DE1668550B - 2 Alkoxyalkylammo 2 phenylcyclohexanonver compounds, their acid addition salts and process for their preparation - Google Patents

Description

N-A-OR

or one of their acid addition salts, in which A and R have the meanings given above, expediently heated in the presence of a high-boiling solvent or b) 2-amino-2-phenylcyclohexanone with a compound of the general formula RO — A — X in the presence of a Reacts base and an inert organic solvent, in which A and R are as defined above and X is a halogen atom., preferably a bromine atom, and optionally after completion Implementation of the reaction mixture acidified in the usual way and the reaction product as Acid addition salt isolated or an optionally obtained acid addition salt in a customary manner Way converted into the free base.

The present invention relates to new 2-alkoxyalkylamino-2-phenylcyclohexanone compounds the general formula

NH-A-OR

position of these connections. In the formula given, A denotes a lower alkylene group 2 to 4 carbon atoms, and R is a lower alkyl group with 1 to 3 carbon atoms, but A and R together contain a maximum of 5 carbon atoms. The group - A - OR is thus an alkoxyalkyl group with at most 5 carbon atoms and can e.g. B. mean the Methoxyälhyl-, Äthoxyäthyl-, Methoxypropyl-, Äthoxypropyl- or Propoxyäthylgruppe.

According to the invention, the compounds mentioned are either a) carried out in a manner known per se Heating a ketimine compound of the general formula

_{/ C} H,

CH ₂ CH ₂

C - CH ₂

N-A-OR

wherein A and R are as defined above, expediently in the presence of a high-boiling solvent, or b) by reacting 2-amino-2-phenylcyclohexanone in the form of its free base of the formula

NH ₂

35

CH ₂ CH ₂
CH ₂

their acid addition salts as well as processes for their corresponding, with a compound of the general formula RO — A — X, in which A and R are as defined above and X is a halogen atom, preferably bromine, in the presence of a base, such as alkali carbonate or bicarbonate, Alkaline earth carbonate, oxide or hydroxide or an organic tertiary amine and an inert organic solvent and optionally acidifying the reaction mixture obtained after the reaction has ended in the customary manner and isolating the reaction product as an acid addition salt or converting an optionally obtained acid addition salt into the free base manufactured. The. Reaction a) is a thermal rearrangement. It can optionally be carried out in the absence of a solvent; however, a high-boiling solvent is preferably used. Some examples of suitable solvents are high boiling hydrocarbons such as hexakosane and biphenyl; high-boiling ethers such as diphenyl ether and pentylphenyl ether; high-boiling net petroleum fractions; Mineral oils and mixtures of these solvents. The eutectic mixture containing 73.5% diphenyl ether and 26.5% biphenyl is preferably used as the solvent. The process is carried out by heating the starting mixture to a temperature of about 175 to 275 ^° C. for 1 to 15 minutes. The preferred reaction conditions are about 200 to 250 ⁰ C and

5 to 10 minutes, the higher temperatures for the rearrangement of the free base and the lower Temperatures for the rearrangement of an acid addition salt are used. Generally will in this process the starting material, preferably. in the form of the Sllure-Addilionssalzes, used. The reaction product is obtained either as the free base or by adjusting the required pH uls acid addition salt isolated,

The ketimines used as starting material in the process according to the invention can have can be produced in different ways. So z. B. Monobrominated cyclopentyl phenyl ketone and that 1-bromocyclopentyl phenyl ketone obtained with melamine to the l-hydrocyclopentyl-phenyJ-N-methylketimine implemented. This compound is converted to 1-hydroxycyelopentyl phenyl ketone by heating with dilute mineral acid hydrolyzed. The same compound is also made by reacting phenyllithium or phenylmagnesium bromide with the tetrahydro-2-pyranyl ether of cyclopentanone cyanohydrin in anhydrous Ether and subsequent saponification of the compound obtained with hot, dilute mineral acid receive. 1-Hydroxycyclopentyl phenyl ketone eventually becomes the starting material with a lower alkoxyalkylamine 1 - Hydroxycyclopentyl - phenyl - N - (alkoxyalkyl) ketimen implemented.

In process b) at least 1 equivalent, preferably a moderate excess of the alkoxyalkyl halide, used. Some of the suitable solvents for this reaction are lower ones aliphatic ketones, e.g. B. acetone, methyl ethyl ketone and diethyl ketone; lower alkanols, such as methanol, Ethanol and isopropyl alcohol, as well as other relatively inert solvents such as tetrahydrofuran, Dioxane, acetonitrile and dimethylformamide. Examples of preferred solvents are acetone and acetonitrile. The time and temperature required for the reaction vary somewhat depending on the one used Alkoxyalkyl halide and solvent used; however, in general, the implementation is practical ended when done at a temperature of 15 to 125 ° C within 1 to 72 hours using the longer reaction times together with the lower temperatures. Preferred reaction conditions are 55 to 85 ° C and 12 to 24 hour response time. The reaction product is used immediately as a free base or after subsequent acidification isolated as their acid addition salt.

The free bases according to the invention form acid addition salts with numerous inorganic and organic acids. Therapeutically useful acid addition salts are obtained by reaction with acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, citric acid, Maleic acid and pamoic acid are formed. The acid addition salts are treated with a base, e.g. B. reacted with sodium hydroxide, potassium carbonate or potassium bicarbonate to form the free bases. The free Bases and their acid addition salts differ in their solubility, but are generally equivalent in all other respects for the purposes of the invention.

The compounds according to the invention are anesthetics and also have an antispasmodic effect. Their anticonvulsant effects can be measured by determining their ability to occur to prevent convulsions after electric shock. A preferred anti-spasmodic after the Invention is 2- (3-methoxypropyl) -amino-2 »phenylcyclohexanone. As anesthetics, the compounds according to the invention are about as effective as compounds described in Belgian patent 634 208 and British patent 1014060, however, they have the advantage of shorter anesthesia and thus lead to one faster patient recovery. Compared with structurally similar anesthetics is in the case of the Compounds, the ratio of strength to duration of action is relatively high. The connections act when administered orally as well as when administered parenterally.

This effect is shown by the following data, in which the relative duration of anesthesia in monkeys is compared with the duration of the anesthetic effect of the standard compound 1- (1-phenylcyclohexyO-piperidine hydrochloride, for which the value 1.0 is assumed

The following compounds were each examined in the form of their hydrochloride.

2-Ethylamino-2-phenylcyclohexanone (comparison):

relative duration of action 0.66.
2- (2-Ethoxyethyl) -amino-2-phenylcyclohexanone

(Example 1): relative duration of action 0.33.
2- (2-Methoxyethyl) -amino-2-phenylcyclohexanone (Example 2): relative duration of action 0.33.

The invention is illustrated in more detail by the following examples.

example 1

An excess of dry hydrogen chloride was introduced into a solution of 25 g of 1-hydroxycyclopentylphenyl-N- (2-ethoxyethyl) ketimine in 300 cm ^{3 of} a mixture of 73.5% diphenyl ether and 26.5% diphenyl. The resulting mixture, containing ketimine hydrochloride, was heated rapidly to 200 ° C., kept at this temperature for 10 minutes, then cooled to room temperature and diluted with ether. The insoluble product was collected on a filter. It was 2- (2-ethoxyethyl) amino-2-phenylcyclohexanonhydrochlorid of mp. 208-209 ^above C after recrystallization in isopropyl ether. The free base was obtained by dissolving the hydrochloride in water, adding potassium carbonate and extracting with ether. It is a colorless oil. The hydrobromide and sulfate were obtained by treating the free base with dry hydrogen bromide and sulfuric acid, respectively. The hydrobromide has a melting point of 196 to 197 ° C. A salt with citric acid was obtained by mixing a solution of the free base in methanol with a solution of citric acid in methanol and concentrating the mixture.

According to this procedure, 1-hydroxycyclopentyl-phenyl-N- (3-methoxypropyl) -ketimine was obtained with an equal amount by weight instead of 1-hydroxycyclopentyl-phenyl-N- (2-ethoxyethy I) -ketimine the 2 - (3 - methoxypropyl) - amino - 2 - phenylcyclohexanone hydrochloride with a melting point of 176 ° to 177 ° C. was obtained.

Example 2

A mixture of 18.9 g of 2-amino-2-phenylcyclohexanone, 23.5 g of 2-methoxyethyl bromide, 42 g of potassium

1 688

carbonate, 0.5 g potassium joelide and 300 cm x ¹ acetonitrile were stirred and refluxed for 20 hours and the mixture was cooled, diluted with a large volume of ether and filtered to remove the inorganic salts. The filtrate was washed with water and extracted with a small excess of dilute hydrochloric acid. The ice cream was treated with charcoal and filtered. The filtrate was basified with sodium hydroxide solution and extracted with ether. The ether extract was dried and treated with a slight excess of dry hydrogen chloride. The insoluble precipitate was collected on a filter; it was 2- (2-methoxyethyl) amino-2-phenylcyclohexanonhydrochlorid with mp. 176-177 ⁰ C after recrystallization from isopropyl alcohol-ether. The free base was obtained by dissolving the hydrochloride in water, adding sodium carbonate and extracting with ether. It is a colorless oil. The addition salt with tartaric acid was obtained by reacting the free base with tartaric acid in methanol. The hydrobromide has a melting point of 188 to 19O ⁰ C.

Preparation of the starting compounds

With continuous stirring, 160 g of bromine were added in small portions to a solution of 174 g of cyclopentylphenyl ketone in 600 cm ^{3 of} carbon tetrachloride and after each addition it was waited until the bromine had decolorized. The resulting solution was evaporated under reduced pressure and left a residue of 1- Bromocyclopentyl phenyl ketone, m.p. 60 to 61 ^° C.

With stirring, 235 g of 1-bromocyclopentylphenyl ketone were added in small portions to 150 cm ^{3 of} liquid methylamine; The at -60 to - 50 ⁰ C was maintained. The solution was allowed to warm to room temperature; it was then diluted with an equal volume of ether and evaporated. The ether dilution and evaporation were repeated three times. The residue was again diluted with ether and the insoluble methylamine hydrobromide was filtered off. The filtrate was evaporated to dryness and the residue recrystallized from PetroUither, the 1-hydroxycyclopentyl-phenyl-N-methylkelimin melted at 66 to 68 ⁰ C.

A solution of 102 g l-Hydroxycyclopcntylphenyl-N-methylketimin in 1000 cm x ¹ 1 η HCI were heated for 1 hour at 90 to 100 ° C and then cooled and extracted with ether. The ether extract was washed with water, dried and evaporated and the residue was distilled under reduced pressure. A fraction of 1-hydroxycyclopentylphenyl ketone was obtained, boiling point 92 to 94 ° C./0.15 mm Hg.

A solution of 18.2 g of 1-Hydroxycyclopcntylphenylketon and 15 g of 2-Äthoxyäthylamin in 250 cm ^{3 of} toluene was heated under reflux and the water formed in this reaction continuously removed until the theoretical amount of water had been obtained.

The toluene solution was evaporated under reduced pressure and left a residue of 1-hydroxycyclopentyl-pheriyl-N- (2-ethoxyethyl) ketimine. This compound had an IR absorption maximum at 1650 cm " ¹ and was suitable for use without further purification. In the same way, with the same weight of 3-methoxypropylamine, 1-hydroxycyclopentyl-phenyl-N- (3-methoxypropyl ) - ketimine with an IR absorption maximum at 1650 cm " ¹ .

A phenyllithium solution was prepared from 470 g bromobenzene and 48 g lithium in 31 ether. 400 g of the tetrahydro-2-pyranyl ether of cyclopentanol cyanohydrin were added with stirring and the mixture was stirred for a further 4 hours at room temperature. With continuous stirring, the mixture was ^{diluted with 600 cm 3 of} water and the layers were separated. The ether layer was washed with water, dried and evaporated. The residue was heated on a steam bath for 30 minutes with 21 2 N HCl, the mixture cooled and extracted with ether. The ether extract was washed with water, dried and evaporated and the residue was distilled under reduced pressure. 1-Hydroxycyclopentyl phenyl ketone was collected as a fraction with a boiling point of 92 to 94 ° C / 0.15 mm Hg.

Claims (2)

Patent claims: 1. 2-Alkoxyalkylamino-2-phenylcyelohexanone compounds the general formula IO wherein A is a lower alkylene group having 2 to 4 carbon atoms and R is a lower alkyl group with 1 to 3 carbon atoms, where A and R together but not more than 5 carbon atoms contain, as well as their acid addition salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that either a) a ketimine compound of the general formula is used in a manner known per se