NO133072B - - Google Patents

Description

The present invention relates to the production of new

therapeutically active aminoalkynylsuccinimide derivatives of the formula:

and physiologically acceptable salts thereof, where n is the number 6 or 7 and A is

when n is 6 and - CE^- CE^- when n is 7•

According to the invention, the following wood is thus produced

connections:

For years, N-(4-pyrrolidino-2-butynyl)-pyrrolidone-(oxotremorine) has been used to induce tremors and convulsions in several types of laboratory animals.

Oxotremorine develops violent tremors, convulsions, hypokinesia and parasympathomimetic effects immediately after an intravenous injection. The compound thus produces both central and peripheral cholinergic reactions.

A number of compounds such as atropine and caramifen are known to antagonize oxytremorin-induced convulsions, but these also have the side effect of antagonizing the peripheral cholinergic effects of oxytremorin. The peripheral cholinergic effects can conveniently be measured by observing pupil dilation. The mydriatic effect is therefore often taken as an appropriate index of the degree to which a given compound will antagonize the peripheral cholinergic effects of octotremorine. The ratio of tremorolytic activity to mydriatic activity is an index of the compounds' specificity.

In order to illustrate the therapeutic effect of compounds of formula I, comparison experiments were carried out using previously known compounds, and experiments were carried out with regard to antitremor dose in mice. The compound of formula I used was N-(1-methyl-yl-perhydroazepino-2-butynyl)-succinimide (compound A), while the known compounds were N-(1-methyl-M-piperidino-2 -butynyl)-succinimide (compound B) and N-(1-methyl-4-pyrrolidino-2-butynyl)-succinimide, compound C).

The antitremor dose in mice was determined using the experimental method set forth in Example 22 of US Patent No. 3,444,171. The concentration of the test compound required to reduce the oxotremorine-induced tremor index by one unit as described in said patent was determined. The method consists of giving groups of 5 male mice, each weighing 18-22 g, intra-peritoneal injections of the test compounds in a volume not exceeding 10 mg/kg in a series of doses that increase by a factor of 2 after each step..Oxotremorine was then injected intravenously in a dose of 150 ug/kg and after 15-20 min. the tremor intensity was judged visually according to the scale given in the said patent. Tremors that were continuous and immobilized the animals were given 4 points. Tremors that were intermittent but occurred most of the time were given 3 points. Tremors that were intermittent and sporadic were given 2 points, while tremors that did not occur spontaneously but appeared under duress were given 1 point, and in cases where no tremors were observed, the value was set to zero. The mean results were calculated for each group of 5 mice. All the test compounds were tested until each was used at a dose that would produce an oxotremorine-induced tremor of 3. The experiment was repeated using a larger dose of the test compound to reduce the tremor index by one unit, so that a tremor was observed that gave 2 points. The table below indicates the antitremor dose in mice for each of the test compounds required to produce a reduction in the tremor index of one unit.

These experiments show that the compound produced according to the present invention has an antitremor dose which is considerably less than that of the known compounds, and thus much more advantageous.

It has unexpectedly been found that the new compounds of formula I have high specificity as antagonists for the tremoromimetic effects of oxotremorine, i.e. that they are characterized by only weak peripheral anti-cholinergic effects as indicated by the mydriatic effect.

The compounds block the central cholinergic effects produced by oxotremorine, e.g. motor disturbances, in the same low dose as atropine, but the effects on the peripheral cholinergic symptoms are far less prominent, which means that the compounds have a high degree of specificity as centrally acting anti-cholinergic agents.

In order to achieve a central anti-cholinergic effect, it is necessary that the compounds are able to penetrate into the brain. Consequently, when they are used as oxotremorine antagonists, they should therefore be in the free base form. However, it is obvious that non-toxic addition salts can be appropriately used in the preparation of the compounds in order to thereby simplify the process for their preparation, e.g. by a fractional crystallization.

Typical acid addition salts are therefore included in the present invention. Such salts include, for example, hydrogen halides, especially hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid and succinic acid, and of these, hydrochloric acid and hydrobromic acid are preferred due to their easy availability.

It dare be'well known that the tremoromimetic effect

by oxotremorine has been proposed as a pharmacological model of Parkinson's disease. The fact that the compounds of formula I have

high specificity as antagonists against the tremoromimetic effect of oxotremorine thus indicates that they can be used for the treatment of Parkinson's disease.

According to the present invention, the compounds of formula I are prepared by

a) reacts an acetylenic succinimide with the formula:

with formaldehyde and an amine of the formula: for the formation of a compound of formula I, in which formulas A and n have the meanings given above, or b) reacts succinic acid or a functionally equivalent derivative thereof, such as its acid chloride, anhydride or mixed

anhydride, with an acetylenic diamine of the formula:

for the formation of a compound of formula I, in which formula A and n have the meaning indicated above, or

c) ring-closing a succinic acid with the formula:

for the formation of a compound of formula I, in which formula A and

n has the above meaning, or

d) reacts succinimide or a reactive derivative thereof, such as a metal salt, with a compound of the formula:

for the formation of a compound of formula I, in which formula A and n have the meaning given above and X is a halogen atom,

and, if desired, converts a product obtained according to a), b), c) or d) into a physiologically acceptable salt thereof.

The following examples illustrate the invention.

Example 1

Preparation of N-(1-methyl-4-perhydroazepino-2-butynyl)succinimide

A mixture of N-(1-methyl-2-propynyl)succinimide (0.1 mol), paraformaldehyde (0.12 mol), perhydroazepine (cyclohexamethyleneimine)

(0.11 mol) and copper chloride (0.2 g) in 20<*>ml of dioxane were refluxed for one hour. After cooling, 100 ml of water was added, and the mixture was acidified with 5 molar HCl and extracted with 50 ml of ether. The aqueous phase was made alkaline with 1-molar Na 2 CO 3 under cooling and extracted with 6-50 ml portions of CHCl 2 . The extract was dried over Na 2 SO 4 and the solvent evaporated under vacuum.

The oily reaction product was purified by chromatography on an Al 2 O 4 column and was further characterized as the oxalate.

This salt melted at 113-115°C after recrystallization from ethanol-ether.

The following was prepared in a similar manner: N-(1,1"dimethyl-4-perhydroazepino-2-butynyl)xuccinimide oxalate, melting point 144-146°C, N-(1,1-dimethyl-4-perhydroazocino-2- butynyl)succinimide oxalate, melting point 122-124°C,

N-(5-perhydroazepino-3-pentynyl)succinimide oxalate, melting point 84-86°C, and

N-(5-perhydroazocino-3-pentynyl)succinimide oxalate, melting point 140-14.2°C.

Example 2

Preparation of N-6-perhydroazepino-4-hexenyl)succinimide

A solution of 0.05 mol of 6-perhydroazepino-4-hexynylamine in 10 ml of acetone was added dropwise to a boiling solution of 0.05 mol of succinic anhydride in 50 ml of acetone. The solution was refluxed for one hour, after which the acetone was distilled off. The residue, N-(6-perhydroazepino-4-hexynyl)succinamic acid, was mixed with 2.6 g of anhydrous sodium acetate and 25 ml of acetic anhydride, and the mixture stirred at 70°C for one hour. 50 ml of ice water was added and the mixture was left overnight at room temperature. The solution was extracted with ether, and the aqueous layer made alkaline with NaOH under cooling. The mixture was extracted with 4.20 ml portions of C-HClj and the extract dried over Na2SOi). The solvent was evaporated, and the oily product was purified by chromatography on alumina and characterized as the oxalate, which melted at 118-119°C after recrystallization from ethanol-ether.

N-(6-perhydroazocino-4-hexynyl)succinimide oxalate, melting point 113-H5°C, was prepared in a similar manner.

Example 3

Preparation of N-(1,1-dimethyl-4-perhydroazepithio-2-butynyl)succinimide

A solution of 2-amino-5-perhydroazepino-2-methyl-3-pentyne (0.05 mol) in acetone (10 mL) was added dropwise to a refluxing solution of succinic anhydride (0.05 mol) in 50 mL of acetone. The solution was refluxed for one hour and acetone was distilled off. The residue, N-(4-perhydroazepino-1,1-dimethyl-2-butynyl)succinamic acid, was mixed with anhydrous sodium acetate (2.6 g) and acetic anhydride (25 ml) and the mixture was stirred at 70°C for one hour. Ice water (50 mL) was then added and the mixture was left overnight at room temperature. The solution was extracted with ether and the aqueous layer was made alkaline with NaOH while cooling. The mixture was extracted with 4-20 ml portions of CHCl 4 and the extract was dried over Na 2 SO 4 . The solvent was evaporated and the oily reaction product was purified by chromatography on alumina and was characterized as the oxalate, which melted at -144-146°C after recrystallization from ethanol-ether.

Example 4

Preparation of N-(1-methyl-4-perhydroazepino-2-butynyl)succinimide

7.0 g of N-(1-methyl-4-perhydroazepino-2-butynyl)-succinamic acid, 1.5 g of anhydrous sodium acetate and 15 ml of acetic anhydride were mixed and heated to 70°C with stirring for one hour. After cooling, 25 ml of ice water was added and the mixture was left overnight. The aqueous phase was extracted with ether (2 x 20 mL), after which it was made alkaline under cooling with NaOH. The alkaline aqueous phase was extracted with chloroform (4 x 20 mL) and the chloroform extract was dried over sodium sulfate. After evaporation of the solvent in vacuo, the oily reaction product was purified by chromatography

on aluminum oxide. The product was characterized by transfer to oxalate with melting point 113-H5°C (after recrystallization from ethanol-ether) and to perchlorate with melting point 165-167°C (after recrystallization from ethanol).

Example 5

Preparation of N-(5-perhydroazocino-3-pentynyl)succinimide

To a suspension of sodium hydride (0.1 mol) in dimethylformamide (30 ml) succinimide (0.1 mol) dissolved in 35 ml of dimethylformamide was added. The mixture was stirred under hydrogen gas at 100°C for 4 hours, after which 5-perhydroazocino-3-pentynyl bromide (0.12 mol) was added and stirring continued for another hour. The reaction mixture was then filtered and the solvent distilled off in vacuo. The residue was dissolved in ether and passed through an alumina column. The ether was evaporated, after which the oily reaction product was transferred to oxalate, melting point 140-142°C after purification by recrystallization from ethanol-ether.

In the following table, the central and peripheral anti-cholinergic effects in mice for certain compounds of formula I are compared with the corresponding effects for atropine and benzhexol, two standard agents in the treatment of Parkinson's disease. As a standard for the central effect, the dose in mg/kg that inhibits the effect of 150 ug/kg of oxotremorine by intravenous administration is stated. This "tremorolytic" dose is designated T. As a standard for the peripheral effect, the dose of the compound in mg/kg which doubles the diameter of the pupil is given. The "mydriatic" dose is designated M. The ratio between M and T constitutes a standard for it

■specific central effect for the compound, and a higher value for M/T corresponds to a higher specificity.

In those cases where optical isomers are possible, it is obvious that the production of these is also covered by the present invention.

Por a compound with the formula:

the following pharmacological data have been found:

Claims (1)

Analogous process for the preparation of therapeutically effective aminoalkynylsuccinimide derivatives with the formula: and physiologically acceptable salts thereof, where n is the number 6 or 7 and A is when n is 6 and -CH^-CH,,- when n is 7, characterized by a) reacting an acetylenic succinimide with the formula: with formaldehyde and an amine with the formula: for the formation of a compound of formula I, in which formulas A and n have the above meaning, or b) reacts succinic acid or a functionally equivalent derivative thereof, such as its acid chloride, anhydride or mixed anhydride, with an acetylenic diamine of the formula: for the formation of a compound of formula I, in which formulas A and n have the meaning indicated above, or c) ring-closing a succinic acid with the formula: for the formation of a compound of formula I, in which formulas A and n have the meaning indicated above , or d) converts succinimide or a reactive derivative thereof, such as a metal salt, with a compound of the formula: for the formation of a compound of formula I, in which formula A and n has the above meaning and X is a halogen atom, and, if desired, conversion of a product thus obtained into a physiologically acceptable salt thereof.