NO146548B - DEVICE FOR SPROSSE WINDOW CONSTRUCTIONS - Google Patents

Description

Process for the production of new pharmacologically active bicyclic amino ketones and salts thereof.

The present invention relates to a

method for the production of pharmacologically active bicyclic amino ketones with the following general formula I.

In this formula R, and R2 denote lower

alkyl, cycloalkyl, aryl, aralkyl or, together with the nitrogen atom, a pyrrolidine, piperidine, morpholine or piperazine ring,

which can also be substituted with lower alkyl residues, while X denotes -CH 2 - or CH, -CH 2 -.

It is known that cycloaliphatic ketones

can be transferred to aminoketones by reaction with formaldehyde and secondary amines. Among these amino ketones, pharmacologically active substances have been found (see Swiss patent no. 347,829, Badische Anilin- und Sodafabrik AG).

It was now found that by applying this reaction to bicyclo-[2,2,1"!-heptanone-(2) and bicyclo-[2,2,2]-octanone compounds with valuable pharmacological properties are obtained .

Production of the new amino ketones takes place according to the invention by reacting bicyclo-[2,2,1]-heptanone-(2) or bicyclo-[2,2,2]-octanone with secondary amines or salts thereof and formaldehyde in aqueous solution when heating during reflux cooling. Unreacted starting material, i.e. ketone, can be recovered from the reaction mixture by being taken up in organic solvents or by stripping with steam.

The new amino ketones can be directly isolated from the reaction mixture as hydric chlorides, or as free amino ketones after the reaction mixture has been made alkaline.

These new bicyclic aminoketones are stable compounds, they can be distilled in high vacuum without splitting. The free amino ketones are poorly soluble or insoluble in water, but their salts, e.g. the hydrochlorides and methobromides dissolve easily in water.

The new amino ketones obtained by the method according to the invention are relatively untoxic. Thus, for example, the dose that causes 50 percent mortality (DL-n) in albino Swiss-Webster mice is approximately 800 mg /kg body weight for 3-dimethyl-aminomethyl- and 3-piperidino-methyl-bicyclo-[2,2,1]-heptanone-(2). In animal poisoning: these aminoketones show an analgesic: action corresponding to the action of acetylsalicylic acid (see Arzneim .—Forsch. (Drug Re-search) 13, 414-15 (1963)).

Bicyclo-[2,2,1]-heptane derivatives appear as known in endo-exo-isomeric forms:

It was now found that the group

-CHgNRjRj in the general formula I takes the exo-position, since from 3-dimethylamino-methyl-bicyclo- [ 2,2,1 ]-heptanone- (2) upon removal of the carbonyl group by method I according to Huang-Minlon, exo- 3-dimethylaminomethyl-bicyclo-[2,2,1]-heptane if the configuration is established. IN

In the following, some embodiments of the invention are described as examples.

Example 1.

110 g of bicyclo-[2,2,1]-heptanone-(2) (1 mol) are heated for 20 hours under reflux with 123.5 g of morpholine hydrochloride (1 mol) and 120 ml of 40% formaldehyde hydopplosnihg (1.6 mol) while adding 1 ml of concentrated hydrochloric acid. After cooling, the unreacted bicyclo-[2,2,1]-heptanone-(2) is removed by decantation (or stripped off directly with steam). The aqueous solution is then made alkaline with solid potassium carbonate and extracted again. After the solution in ether has been freed from water and the ether distilled off, the residue is distilled in high vacuum. The 3-morph olinomethyl-bicyclo-[2,2,1]-hepta-non-(2) obtained is distilled at 102-106°C, 0.04 Torr. The yield is 72 percent of the theoretical calculated for converted bicyclo-[2,2,1]-hepta-non-(2). The aqueous solution can also be evaporated as such under reduced pressure and the hydrochloride obtained recrystallized from; n-propanol, which gives

it in its pure state with a melting point of 194.0— 194.5°C.

Tables I and II below list physical data for free amino ketones as well as the melting points for hydrochlorides and methobromides as well as the results of halogen determinations of certain amino ketones which are obtained by the method according to the invention and which are derived from bicyclo-[2 ,2,1]-heptanone-(2). The preparation of these compounds was carried out as indicated in example 1 with the exception of the dimethylamino-ethyl compound which was prepared as indicated in the following example 2.

Example 2.

110 g of bicyclo-[2,2,1]-heptanone-(2) (1 mol) are heated for 20 hours under reflux with 135 ml of 33% dimethylamine (1 mol), 120 ml of 40% 's formalin (1.6

mol) and 100 ml concentrated hydrochloric acid. The preparation takes place in the manner described in example 1. The obtained dimethyl-aminomethyl-bicyclo-[2,2,1]-heptanone-(2) boils at 58-61°C/0.02 Torr. The dividend

is 48 percent of the theoretical, calculated on converted bicyclo-[2,2,1]-heptanone-(2).

Instead of formaldehyde, paraformaldehyde can be used.

The production of the salts takes place at i

and known manner.

The reaction with bicyclo-[2,2,2]-octanone can be carried out in the manner described in examples 1 and 2. 3-piperidino-methyl-bicyclo-[2,2,2]-octanone boils at

115—120°C/0.03 Torr, nn2o 1.5060, D42o 1.0159, Mn 64.73 (MD lier <6>4.20). Metho-dide's m.p. 206.5-208°C (from ethanol-ether (2:1)). Formula: C15<H>2G<N>OJ (363.28), calculated C 49.59%, H 7.21% and N 3.85%, found C 49.35%, H 7, 36 per cent, N 3.97 per cent.

Claims (1)

Process for the preparation of pharmacologically active bicyclic amino ketones of the general formula: (in which R, and R 2 denote lower alkyl, cycloalkyl, aryl, aralkyl, or together with the nitrogen atom denote a pyrrolidine, piperidine, morpholine or piperazine ring which can also be substituted with low molecular weight alkyl residues, while X denotes -CH2- or -CH2-CH2-), or salts thereof, characterized by reacting bicyclo-[2,2,1]-heptanone-(2) or bicyclo -[2,2,2]-octanone with secondary amines of the general formula: NH(R,R2), or with salts thereof, and formaldehyde, whereupon the free amino ketones obtained are optionally transferred to the desired salts.