Quinuclidine derivatives

(54) Name: Process for the preparation of 6-oxa-1-azatricyclo (4.2.2.02'7) dodecan-5-one _{me C}| therapeutic effect (56) Published publications: -

8003351-7

The present invention relates to a process for the preparation of novel heterocyclic compounds of the general formula

<img file="SE435929B_D0001.tif" />

where R is phenyl, methylphenyl, methoxyphenyl or chlorophenyl, and physiologically acceptable salts thereof.

These compounds include the conjugated quinuclidine-valerolactone system, 6-oxa-1-azatricyclo (4.2.2.0 ') dodecan-5-one. Furthermore, various stereoisomers and optically active isomers of these compounds and salts thereof are included.

Examples of physiologically acceptable salts include hydrochlorides, sulfates, methanesulfonates and salts with organic acids.

The novel compounds of formula I are prepared according to the invention by adding 2-methylene quinuclidin-3-one of formula O (II)

<img file="SE435929B_D0002.tif" />

is reacted with an alkylaryl acetate of the formula

R - CH₂ - COOR 3 (III) where R is as defined above and represents an alkyl group, in the presence of a sodium alkoxide to form a compound of formula (IV)

<img file="SE435929B_D0003.tif" />

Wherein R and R have the meanings given above, after which this compound is reduced by sodium borohydride to the corresponding hydroxy compound of the formula

0H

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R (V)

8003351-7 where R and have the above meanings, after which this compound is cyclized by treatment with a concentrated mineral acid, whereupon the resulting solution of formula I is optionally converted to a physiologically acceptable salt thereof.

Examples of starting materials of formula III include ortho, meta and parasubstituted esters of phenylacetic acid such as ethyl p-methylphenyl acetate and ethyl m-methoxyphenyl acetate.

The novel compounds of formula I and their physiologically acceptable salts can be used as active ingredients in pharmaceutical compositions. The compounds can be used to relieve the manifestations of Parkinson's disease. Furthermore, the compounds are generally psychomotor stimulants, and are therefore of particular value in geriatrics. The new compounds can be used in the treatment of diseases that cause impaired mobility, and they can be used in ophthalmology such as mydriatics. Furthermore, the compounds can be used in smoking cessation to relieve any withdrawal symptoms. Moreover, the new compounds are effective waking agents and can therefore be used in combination with barbiturates. Furthermore, the compounds can be used to counteract the drowsiness caused by antihistamines and similar drugs.

The new compounds can also be used in the treatment of hyperkinesia in children, in the treatment of narcolepsy, in the treatment of mental depression of organic origin and in the treatment of obesity.

The dose used of the new compounds is usually between 10 and 100 mg / day for adults. The administration can e.g. by injection, when the compounds are used in the form of compositions containing suitable diluents or carriers. The compounds may also be given orally or in the form of suppositories. The administration can also be done in some other usual way, such as by infusion etc.

The novel compounds of formula I are of particular value when used in combination with antihistamines, which are taken during the daytime, since such a combination does not make the treated person sleepy.

When used for ophthalmological purposes, the compounds are suitably used in a conventional carrier or buffer. The concentration of the active compound may vary depending on the desired effect, but the concentration of the active compound is usually between 2 and 10% by weight.

0003351-7

The invention also encompasses the preparation of stereoisomers and optically active isomers of the compounds defined above. In the novel compounds of formula I, the isomerine is dependent on the asymmetric carbon atoms in the 2-, 4- and 7-positions.

The invention is illustrated by the following examples.

Example 1. 49.2 g of ethylphenyl acetate was added to a sodium ethoxide solution prepared from 2.9 g of metallic sodium and 100 ml of ethanol. The resulting mixture was cooled to 5 ° C, then added dropwise and with stirring, a solution of 39.4 g of 3-methylene quinuclidine.

3 oz in 50 ml of ethanol. After 16 hours at room temperature, the solution was neutralized with acetic acid, then evaporated under reduced pressure. 100 ml of water was added to the residue and the resulting mixture was extracted with chloroform. After evaporation of the chloroform, 54 g (60%) of ethyl (3-oxoquinuclidin-2-yl) methylphenyl acetate was obtained which had a boiling point of 195 ~ 200 ° C at 1 mm Hg. The compound's methyl iodide salt melted at 194.7-195.6 ° C.

22.4 g of the above compound were dissolved in 100 ml of ethanol and the resulting solution was treated at 5 ° C with a solution of 1.2 g of sodium borohydride in 200 ml of ethanol. The borohydride solution was added in small portions over a period of 6 hours. After 20 hours, the mixture was neutralized with concentrated hydrochloric acid, then evaporated under reduced pressure, the residue was taken up in 200 ml of water and extracted with chloroform. After evaporation of the chloroform, 19.5 g (80%) of ethyl (3-hydroxyquinuclidin-2-yl) methylphenyl acetate was obtained, which after recrystallization in acetone had a melting point of 147.7-148.2 ° C.

A mixture of 16.9 g of the above-obtained compound, 100 ml of concentrated hydrochloric acid and 30 ml of water was refluxed for 20 hours. After evaporation of the solvent under reduced pressure, a vitreous residue was obtained which was dissolved in 50 ml of water. The resulting solution was neutralized with sodium bicarbonate and extracted with chloroform. After evaporation of this solvent, a residue was obtained which was ripped with petroleum ether. To give 2.7 g (18 µ) of crystalline 4-phenyl-6-oxa-1-azatricyclo (4.2.2.0^2,) dodecan-5-one having a melting point of 162-163 ° C.

Examples 2-4. In the same manner as in Example 1, the compounds listed below were prepared.

4- p-methylphenyl-6-oxa-1-azatricyclo (4.2.2.0²- dodecane-5-one hydrochloride; melting point above 300 ° C;

4-p-chlorophenyl-6-oxa-azatricyclo (4.2.2.0²8003351-7 dodecane-5-one hydrochloride; melting point above 300 ° C

4-m-methoxyphenyl-6-oxa-1-azatricyclo- (4.2.2.0^2j7) dodecan-5-one; mp 144.8 ° C.

The acute toxicity of the new compounds has been determined by the method described by Litchfield et al., J. Pharmacol. Exp. Ther. 96, 39 (1949) · In each experiment at least five groups of 6 mice were used for each dose, and the value of LD 2 was determined with a confidence interval of - 95 $. values ​​of between 75 and 275 mg / kg of body weight have been obtained.

In guinea pig ileum experiments, the peripheral antimuscarinic activity of the new compounds was determined by the cumulative dose method described by Kuhnen-Klausen, Toxicol. App. Pharmacol. 23, 443 (1972).

The antagonism activity of the compounds against oxotremorin has been determined according to the method described by Brinclecombe et al., J. Pharm. Pharmacol. 23, 745-757 (1971).

The new compounds can prevent tremors in mice by intraperitoneal administration of 200 µg oxotremorin per mouse. The effective dose of ED_cn for subcutaneous administration is 6 mg / kg for the compound I wherein R is phenyl. The therapeutic index in this case is between 25 and 50. The equipotent molar ratio to atropine is 10: 8. Compared to atropine, the peripheral anti-cholinergic action of the novel compounds of formula I is negligible. In preventing the contraction of marin ileum, the following equipotent molar ratio is obtained: Atropine 1; compound I, where R is phenyl, 9000. The central effect of the new compounds is thus much more pronounced than their peripheral effect. The ratio of central to peripheral effect is for atropine 1:35, while this ratio is 3: 1 for the novel compounds of formula I; as determined by Inch et al., J. Pharm. Pharmacol. 25, 359 (1973).

Among the other effects of the new compounds can be mentioned rapid pupil enlargement in local application of solutions to the eye. For example, when a 2 $ solution is applied to a rabbit eye, a beginning pupil enlargement is obtained after 8-10 minutes, and the effect lasts for about 1 hour. When the new compounds are injected into mice, they produce a slight increase in temperature (not exceeding +0.8 C), and the temperature increase reaches a maximum after 20 minutes. Furthermore, increased psychomotor activity has been observed after administration

8003351-7 to mice. An enhancement of the action of nicotine has been demonstrated after the application of the new compounds to the upper neck ganglion of cats. Formation of muscle bundles of striated muscles is induced only by the administration of very high doses, close to the lethal dose.