NO141985B - PROCEDURE TO AA CONNECT THE END OF TRANSPORT BANDS - Google Patents

Description

Process for the preparation of therapeutically effective spiro-(piperidyl-4)-succinimides.

The invention relates to a process for the preparation of new spiro-(piperidyl-4)-succinimides with the general formula I

their salts with inorganic and organic

acids. In formula I, R means a hydrogen atom,

a lower alkyl residue or the benzyl residue and R.,

means a hydrogen, fluorine, chlorine or

bromine atom, or a lower alkyl or

alkoxy group.

According to the invention, the compounds of formula I are obtained by a substituted succinimide of the general formula II

where R has the same meaning as above is reacted with a compound of the general formula III

where R 1 has the same meaning as above, in the presence of an alkaline condensing agent, preferably in the presence of another mole of the base II.

The compounds of formula I have not previously been described in the literature. At room temperature, they are colourless, solid crystallized compounds that dissolve easily in the usual organic solvents, e.g. methanol, ethanol, acetone, benzene, etc. Together with inorganic and organic acids, they form permanent salts that are crystallized at room temperature.

The new substances are partly distinguished by valuable pharmacodynamic properties, particularly by peripheral and central effects on the nervous system, e.g. painkillers, potentiation of anesthesia and increase of the cramp threshold. Furthermore, the substances inhibit the conditioned flight reaction in the rat, as well as the emotional reactions that occur during stress. Likewise, they inhibit the spontaneous activity of mice as well as the arousal state produced in animals by amphetamine ingestion. Some compounds can be used therapeutically, especially as neuroleptics in the treatment of the most diverse arousal syndromes, others are suitable as intermediates in the production of new pharmacodynamically interesting compounds.

The partially as yet unknown starting products with formula III can, for example, be prepared in the following way: 800 cm<3> abs. toluene and 141 g of aluminum chloride (1.06 mol) are mixed in a flask and brought to a temperature of 15° C by cooling in ice water. Then, while cooling in ice water, 141 g (1 mol) of y-chlorobutyric acid chloride is added dropwise so quickly that tem- the temperature 15-20° is not exceeded. The addition requires approx. 20 min. The stirring is continued for a further 20 min. at this temperature and the reaction mixture is poured onto ice. 40 cm<3> conc. is added. hydrochloric acid, cool and extract several times with ether. The combined ether extracts are washed three times with dilute soda solution, dried over calcium chloride and the ether evaporated. After a single distillation in high vacuum, the compound is sufficiently pure for the subsequent reaction. For analysis, still a distillation is carried out in high vacuum. Pure 4-chloro-p-methyl-butyrophenone. boils at 109°/

20

0.07 mm Hg, n D = 1.5414.

If by the reaction described above, instead of abs. toluene is used abs. benzene or anhydrous, differently substituted benzenes, e.g. chloro-, bromo- or tert.-butyl-benzene, anisole or phen-tol, correspondingly substituted 4-chloro-butyrphenones are obtained. With the aforementioned substituents, the reaction of the γ-chlorobutyric acid chloride with the phenyl nucleus always takes place in the p-position.

The succinimides of formula II which are used as starting products can be prepared in the following way: 1-benzyl-4-piperidone is dissolved in an inert organic solvent, e.g. benzene, toluene, xylol, tetralin, etc. together with a cyanoacetic acid alkyl ester in the presence of a water-splitting catalyst or a catalyst mixture, e.g. glacial acetic acid with ammonium acetate, and using a water separator working continuously converted to a (1-benzyl-4-piperidylidene)-cyanoacetic acid alkyl ester. Hydrocyanic acid is added to the double bond of this derivative and the resulting compound is saponified with conc. hydrochloric acid and decarboxylated to the corresponding substituted succinic acid of formula IV This is esterified with an abs. alkanol and hydrogen chloride to corresponding dialkyl esters. The substituted succinic diester becomes, on heating with a nitrogen compound of the formula R,-NH„, e.g. conc. aqueous ammonia or a primary alkylamine, e.g. methylamine, ethylamine, etc., or benzylamine, preferably in a closed vessel, transferred to the desired substituted 8-benzyl^2,8-diazaspiro[4,5]decane-1,3-dione of formula V

For quantitative cyclization, heating is finally carried out to a high temperature, e.g. 180—250° at normal pressure. The compound V is then hydrogenated in a lower aliphatic alcohol with hydrogen in the presence of a palladium catalyst until the hydrogen absorption stops. The succinimide of formula II which is obtained can be purified by distillation in vacuo or by recrystallization of its salts.

In the examples that will now be given of how the method can be carried out, all temperature indications are in degrees Celsius. The melting and boiling points have been corrected.

Example 1: 2-methyl-8-(4'-p-fluorophenyl-4'-oxo-butyl)-2,8-diazaspiro[4,5]decane-1,3-dione.

4.1 g of 2-methyl-2,8-diazaspiro [4,5] decane-1,

3-dione, 4.8 g of 4-chloro-p-fluoro-butyrphenone and 8 g of anhydrous soda were heated for 24 hours

in 50 cm<3> n-butanol to 120°. Decantation was carried out from the soda. Already in the heat, part of the condensation product was precipitated. Hot filtration was carried out, evaporation to dryness and the residue was extracted with ethanol. The ethanol extract was combined with the above filter residue, the substance which was only slightly soluble in all common solvents was overheated with an excess of 2-n. hydrochloric acid and the solution was evaporated in vacuo at 80° to dryness. The remaining residue was first recrystallized from ethanol and then from water. 2-methyl-8-(4'-p-fluorophenyl-4'-oxo-

butyl)-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride melted at 285-286°. The 2-methyl-2,8-diazaspiro[4,5]decane-1,3-dione which was used as starting product was, for example, prepared in the following way: Cyanacetic acid ethyl ester and l-benzyl-4-piperidone were heated under reflux together with a little glacial acetic acid and ammonium acetate in benzene under continuous water separation, during which (1-benzyl-4-piperidylidene)-cyanoacetic acid ethyl ester was formed. Yellow crystals with m.p. 70—71° from ether petroleum ether. By treating the piperidylidene compound with potassium cyanide in aqueous ethanol, prussic acid was deposited on the double bond, the deposition product was saponified with conc. hydrochloric acid and decarboxylated and the substituted succinic acid formed was esterified with abs. ethanolic hydrogen chloride. [ (1-Benzyl-4-ethoxycarbonyl-piperidyl)-4]-acetic acid ethyl ester boiled at 150°/ 0.03 mm Hg (temperature measured in the air bath); slightly yellow colored oil. The diester was heated together with liquid methylamine in a closed vessel to 180°. After cooling, the excess of methylamine was allowed to evaporate and the crystallized residue was heated to 200°, during which methylamine and ethanol were split off during melting. From ethanol, 2-methyl-8-benzyl-2, 8-diazaspiro [4,5] decane-1, 3-dione crystallized in large colorless prisms with m.p. 111-112°. The compound was hydrated in ethanol with hydrogen in the presence of a palladium catalyst on activated carbon at normal pressure and room temperature. 2-methyl-

2,8-diazaspiro[4,5]decane-1,3-dione boiled at 99°/0.02 mm Hg (temperature measured in the air bath). Strongly hygroscopic substance that crystallized in right-angled prisms with m.p. 67°.

Example 2: 2-methyl-8-(4'-p-fluorophenyl-4'-oxo-butyl)-2,8-diazaspiro[4,5]decane-1,3-dione.

23.1 g of 2-methyl-2,8-diazaspiro[4,5]decane-1,3-dione (0.127 mol), 12.7 g of 4-chloro-p-fluoro-butyrphenone (0.0635 mol) and 0.1 g of potassium iodide was heated at 80 cm'<1> abs. toluene for 36 hours at 130° in a closed vessel. After cooling, the crystalline reaction mixture was rinsed with benzene and filtered. The residue consisted of 2-methyl-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride, m.p. 281° after drying by water jet vacuum. The filtrate was freed from the solvent in vacuo at 70°. A red colored oil was obtained which crystallized on mixing with ethanolic hydrochloric acid until a Congo acid reaction. 40 cm<3> of ether was added and after four hours in a refrigerator, filtration was carried out. The residue was recrystallized from water. 2-Methyl-8-(4'-p-fluorophenyl-4'-oxo-butyl)-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride melted at 285-286°.

Following the same procedure as in examples 1 and 2, the following additional compounds were prepared from 2-methyl-2,8-diazaspiro[4,5]decane-1,3-dione and p-substituted 4-halo-butyro-phenones:

Following the same procedure as described in examples 1 and 2, the compounds indicated were prepared from 4-chloro-p-fluoro-butyrophenone and 2-substituted 2,8-diazaspiro[4,5]decane-1,3-diones in the following table. This table also shows the properties of the starting products with formula II as well as their precursors with formula V. Their production takes place according to the same procedure as described in detail in example 1.

Claims (1)

Method of manufacture of new, therapeutically effective spiro-(piperi- dyl-4)-succinimides of the general formula I where R, means a hydrogen atom, a lower alkyl residue or the benzyl residue and R., means a hydrogen, fluorine, chlorine or bromine atom, or a lower alkyl or alkoxy group, and their salts, characterized in that a succinimide with the general formula II where R, has the same meaning as above, is reacted with a compound of the general formula III where R., has the same meaning as above, in the presence of an alkaline condensing agent, preferably another mole of the base with formula II, and that the reaction product is eventually transferred to the corresponding salts by treatment with inorganic acids.