of esters, the alcohol may be used, e.g. in the form of an alkali metal salt, preferably the lithium salt. Such salts may be produced in conventional manner, e.g. by reaction of n-butyl lithium vith the alcohol in the tetrahydrofuran. If desired, a heterocyclic or tertiary amine, e.g. pyridine or triethylamine, may be present. 35 Suitable reaction temperatures may be from about -10 degrees Centi-2- grade to about 10 degrees Centigrade. 10 15 20 i 25 30 4 35 $ V Suitable inert organic solvents include, e.g. tetrahydrofuran or dime-thoxyethane.

The alcohol may be reacted if desired as a mixture of endo and exo isomers and the pure endo or exo isomer isolated, e.g. by chromatography or crystallization.

The compound of the invention may be isolated and purified in conventional manner.

Insofar as the production of any starting material is n©tparticularly described herein, it is known, or may be produced in analogous manner to that described herein, e.g. the examples, or to known procedures for analogous manner.

Any mixture of the exo and endo forms may be separated by chromatography.

The free base form of the compound of tha invention may-.ae converted into acid addition salt forms. For example, acid addition salts may be produced from the free base forsi in conventional manner by reacting vith a suitable acid, and vice versa. Suitable acids for salt formation include hydrochloric acid, malonic acid, hydrobromic acid, maleic acid, malic acid, fumaric acid, methanesulphonic acid, oxalic acid, and tartaric acid.

In the following examples all temperatures are in degrees Centigrade and are uncorrected. All n.m.r. spectra values are in ppm (tetrame-thylsilane - 0 ppm). -3- Nomenclature Endo-8-methyl-8-aza-bicyclo(3.2.1 Joc.t-3 -yl = tropyl or alfa-tropyl.

EXAMPLE; IndoI-3-yl carboxylic acid endo-8-methyI-8-aza-bicyclo-[3.2.1]oct-3-yl aster 6.35 g (4b mM) endo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl (Tropine) in 20 ml absolute tetrahydrofuran are treated at 0 degrees Centigrade to 10 10 degrees Centigrade with 17 ml of a 2 molar solution of butyl lithium in hexane. The mixture is stirred for a further 30 minutes. The hexane is removed under a vacuum and replaced by a corresponding amount of tetrahydrofuran to give the lithium salt. i 4-8 g (27 mM) of indol-3-yl carboxylic acid chloride in 20 ml tetrahydrofuran are added to the mixture and the beige suspension stirred overnight at 20 degrees Centigrade. The mixture is worked up in the usual manner partitioning between methylene chloride and sodium carbonate to give the heading compound in crude form which is ehromato-2Q graphed on silicagel (250 g) eluting the heading comopund with methylene chloride containing 10% methanol and 0.5% ammonia. M.pt. 201-202 degrees Centigrades (methylene chloride/ethyl acetate). M.pt. 283-285 degrees Centigrade (decomp.) - hydrochloride salt.

Alternatively indol-3-yl carboxylic acid chloride may be reacted with N,N'-carbonyl di-imidazole to form the imidazolide. This may be reacted with the above lithium salt at 10 to 15 degrees Centigrade in tetrahydrofuran. 20 The compound of the invention exhibits pharmacological activity.

In particular the compound of the invention exhibits serotonin M receptor antagonist activity as indicated in standard tests. For example, in one test the action of the compound in inhibiting the 35 action of serotonin in reducing the amplitude of the compound action potential from the isolated rabbit vagus nerve was observed according -4- to the principles of Riccioppo Neto, European Journal of Pharmacology (1978), 49 351-356, under conditions permitting differentiation between action potentials generated in myelinated nerve fibres (A fibres) and those generated in small non-myelinated fibres (C fibres) 5 as described by B.Oakley and R.Schafer, Experimental Neurobiology, A Laboratory Manual, University of Michigan Press, 1978, p.85 to 96. Serotonin itself exerts its effect selectively on the C fibres and reduces the amplitude of the action potential in these fibres ; ! progressively with dosage. This action of serotonin is not blocked by 10 the known serotonin antagonists, metitepine, methysergide, BOL-148, which have been said to block D receptors for serotonin, but not H receptors (see Gaddam and Picarelli,Brit.J.Pharmacol. (1957), 12, 323-328). It therefore appears that serotonin reduces the amplitude of the action potential carried by the C fibres through an effect . 15 mediated by M receptors for serotonin which are located on these nerve fibres.

The test may be effected by establishing a dose response curve for serotonin (10_1 - 5 x 10"® H) after setting up the nerve. Tlie 20 serotonin is washed out and when the C fibre action potential has regained its original amplitude the compound of the invention at a set concentration of from about 10"11 M to about 10~6 M is preincubated with the nerve for 30 to 60 minutes. Varying concentrations of serotonin (10"7 to 10"4 M) are then applied with the compound of the 2g invention at the concentration as was present during the preincubaied period.

The M receptor antagonist of the invention either entirely blocks tlie action of serotonin (non-competitive antagonist) and at low doses 30 causes a parallel shift of the serotonin/dose response curve to the right (i.e. increased concentrations ot serotonin were required^ foi effect) (competitive antagonist). The pD'2 or pA2 value may be ; obtained in conventional manner. i 35 The serotonin H receptor antagonist activity is also indicated by inhibiting the effect ot serotonin on the isolated rabbit heart -5- according to the method of J.R.Fozard and A.T.Moborak Ali, European Journal of Pharmacology, (1978), 49, 109-112 at concentrations of 10"11 to 10*5 H of the compound of the invention. pD'2 or pA2 values may be calculated in the conventional manner. 5 The serotonin M receptor antagonist activity is furthermore indicated in the cantharidine blister base test at a concentration of about 10~e M. A blister is produced on the skin of the forearm of human volunteers vith cantharidine. When serotonin is dpplied to the base of 10 such blisters it produces pain which can be measured, the intensify being proportional to the concentration of serotonin applied. The procedure has been described by C.A. Keele and D.Armstrong in Substances producing Pain and Itch, Edward Arnold, London, 1964, p. 30 to 57. This algesic action of serotonin is not inhibited by the 15 serotonin D receptor antagonists such as lysergic acid diethylamide or its bromo derivative and is therefore believed to be mediated by M receptors.

In the procedure followed the area under the curve instead of the peak 2q amplitude is measured by a linear integrator coupled to a pain inten sity Indicator which is operated by the volunteer. Vith increasing concentrations of serotonin a cumulative dose-response curve to serotonin may be obtained. When no further response on increasing the serotonin concentration is obtained, the serotonin is washed off and the blister incubated with physiological buffer solution for at least 40 minutes before the compound of the invention is applied. The test substance is preincubated with the blister base for 30 minutes at a concentration of about 10"° H before varying concentrations of serotonin are applied. A pA2 value may be obtained in conventional 30 manner.

The compound of the invention is therefore indicated for use as a serotonin M receptor antagonist, e.g. for the treatment of pain, e.g. migraine, vascular and cluster headaches and trigeminal neuralgia and 35 also for the treatment of heart circulation disorders, e.g. for the prevention of the syndrome known as sudden death, and possibly as an -6- anti-psychotic.

An indicated daily dose is from about 6 to SO mg conveniently administered individed doses in unit dosage form 2 to 4 times a day containing from about 2 to about 25 mg of the compound or in sustained release form.

A compound of the invention furthermore exhibits anti-arrhythmic activity as indicated by their serotonin H receptor antagonist activity and in standard tests. For example the compound inhibits arrhythmias induced by norepinephrine (3 to 10 microgram/animal body weight) are given until an arrhythmic phase as indicated by ECG measurements lasts longer than 10 seconds duration. After control of 3 consecutive injections of norephinephrine the compound of the invention is injected at from about 10 to about 500 microgram/kg animal body weight followed by norepinephrine injections. The arrhythmic phase is reduced, or abolished depending on the dose of test compound.

The compound of the invention is therefore indicated for use as an anti-arrhythmic agent. An indicated daily dose is from about 10 to about 30 mg conveniently administered orally or by injection in divided doses 2 to 4 times a day or in unit dosage form containing from about 2 to about 15 mg, or in sustained release form.

The compound of the invention may be administered in free base form, or in pharmaceutical^ acceptable acid addition salt form. Such salts exhibit the same order of activity as the free bases. The present invention accordingly also provides a pharmaceutical composition comprising a compound of the invention in free base form or in acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be for example a solution or a tablet. -7-