NO135338B - - Google Patents

Description

Process for the preparation of substituted succinimides.

The present invention relates to a process for the production of new substituted succinimides with the general formula I:

where R, and R., can be the same or different and each means a hydrogen atom or a lower alkyl group.

According to the invention, the compounds of formula I are prepared by a substituted piperidone-4 with the general formula II:

where R,' stands for a lower alkyl or a benzyl group, is reacted with a compound of the general formula III: where X stands for the cyano group or an optionally functionally converted carboxyl group, in the presence of a water-splitting catalyst to a piperidylidene-4- derivative with the general formula IV: after which this, by addition of hydrocyanic acid, is transferred to a compound with the general formula V: and this, by hydrolysis, decarboxylation and esterification with an alcohol, is transferred to a substituted succinic acid diester with the general formula VI:

after which the formed ester is reacted with a nitrogen compound with the general formula R2 - NH„ where R2 has the same meaning as above and, if R,' stands for a benzyl group, this is cleaved off reductively and the secondary amino group formed is optionally alkylated.

Compounds of formula I, where R,, stands for hydrogen, are also obtained, according to a variant of the method, by subjecting the compound of formula V to hydrolysis, decarboxylation and esterification with an alcohol only for a short time, whereby a substituted succinic alkyl is formed -ester amide which, when heated to above the melting point or when boiled in a solvent, undergoes a succinimide which is not substituted at the nitrogen atom.

The preparation of the succinimide (formula I: R, = H) which is not substituted at the piperidine nitrogen preferably takes place over the (1-benzyl-piperidyl-4) compounds with subsequent reductive removal of the benzyl group. For the catalytic deben-zylation, e.g. with hydrogen/palladium, both the salts and the free bases can be used. The succinimide derivative can then be alkylated at the piperidine nitrogen atom, as it is treated e.g. with a lower aliphatic aldehyde or ketone in a hydrogen atmosphere in the presence of a catalyst, or with an alkyl halide, preferably in the presence of an alkaline condensing agent, e.g. sodium carbonate, or is also methylated by treatment with formaldehyde/formic acid.

The method is carried out, for example, in the following way: A 1-alkyl-piperidone-4 in an inert organic solvent, e.g. benzene, toluene, xylol, tetrayl, etc. reacted with a compound of formula III, preferably with a cyanoacetic acid alkyl ester, in the presence of a water splitting catalyst, e.g. glacial acetic acid alone or together with ammondum acetate, and using a continuously operating water separator, to a compound of formula IV. During the double bond of this derivative, prussic acid is added, and the compound of formula V that is formed is saponified and decarfaofcylated with conc. hydrochloric acid to a substituted succinic acid. This is esterified with an abs. alcohol and hydrogen chloride to a substituted succinic acid diester of formula VI. The process up to the diester of formula VI is preferably carried out without isolation or purification of the individual intermediate products.

The substituted succinic diester of formula VI can now be transferred to the desired substituted succinimide of formula I by reaction with conc. aqueous ammonia or that primary alkylamine, e.g. liquid methylamine, ethylamine etc., preferably in a closed vessel. As a substituted succinic acid-diamide derivative is first formed in the last reaction step, the reaction mixture must finally be heated to a high temperature to achieve ring closure of the diamide, e.g. 180— 250°.

The new substituted succinimides of formula I are colorless compounds, which at room temperature are oily or solid crystalline. They dissolve easily in common organic solvents, but not in water. With inorganic or organic acids, they form stable salts which are crystalline at room temperature and which can easily dissolve in water.

The new compounds have interesting, therapeutically valuable, pharmacodynamic properties, which are partly due to a cholinergic mode of action. Thus, e.g. spiro-(1-methyl-plperidyl-4)-N-methyl-succinimide and the corresponding -N-ethyl-succinimide by an extensive parasympathomimetic action, which manifests itself peripherally or centrally. They have a blood pressure-lowering and pulse-rate-lowering effect on animals. At the same time, the motility of the small intestine and urinary bladder increases and the flow of saliva and gastric juice secretion are strongly promoted. The central cholinergic effects manifest themselves in a pronounced potentiation of anesthesia, a clear analgesia and in an inhibition of conditioned reflexes. These include parasympathomimetic effects, as the central effects are also inhibited or abolished by means of large doses of hyoscyamine and other centrally acting anticholinergics. Due to their stimulating properties on gastrointestinal activity and urinary bladder function, the new compounds are to be used for the treatment of gastrointestinal diseases and introduced into urology. At the same time, they can be used for sedation and for the treatment of mental disorders as well as pain conditions. They also constitute valuable 'intermediate products for the manufacture of drugs.

Some examples will now be given of how the method can be carried out, with all temperatures being indicated in degrees Celsius. The melting and boiling points are not corrected.

Example 1.

Spiro-(1-methyl-piperidyl-4)-succinimide.

(8-methyl-2,8-diazaspro [4,5] decane-1,3-dione) a) (1-methyl-piperidylidene-4)-cyanoacetic acid ethyl ester.

113.0 ig of cyanoethylacetic acid ethyl ester, 113.0 g of 1-methyl-piperldone-4 and 23 ems of glacial acetic acid were

boiled for four hours in 250 ems benzol. The water which was separated during the reaction was removed continuously from the tillage run by means of a water separator. After 2½ hours there was a gap of 18 ems of water. After a further 1/2 hour of boiling, a further 300 ems toenzol was added and the whole was shaken out with 150 cm3 of ice-cold saturated pot ash solution. The pobash solution was extracted once more with 150 ems of benzene and the toluene extract washed once with 50 ems of water. After drying over sodium sulphate, the combined toenzole extracts were evaporated and the dark-coloured cob residue was carefully distilled in high vacuum. Just a little overheating, e.g. during the distillation caused considerable cleavage. Pure (1-methyl-piperidylidene-4)-cyanoacetic acid ethyl ester is a colorless, viscous oil with bp.

114—115°/0.05 mm Hg ,n <2>^'<5>= 1.4952.

The hydrochloride forms fine needles with m.p. 182-183° (mp) from ethanol. b) [(1methyl-4-carbethoxy-piperidyl)-4]acetic acid ethyl ester. 87.3 g of (1-methyl-piperidylidene-4)-cyanoacetic acid ethyl ester and 42.5 g of potassium cyanide were heated on a water bath together with 130 cm" of 50% ethanol. After 10 min. a further 15 ems of water was added and the whole thing was allowed to stand for 1 more 5 min. in the water bath. The solution, which was now clear and orange in colour, was cooled to room temperature and, under ice cooling, 80 cm3 conc. hydrochloric acid. The solution was evaporated by water jet vacuum at 60° to a dry state, the residue was taken up in 150 ems of water and the aqueous solution was saturated with chlorine hydrogen gas under ice cooling. Boiling was then carried out for 20 hours at reflux and further evaporation to dryness. The colorless, crystalline residue was dried for 60 hours over phosphorus pentofcyde, slurried in 500 cc of ethanol which had been dried over calcium oxide and the slurry saturated under ice-cooling with dry chlorine hydrogen gas and boiled for 15 hours at reflux. Evaporation was then carried out in 1 nitrogen atmosphere under a water jet vacuum at 60° to <i>/4 of the original volume, dilution under good cooling with double the amount of water, saturation with potassium carbonate and extraction 3 times each time with 250 ems chloroform. The chloroform extracts were washed once with water and dried over sodium sulfate. After evaporation of the chloroform, the oily residue is distilled under high vacuum. Pure [(1-methyl-4-carbethoxy-piperidyl)-4]-acetic acid-ethyl ester is a colorless oil with bp. 95—96/ 20 *i

0.06 mmHg. n ^ = 1.4582. Pikrat. Canary yellow needles from ethanol, m.p. 135-136°.

c) Spiro-(1-methyl-piperidyl-4)-succinimide 6.6 g [(1-methyl-4-carbethoxy-piperidyl)-4]-acetic acid ethyl ester was boiled together with 50 cm3 conc. aqueous ammonia for 46 hours at reflux. After 5 hours was

the originally undissolved ester has completely dissolved. The slightly yellow reaction solution was evaporated to dryness under a water jet vacuum at 60° to dryness. The crystalline flask residue was then heated for 3 hours at 200°, then taken up in water and filtered through cotton wool. The filtrate was evaporated to dryness and the carbon residue dissolved in methanol. The solution was mixed with dry bromine-hydrogen gas, during which the hydrobromide of the desired spiro-(1-methyl-piperidyl-4)-succinimide tole precipitated in colorless small plates. After recrystallization from methanol, the slightly hygroscopic hydrobromide melted at 311-313° (sp).

Example 2.

Spiro-(1-methyl-piperidyl-4)-N-methyl-succinimide.

(2,8-dimethyl-2,8-diazaspiro[4,5]decane-1,3-dione).

First, the prepared (1-methyl-piper-idylden-4)-cyanoacetic acid ethyl ester as indicated in Example 1 under a) and transferred to [(1-methyl-4-carbethoxy-piperidyl)-4]-acetic acid ethyl ester as stated in example 1 under b). 59.5 g of this ester were heated together with an excess of liquid 100% methylamine for 12 hours in a pressure vessel at 140°. Cooling was then carried out and the excess methylamine was allowed to evaporate. The crystalline carbon residue was heated to 185°, below which methylamine was split off during melting. After 2½ hours the methylamine evolution was complete. During cooling, the carbon residue crystallized. It was occupied in 2-n. hydrochloric acid, extracted with ether and the hydrochloric acid solution made alkaline by the addition of solid potassium carbonate. The precipitate that formed below was extracted with methylene chloride, extracted, washed once with water and dried over sodium sulfate. After evaporation of the solvent, a colorless, crystalline residue of spiro-(1-methyl-piperidyl-4)-N-methyl-succinyl was left. The compound can be easily sublimated with a melting point of 80°/0.01 mm Hg, m.p. 94-96°.

The hydrochloride prepared in ethanol was recrystallized from methanol; weakly hygroscopic, colorless prisms with m.p. 318—319° (sp).

Fumarate: Equivalent quantities of the succinimide derivative and fumaric acid (1 mol : 1 mol) were boiled together in ethanol. After cooling, filtration and crystallization from methanol/water were carried out. Colorless polyhedra with m.p. 266° (sp).

Picrate: Excess ethanolic picric acid solution was boiled for a short time together with the sucoinimide derivative. On cooling, the picrate crystallized in fine yellow prisms. Recrystallization from ethanol/water. Temp. 260° (sp) after sintering at 216°.

Example 3.

Spiro-(1-methyl-piperidyl-4)-N-ethyl-succinimide.

(2-ethyl-8-methyl-2,8-diazaspro[4,5]decane-1,3-dione).

First, [(1-methyl-4-carbethoxy-piperidyl)-4]-acetic acid ethyl ester was prepared as indicated in Example 1 under a) and two).

15.0 g of this ester were heated together with 15 cm" of ethylamine 1 for 40 hours in a remelted tube to 150°. The excess amine was evaporated in a water jet vacuum at 40° and the crystallized crude product distilled under high vacuum. Spiro-(1-methyl-piperidyl-4)-N-ethyl-succinimide boiled at 79° under 0.04 mm Hg.

The hydrochloride was obtained by diluting the alkaline solution of the free toase with a solution of ethanolic hydrochloric acid. From ethanol colorless prisms with m.p. 255°.

The hydrobromide tole obtained in a similar manner and melted at 302-304° after recrystallization from ethanol.

Fumarate: A concentrated aqueous solution of -fumaric acid tole mixed with an equivalent amount of the succinimide derivative (1 mol : 1 mol). A little ethanol was added to it and the colorless solution was evaporated to dryness. The residue tole recrystallized from ethanol/water. Colorless polyhedra with m.p. 204—206°.

Picrate: Excess ethanol.sk picric acid solution tole added to the free succlnimid derivative and boiled for a short time. After cooling, filtration and recrystallization were carried out three times from ethanol/water. Temp. 214—217°.

Example 4.

Spiro-(piperidyl-4)-N'-methyl-succinimide.

2-methyl-2,8-diazaspiro[4,5]decane-1,3-dione). a) (l-bemyl-piperidylidene-4)-cyanoacetic acid ethyl ester. 50 g cyanoacetic acid ethyl ester, 70.48 g 1-benzyl-piperidone-4, 12 ems glacial acetic acid and 4 g ammondum acetate were boiled together in 1,400 ems benzene for 7 hours at reflux. The water that formed tole was continuously removed from the tillage run by means of a water separator. After 7 hours, it was separated by 7 cm?>. The reaction mixture was, after being cooled with ice water, shaken out once with a saturated potash solution and the aqueous phase washed once with benzene. The combined benzene layers were washed once with water, dried over sodium sulfate and evaporated. The dark-colored carbon residue, which consisted of crude (1-toenzyl-piperidylidene-4)-cyanoacetic acid ethyl ester, completely crystallized on cooling. The ester cleaner can be used directly without further purification. From ether/petroleum ether it formed yellow crystals with m.p. 70-71°.

two) [ ( 1 - benzyl- 4- carbethoxy-piperidyl)-4]- acetic acid ethyl ester.

The above cob residue was dissolved in 500 cm3 of ethanol, 250 cm3 of water was added and the solution was heated over boiling water. During the heating, 31 g of calcium cyanide was added, which immediately dissolves on stirring. After everything had dissolved, the temperature was kept at 75° for 12-15 min., after which 250 cm3 2-n. hydrochloric acid tole added and the solution evaporated by water jet vacuum to dryness. Then 750 cm 3 of HC1 were added, boiled for 14 hours at reflux, cooled and filtered. The filtrate was evaporated to dryness and the carbon residue and the filter residue were dried over phosphorus pentoxide for 160 hours. About the dried crystal mass, 500 ems of ethanol were added and, under ice cooling, chlorine hydrogen gas was introduced until saturation. Boiling was carried out for 18 hours at reflux, the reaction mixture was cooled and filtered. The filtrate was again evaporated to dryness, the charcoal residue and the filter residue were dissolved in ice water and an excess of pot ash was added to the solution. Extraction was then carried out three times with ether and the ether extracts were washed each time with water. After the ether extract had been dried over sodium sulphate, it was evaporated and the oily cob residue was distilled in a ball tube. [(1-Benzyl-4H-carbethoxy-piperidyl)-4]-acetic acid ethyl ester boiled at 150° below 0.03 mm Hg (temperature measured in the air bath); weak gulf inherited oil. c) Spiro-(benzyl-piperidyl-4)-N-methyl-succinimide.

15.0 g of [(1-benzyl-4-cartoethoxy-piperidyl)-4]-acetic acid ethyl ester were heated together with an excess of liquid methylamine for 12 hours in a steel autoclave at 180°. The excess methylamine tole was then evaporated and the crystalline carbon residue heated for a further 4 hours at 200°, until the product, which had melted at this temperature, showed no further tole formation. The substance tole absorbed in a little ethanol, boiled for a short time with a little activated charcoal and filtered. On cooling, spiro-(1-toenz<y>l-<p>iperid-yl-4)-N-methyl-succinimide was precipitated in large colorless prisms with m.p. 111-112°.

Hydrochloride. From ethanol colorless prisms with m.p. 254—256°. d) Spiro-(piperidyl-4)-N-methyl-succinimide.

3.0 g of spiro-(l-benz<y>l-piperidyl-4)-N-methyl-succinimide in 100 cm?> ethanol tole hydrated with 300 mg of palladium on activated carbon (10 percent) for 12 hours under normal pressure at room temperature. The hydrogen uptake was 315 cma (= 114 per cent). After the ethanol had evaporated, the crude spiro-(piperidyl-4)-N-methyl-succinimide was distilled in a ball tube in high vacuum bp. 99°/0.02 mm Hg (temperature measured in the air bath). It was a strongly hygroscopic substance that crystallized in right-angled prisms with m.p. 67°.

Hydrobromide: Entangled, fine needles with m.p. 292—294° after recrystallization from ethanol/water.

Example 5.

Spiro-(piperidyl-4)-succinimide.

(2,8-diazaspiro-[4,5]-decane-1,3-dione). a) Spiro-(1-benzyl-piperidyl-4)-succinimide.

Following the same procedure as described in example 4, under a), (1-thoenzyl-plperidylidene-4)-cyano-acetic acid ethyl ester was first prepared. Yellow crystals with m.p. 70—71° from ether-petroleum ether.

The hydrocyanic acid deposition took place by treatment with alkali cyanide as described in example 4 under two). Saponification was now carried out with conc. hydrochloric acid for only 3 hours (carbon dioxide evolution is no longer detected). After cooling, filtration was carried out, the filtrate was evaporated to dryness and the residue was dried well over phosphorus pentoxide. The esterification took place with ethanol/hydrogen chloride at room temperature. The reaction mixture was evaporated to dryness, the residue taken up in a little water, made alkaline with pot ash under ice cooling and extracted with chloroform. The chloroform extract was concentrated, during which the compound, freed from the solvent, crystallized. It was about [(1-benzyl-4-carbamoyl-piperidyl)-4]-acetic acid ethyl ester which, when heated above the melting point, converted into the desired spiro-(1-thobenzyl-piperidyl-4)-succinimide. Temp. 185° after crystallization from ethanol. Hydrochloride: m.p. 312° (sp) after crystallization from ethanol.

b) Spiro-(piperidyl-4)-succinimide.

A compound thus obtained

as described above was subjected to a catalytic hydrogenation to cleave off the benzyl group. The hydrogenation was carried out as described in example 4 under d). Spiro-(piperidyl-4)-succinimide melted at 243-244° (sp) after recrystallization from ethanol. Hydrochloride: m.p. 356° (sp) after recrystallization from ethanol/water.

Example 6.

Spiro-(1-ethyl-piperidyl-4)-N-ethyl-succinimide.

(2,8-diethyl-2,8-diazaspiro[4,5]decane-1,3-dione).

First, spiro-(1-toenzyl-piperidyl-4)-N-ethyl-succinimide was prepared from [(1-benzyl-4-carbethoxy-piperidyl)-4]-acetic acid ethyl ester and ethylamine using the same procedure as that which is described in example 4. Smp. 104—105° after recrystallization from ethanol.

The cleavage of the benzyl group took place in a similar manner as in the previous example and led to spiro-(piperidyl-4)-N-ethyl-succinimide. Very viscous oil with m.p. 107°/0.05 mm Hg. The compound did not crystallize.

13 g of the compound, 25 ems of freshly distilled acetaldehyde, 75 cm3 ethanol and 3 g Raney nickel were shaken for 24 hours under a hydrogen atmosphere at normal pressure and room temperature. Filtration from the catalyst was carried out, the solvent was evaporated and the residue was distilled under reduced pressure. The fraction that transitioned at 132°/0.2 mm Hg formed spiro-(1-ethyl-piperidyl-4)-N-ethyl-succinimide. The hydrobromide melted at 293° after recrystallization from methanol.

Example 7.

Spiro-(l-n-butyl-piperidyl-4)-

N-ethyl succinimide.

(2-ethyl-8-n-butyl-2,8-diazaspiro[4,5]decane-1,3-dione).

3.10 g of spiro-(piperidyl-4)-N-ethyl-suc-

cinimide, prepared as described in Example 6, was heated together with 2.17 g of n-butyl toramide and 5 g of sodium carbonate in 25 ems of n-tautonol for 24 hours at reflux. The reaction mixture was evaporated to dryness and the residue taken up in 2-n. hydrochloric acid while cooling. The acidic solution was shaken out once with ether, made alkaline with potash and extracted with ether. From the ether extract tole the hydrochloride of spiro-(1-n-butyl-piperidyl-4)-N-ethyl-succinimide prepared by the addition of ethanolic hydrochloric acid. Temp. 269° after recrystallization from ethanol.

Following the same procedure as stated in the preceding examples, compounds have been produced which, together with their properties, are indicated in the attached table.

Claims (2)

1. Process for the preparation of therapeutically effective, substituted succinimides with the general formula I: where R1 and R2 can be the same or different and each means a hydrogen atom or a lower alkyl group, characterized in that a substituted piperidone-4 with the general formula II: where R/ stands for a lower alkyl or a benzyl group, is reacted with a compound of the general formula III: where X stands for the cyano group or an optionally functionally converted carboxyl group, in the presence of a water-splitting catalyst to a piperidylidene-4 derivative with the general formula IV: after which, by addition of hydrocyanic acid, this is transferred to a compound with the general formula V: and this by hydrolysis, decarboxylation and esterification with an alcohol is transferred to a substituted succinic acid diester with the general formula VI: after which the formed ester is reacted with a nitrogen compound of the general formula R.sub.1-NH2, where R.sub.0 has the same meaning as above and, if R.sub.1 stands for a benzyl group, this is cleaved off reductively and the formed secondary amino group is optionally alkylated. 2. Modification of the method stated in claim 1 for the production of a succinimide, which is not substituted on the nitrogen atom, characterized in that the compound of formula V is subjected to hydrolysis, decarboxylation and esterification with an alcohol only for a short time, and the substituted succinic acid formed -alkyl ester amide is heated above the melting point or boiled in a solvent.