DK172558B1 - The hydrochloride salt of endo-8-methyl-8-aza- bicyclo[3.2.1]oct-3-yl indol-3-ylcarboxylate, and pharmaceutical preparation comprising this salt - Google Patents

Description

DK PR 172558 B1

The present invention relates to the hydrochloride salt of indol-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl ester and a pharmaceutical composition containing it.

5 In the following example, all temprature is uncorrected.

All NMR spectrum values are in ppm (tetramethylsilane = 0 ppm).

The configurations of the title compound in the example have been confirmed by X-ray analysis.

EXAMPLE

Indol-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo [3.2.1] -oct-3-yl ester 6.35 g (45 millimoles) of endo-8-methyl-8-aza -bicyclo [3.2.1] -octan-3-ol (Tropin) in 20 ml of absolute tetrahydrofuran is treated at 0 ° C to 10 ° C with 17 ml of a 2 M solution of butyllithium in hexane. The mixture is stirred for an additional 30 minutes. The hexane is removed under vacuum and replaced with a corresponding amount of tetrahydrofuran to give the lithium salt.

4.8 g (27 millimoles) of indol-3-yl carboxylic acid chloride in 20 ml of tetrahydrofuran are added to the mixture and the beige colored suspension is stirred overnight at 20 ° C. The mixture is worked up in the usual manner by partitioning between methylene chloride and sodium carbonate to give the title compound in crude form which is chromatographed on silica gel (250 g) eluting the title compound with methylene chloride containing 10% methanol and 0.5% ammonia. Melting point 201-202 ° C (methylene chloride / ethyl acetate).

2 DK PR 172558 B1

Melting point 283-285 ° C (dec.) Of the hydrochloride salt. Methioiodide melting point 285-287 ° C (dec.).

Alternatively, indol-3-yl-carboxylic acid chloride may be reacted with 5 N, N'-carbonyl-diimidazole to form the imidazolid. This can be reacted with the above lithium salt at 10-15 ° C in tetrahydrofuran.

The compound of the invention exhibits pharmacological action and is therefore useful as a drug, e.g. for therapy.

In particular, the compound exhibits serotonin-M receptor antagonist activity, as shown by standard tests. Eg. In one test, the effect of the compound was observed by inhibiting the action of serotonin by reducing the amplitude of the total action potential of the isolated rabbit vagus nerve according to the principles described by Ricciop-po Neto, European Journal and Pharmacology, (1978) 49, 351 -356, under conditions that allow differentiation 20 between action potentials generated in myelinated nerve fibers (A fibers) and those generated in small non-myelinated fibers (C fibers) as described by B. Oakley and R. Schater, Experimental Neurobiology, A Laboratory Manual, University and Michigan Press, 1978, pp. 85-96. Serotonin itself selectively exerts its effect on the C fibers 25 and progressively reduces the amplitude of the action potential of these fibers relative to dose. This effect of serotonin is not blocked by the known serotonin antagonists, namely metitepin, methysergide, BOL-148, which is said to block D receptors for serotonone but not M receptors (cf. Gaddam and Picarelli, Brit. J. Pharmacol.

(1957), 12, pp. 323-328). Therefore, it appears that serotonin reduces the amplitude of the action potential carried by the C fibers through an effect mediated by M-DK PR 172558 B1 3 receptors for serotonin located on these nerve fibers.

The test can be performed by establishing a dose-response curve 5 for serotonin (10'7 - 5 x 10 "* M) after the nerve is set up. the invention at a fixed concentration of from about 10'1 * M to about 10 '* M for 30-60 10 minutes. Varying concentrations of serotonin (10 "7 to ΙΟ" 4 M) are then applied to the compound of the invention at the concentration present during the preincubation period.

The 15 M receptor antagonist of the invention either completely blocks the action of serotonin (non-competitive antagonist) or causes a parallel shift of the serotonin / dose response curve to the right (i.e., increased concentrations of serotonin are required for action) (competitive an-20 antagonist). The pD'2 or pA2 value can be obtained by conventional means.

The serotonin M receptor antagonist effect is also indicated by inhibiting the action of serotonin on the isolated rabbit heart according to the method described by J.R. Fozard and A.T.

Moborak Ali, European Journal of Pharmacology, (1978) 49, 109-112 at concentrations of from 10'11 to 10 "M of the compound of the invention. PD'2 or pA2 values can be calculated in a conventional manner. The pA2 value for the compound 30 of the invention is 10.2.

4 DK PR 172558 B1

The effect of the compound as a serotonin M receptor antagonist in the treatment of analgesia is confirmed by the efficacy of the hot plate test at a dose of from ca. 0.1 to 100 mg / kg subcutaneously or orally.

5

The serotonin M receptor antagonist effect is also indicated in the cantharidine wafer base test at concentration of 10 'M. With cantharidine, a worm forms in the skin of the forearm of volunteers. When applied to such blisters, serotonin produces pain that can be measured, the intensity 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", Edvward Arnold, London, 1964, pp. 30-57. This algesic effect of serotonin is not inhibited by serotonin D receptor antagonists such as lysergic acid diethylamide or its bromine derivative, and is therefore believed to be mediated by M receptors.

In the procedure followed, instead of the peak amplitude, the area under the curve is measured by a linear integrator coupled to a pain intensity indicator operated by the volunteer. With increasing concentrations of serotonin, a cumulative dose-response curve for serotonin can be obtained. When no further response is obtained by increasing the serotonin concentration, the serotonin is washed off and the blister is 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 base of the wafer for 30 minutes at a concentration of approx.

o 10 M before varying concentrations of serotonin are applied. A pA2 value can be calculated in conventional manner. The pA2 value of the compound of the invention is 10.6.

DK PR 172558 B1 5

Therefore, the compound of the invention is indicated for use as a serotonin M receptor antagonist, e.g. in the treatment of pain, especially migraine, vascular and cluster headaches, and trigeminal neuralgia and also in the treatment of cardiovascular disease 5, e.g. in the treatment of sudden death, and possibly as anti-psychotic agents.

An indicated daily dose is from approx. 0.5 to 500 mg conveniently administered in divided doses in unit dosage form 2-4 10 times daily containing from ca. 0.2 to approx. 250 mg of the compound, or in sustained release formulation.

Furthermore, the compound of the invention exhibits antiarrhythmic activity as indicated by its serotonin M-15 receptor antagonist activity and in standard tests. Eg. The compound prevents arrhythmia induced by norepinephrine in anesthetized rats. In this test, infusions of norepinephrine (3-10 pg / kg animal body weight) are given until an arrhythmic phase, which in ECG measurements is shown to last 20 longer than 10 seconds. After controlling for three consecutive injections of norepinephrine, the compound of the invention is injected at doses of from 10 to approx. 500 µg / kg animal body weight followed by norepinephrine injections. The arrhythmic phase decreases or disappears depending on the dose of the test compound.

The compound is therefore indicated for use as antiarrhythmic agents. An indicated daily dose is from approx.

0.5 to approx. 500 mg, orally or preferably administered by injection in divided doses 2-4 times daily or in unit dosage form containing from ca. 0.2 to approx. 250 mg, or in prolonged-release formulation.

DK PR 172558 B1 6

Thus, the compound of the invention can be used as a pharmaceutical agent, especially for use as serotonin M antagonist in those diseases where blocking of serotonin M receptors is expected to have beneficial effects, e.g. as an analgesic, especially as an anti-migraine agent and as an anti-arrhythmic agent.

The preferred use is the analgesic use.

The invention also provides for a pharmaceutical composition comprising the hydrochloride salt of indol-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl ester in combination with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner and may e.g. be a solution or tablet.

Claims (2)

1. The hydrochloride salt of indol-3-yl-carboxylic acid endo-8- 5 methyl-8-aza-bicyclo [3.2.1] oct-3-yl ester. A pharmaceutical composition comprising the hydrochloride salt of indol-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo- [3.2.1] oct-3-yl ester in combination with one or more pharmaceutically acceptable carriers or diluents . 10