FI62664C - FRAMEWORK FOR THE FRAMEWORK OF THERAPEUTIC ANVAENDBARA 6-PIPERAZINYL-11-METHYLENE-MORPHANTRIDINE DERIVATIVES - Google Patents

Description

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Switzerland-Switzerland (CH) 1021 * 7/75 (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Franz Martin Kiinzle, Bern, Switzerland -Schweiz (CH) (7M Oy Kolster Ab (5 ^ +) Process for the preparation of new therapeutically useful 6-piperazinyl-11-methylene-morphanthridine derivatives - For the preparation of new therapeutically useful 6-piperazinyl-11-methylene-morphanthridine derivatives

The present invention relates to a process for the preparation of novel therapeutically useful 6-piperazinyl-11-methylene-morphanthridine derivatives of the formula I, r "N" and CH 2 2,62664 containing hydrogen, C 1-4 alkyl or hydroxyalkyl having up to 4 carbon atoms , and R 2 is hydrogen or halogen, as well as their acid addition salts.

When R 1 is alkyl, it is preferably methyl. When hydroxyalkyl is present, it preferably has 2 to 4 carbon atoms. The hydroxyl group is preferably in the terminal position. is e.g. β-hydroxyethyl. R 1 is preferably hydrogen or alkyl.

When R2 is halogen, halogen means fluorine, chlorine or bromine, in particular fluorine or chlorine.

Finnish patent publication 42,561 discloses morphanthridines which have neuroleptic, analgesic and cat-leptogenic effects. Neuroleptic agents with cat-leptogenic activity cause extrapyramidal side effects and late movement disorders in humans. In contrast, the compounds of formula I prepared according to the invention are not cataleptogenic.

The process according to the invention for the preparation of the compounds of the formula X and their acid addition salts is characterized in that the compounds of the formula II

X

CH 2 wherein R 2 is as defined above and X is a hydrogen cleavable group from secondary amines is reacted with compounds of formula III, where H 1 is as defined above, and if desired the compounds obtained are converted acid addition salts.

3 ή ^ 6 4

Thus, the compounds of formula I can be converted into their acid addition salts and vice versa.

The process according to the invention can also be carried out in the same manner as for the preparation of analogous compounds in a manner known per se:

In the compounds of the formula II, X is preferably halogen, in particular chlorine, or also sulfhydryl, alkoxy or alkylthio having 1 to 5 carbon atoms, e.g. methoxy or methylthio, p-nitrobenzylthio, tosyl or amino, optionally substituted by one or two alkyls. The reaction is most conveniently carried out in an inert organic solvent, e.g. xylene or dioxane, at a temperature of 50 to 170 ° C, preferably 100 to 140 ° C.

If the reactive group X is an optionally substituted amino, the reaction is most conveniently carried out in the presence of catalytic amounts of acid, e.g. p-toluenesulfonic acid or sulfuric acid, or acid addition salts of the corresponding compounds of formula II.

The compounds of formula I obtained are isolated and purified in a manner known per se.

The compounds of formula II used as starting materials in the above process are obtained, for example, by reacting compounds of formula IV

wherein R 2 has the meaning given above, to react with compounds of formula V

CH 2 -MgY V

wherein Y is chlorine, bromine or iodine, in particular bromine, under the conditions customary in Grignard reactions, by hydrolysing the reaction product in a manner known per se, by cleaving 4 6 2 6 64 11-methyl-11-hydroxy reaction products in a manner known per se, and subjecting the compounds of formula VI obtained,

R x, / NH-CO

i j Ί .. ..

CH2 in which R2 has the abovementioned meaning, to react in a manner known per se to compounds of the formula II in which X is halogen and then to compounds of the formula II in which X has, with the exception of halogen, the abovementioned meaning.

If the preparation of the required starting materials has not been described, these are known or can be prepared by known methods or by known methods described herein or equivalent.

The compounds of formula I available according to the invention have advantageous pharmacodynamic properties. They can be used both as antidepressants (in particular compounds of the formula I in which R2 is halogen) and as hypnotics (in particular compounds of the formula I in which R2 is hydrogen).

Particularly preferred compounds of this invention are 6- (4-methyl-piperazinyl-1) -3-chloro-11-methylene-morphanthridine as an antidepressant and 6- (piperazinyl-1) -11-methylene-morphanthridine as a hypnotic.

The compounds of formula I may also be administered in the form of their pharmaceutically acceptable acid addition salts, e.g. the hydrochloride, methanesulphonate or maleinate, which have the same degree of activity as the free bases.

The compounds of the formula I or their salts can be administered either orally in the form of tablets, granules, capsules or dragees, or parenterally in the form of injection solutions.

In the following examples, temperatures are expressed in degrees Celsius and are uncorrected.

5 6 l 6 fr 4

Example 1 6- (4-Methyl-piperazinyl-1) -11-methylene-morphanthridine 1a) 6-chloro-11-methylene-morphanthridine

A mixture of 8 g of 5,6-dihydro-11-methylene-morphanthridin-6-one together with 3 ml of Ν, Ν-dimethylaniline and 80 ml of phosphorus oxychloride is heated for 2 hours. The dark solution obtained is evaporated to dryness in vacuo, absolute xylene is added to the residue and evaporated to dryness once more in vacuo. The residue is dissolved in 80 ml of xylene and the solution is poured into an ice-water mixture. The mixture is shaken thoroughly 2 times with xylene. The xylene extracts are combined, washed successively with dilute hydrochloric acid, water and saturated brine, dried over sodium sulfate and finally treated with activated carbon.

The xylene solution is filtered through Al 2 O 3 and evaporated in vacuo to a volume of 100-150 ml. This solution contains 6-chloro-11-methylene-morphanthridine, which is added in this form to the reaction in the next step.

b) 6- (4-Methyl-piperazinyl-1) -11-methylene-morphanthridine

To the xylene solution of 6-chloro-11-methylene-morphanthridine obtained in step a) is added 8 g of N-methyl-piperazine and the mixture is boiled for 4 hours. In this case, the hydrochloric acid salt of N-methyl-piperazine is separated. Water and 25 ml of concentrated sodium hydroxide solution are added to the mixture. It is then shaken twice with ether, the organic phase is washed with water and extracted with 2N hydrochloric acid.

The acidic extract is washed with 2N aqueous sodium hydroxide solution to alkaline and the separated oil is extracted twice with ether. The ether solutions are combined, washed with water and saturated aqueous beaker, dried over sodium sulfate, treated with activated carbon, and then filtered through alumina. After recrystallization of the residue from ether / petroleum ether, the resulting 6- (4-methyl-piperazinyl-1) -11-methylene-morphanthridine (prisms) melts at 119-120 ° C.

Using the procedure described in Example 1 and the appropriate starting materials, the following compounds of formula I are obtained: ® ό / '(S <' 4

Example R 2 R 2 Sp.

2 H H 190-195 ° C (dec.) (Maleinate) 208-211 ° C (dec.) (Methanesulfonate)

3 HO-CH2-CH2-H 151-155 ° C

(Maleate)

4 HO-CH2-CH2-Cl14 7-149 ° C

5 H Cl 130-138 ° C

(Maleate)

6 CH 3 Cl 162-164 ° C

7 H F 125-126 ° C

8 CH3 F 138-140 ° C

Manufacture of starting material;

The preparation of 3-halo-11-methylene-5,6-dihydro-morphanthridin-6-one used as a starting material in the above examples can be carried out as follows: a) 3-Fluoro-5,6-dihydro-morphanthridine-6,11-dione Solution, 88 g of chromium IV oxide in 60 ml of water are added dropwise over 4 hours to 60 ° C in a stirred solution of 68 g of 3-fluoro-5,6-dihydromorphanthridin-6-one 1.5 per liter of glacial vinegar. Heat to reflux for a further hour, allow to cool and pour into ice water. The crystallization is filtered off and washed with a large amount of water. After drying, the title compound is obtained, m.p. is 282-285 ° C (sublimation).

The correspondingly prepared 3-chloro-5,6-dihydromorph anthridine-6,11-dione melts at 293-295 ° C.

b) 3-Fluoro-11-methylene-5,6-dihydro-morphanthridin-6-one in a Grignard solution prepared from 5.6 g of magnesium, 30.6 g of methyl iodide and 80 ml of absolute ether , add 150 mg of absolute tetrahydrofuran (portionwise - (exothermic reaction)) and cool to 10 ° C.

Under a nitrogen blanket, a suspension of 19 g of 3-fluoro-5,6-dihydromorphantridine-6,11-dione in about 200 ml of absolute tetrahydrofuran is added in small portions to the mixture. Stir for a further 7 6 ^ 664 for 4 hours at room temperature and then pour into ice-cold aqueous ammoniacal ammonium chloride solution. It is then extracted with ether, washed with brine and evaporated to dryness. The residue of the resin is dissolved in a small amount of acetone, 18 g of pyridine hydrochloride are added and the mixture is heated under nitrogen. After removal of the acetone, heat for 90 minutes at 130-140 ° C, cool slightly, mix with water, filter and evaporate to dryness. After recrystallization from acetone / petroleum ether, the title compound is obtained, m.p. is 220-230 ° C (crystal change from 160 ° C).

The correspondingly prepared 3-chloro-11-methylene-5,6-dihydromorphanthridin-6-one melts at 247-249 ° C.

Claims (1)

A process for the preparation of new therapeutically useful 6-piperazinyl-11-methylene-morphanthridine derivatives of the formula I, I1 / N v. Γ), I! ! R 9 ^ N = C · Ok o Ύ CH 2 containing hydrogen, C 1-4 alkyl or hydroxyalkyl having up to 4 carbon atoms and being hydrogen or halogen, and for the preparation of their acid addition salts, characterized in that the compounds of the formula II, XR, ^ ^ 2 ': j II Y CH2 wherein R2 is as defined above and X is a hydrogen cleavable group from secondary amines is reacted with compounds of formula III, / ~ \ HN NR, III V__ / wherein means the same as above, and if desired, the compounds obtained are converted into their acid addition salts.