CS207615B2 - Method of making the 4a,9b-trans-hexahydro-gama-carboline derivatives - Google Patents

Description

(54) A method for producing 4a, 9b-trans-hexahydro; -carboline derivatives

The invention relates to a process for the manufacture of certain

4a, 9b-trans-hexahydro y-carboline derivatives, which are useful as starting materials for preparing tranquilizing effective trainls isubst.-2-aryl-5 ^j-2,3,4,4a, 5,9b4iexahydro-lH-pyrido [ 4,3-b] indole derivatives.

Following the introduction of eserpine and chlorpromazine into psychotherapy medicine in the early 1950s, a great deal of effort was sought to develop and develop other tranquilizing agents with improved biological properties. Some of these agents are γ-carboline derivatives also known in the art as pyridoyl 4,3-b) indole derivatives.

U.S. Pat. No. 3,687,961 discloses 8-fluoro-2- [3- (4-fluorophenylanilino) propyl] -1,2,3,4-tetrahydro-γ-carboline as a useful tranquilizing agent for warm-blooded animals. U.S. Pat. No. 3,755,584 discloses structurally related compounds having a fluorine atom at the 8-position and a characteristic β-substituted phenylalkyl radical at the 2-position, which have been found to have similar activity.

U.S. Pat. No. 3,983,239 discloses hexahydro-γ-carbolines of the general formula

in which

R ¹ represents a methyl or ethyl group, and

R ^{2 * * * 6} represents hydrogen, methyl or ethyl.

There is no mention of the stereochemical arrangement of the hydrogen atoms at the 4a and 9b positions in this work, but their relative arrangement could be expected to be cis due to the formation of the hexahydro-γ-carboline nucleus from the starting 1,2,3,4-tetrahydro-γ -carboline by catalytic hydrogenation in the presence of platinum, which is a known method of introducing the hydrogen atoms in the cis configuration to the double bond between carbon atoms. The compounds protected by this patent are neuroleiptic agents which are said to be useful in the treatment of schizophrenia.

U.S. Pat. No. 3,991,199 discloses hexahydropyrimido [4,3-b] indoles. useful as analgesics and sedatives, some of which are of interest as tranquilizers, some as muscle relaxants, and many of them exhibit hypotensive efficacy. Said substances are compounds of the general formula

x * · 1 i H 1 l r rS ^H T X ^A in which The hydrogen atoms bonded to the carbon atoms at positions 4a and 9b are

trans disposed therein, and wherein in the event that ^Y is hydrogen ^and X represents hydrogen, chlorine, bromine, methyl, tert-butyl or methoxy and, when Y represents ^a trifluoromethyl group, X represents ^and hydrogen and R ^a is hydrogen, 3-chloro-2-butenyl, 2-bromallylovou, benzyl, benzyl substituted in the ring by methyl, methoxy or chlorine atom fenethyíovou group, 3-phenylpropyl, 3 -phenylpropyl substituted in the ring by chlorine, bromine or methoxy, furfuryl, 2-thenyl, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, a cinnamyl group, a cinnamyl group substituted in the ring by a chlorine atom, a bromine atom or a methoxy group, a 3-phenyl-2-propynyl group, a cycloalkyl group having 3 and 7 to 7 carbon atoms, C 4 -C 8 -cycloalkylmethyl, (methylcyclopropyl) methyl, (cis-2,3-dimethylcyclopropyl) methyl, C 6 -C 8 cycloalkenylmethyl, C 6 -C 8 cycloalkadienylmethyl; , 3-dimethylcycloprop-2-en-1-yl] methyl, exo-7-norarylmethyl, (cis-1,6-dimethylenedo-3-noraren-7-yl) methyl, (4-methylbicyclo [2.2. 2] ok-1-yl-methyl, (4-methylbicyclo [2.2.2] oct-2-en-1-yl) methyl, (bicyclo [2,2,2] hept-2-yl) methyl , (bicyclo [2.2.2] hept-2-en-5-yl) methyl, 1-adamantylmethyl or 2-adamantylmethyl, and pharmaceutically acceptable salts thereof.

More recently, Belgian Patent Publication No. 845,368 (Derwent No. 00043Y) discloses 5-phenyl-hexahydro- [beta] -carbolines optionally substituted in the 2- and 4-positions by methyl or ethyl and in the 3-position by a C1-C3 alkyl group carbon atoms, allyl or propargyl. These compounds are useful as antidepressants.

Recently, DOS No. 2,631,836 (Derwent No. 09738Y) discloses structurally related dttahydiropyrido'1 [4 ', 3': 2,3] indole [1,7-aib] [1] benzazepines, which can be illustrated by the above general of the formula wherein Y ^a represents an ethylene bridge between two benzene rings, X ^a represents a hydrogen atom and R ^a represents a group -CH 2 CH 2 COCH 3 or -CH 2 CH 2 COC 6 H 5. These substances are said to be useful as analgesics and tranquilizing agents.

U.S. Pat. No. 4,001,263 discloses transquillizing 5-aryl-1,2,3,4-tetrahydro-γ-carbolines of the general formula

in which X ^b and Z ^b represent a hydrogen or fluorine atom and R ^b has the same meaning as the shoira R indicated in the general formula I.

As mentioned above, the invention relates to a process for the preparation of starting materials used for the preparation of valuable tranquilizing agents which are enantiomeric and racemic compounds of formula II

in which the hydrogen atoms bonded to the carbons at positions 4a and 9b are trans to each other, each of Xi and Yi, which may be the same or different, represents a hydrogen or fluorine atom, n is 3 or · 4,

M represents a group —targeting

or —CH—, and

OH

Z 1 represents a hydrogen atom, a fluorine atom or a methoxy group, and pharmaceutically acceptable salts thereof.

The preparation and use of these tranquilizing agents is described in our related Czechoslovak patents Nos. 207 612 - 207 613.

The present invention provides a process for the preparation of 4a, 9b-trans-hexahydro - / - carboline derivatives of formula III

wherein X and Y are hydrogen atoms, wherein the 4α, 9β-trans-hexahydro-1H-carboline derivative of formula (IV) is:

in which X and Y represent a hydrogen atom and R 2 represents a benzyl group, undergoes a reduction.

The reduction according to the invention is expediently carried out by catalytic debenzylation in the presence of palladium on carbon as a catalyst. The reaction is usually carried out using the hydrochloride of the compound of formula IV at a temperature of about 50 to 100 ° C, preferably 60 to 75 ° C, under a hydrogen pressure of about 0.14 to 0.7 MPa, in the presence of an inert solvent such as methanol. , ethanol, isopropanol, ethyl acetate or mixtures thereof with water. After the hydrogen uptake is complete, the catalyst is filtered off and the product of formula III is precipitated by the addition of a non-solvent such as ethyl ether, benzene or hexane. Alternatively, the free base of formula III can be isolated by evaporating the filtrate from the debenzylation reaction to dryness, partitioning the residue between an aqueous base solution such as sodium hydroxide and a solvent such as chloroform or ethyl ether. The free base is then isolated by conventional methods.

The starting materials of the formula IV can be obtained by reducing the tetrahydro-γ-carbolines of the formula V

as described in detail in our Related Czechoslovak Patent Publication No. 207,614.

2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-1H-carboline was prepared by Fischer indole synthesis using N, N-diphenylhydrazine and N-benzyl-4-piperidone. The starting mono- or difluorosubstituted tetrahydro-1H-carholines of formula V, wherein at least one of X and Y are fluorine and R 2 is benzyl, are prepared from the corresponding compounds of formula V in which R 2 is hydrogen by reaction with a henzyl halide such as · Benzyl bromide, starting materials being used in equimolar amounts. The required compounds of formula V wherein R 2 is hydrogen are prepared as described in U.S. Pat. No. 4,001,263.

Other starting materials are either commercially available, or their preparation is specifically described in the chemical literature, or can be prepared by methods known per se. For example, phenylhydrazines are commercially available or can be prepared by reduction of phenyldiazonium salts as described by Wagner and Zook in "Synthetic Organic Chemistry", John Wiley & Sons, New York, NY, 1956 (see Chapter 26, J. 1-substituted 4-piperidones are commercial substances or can be prepared as described by McElvain and Rorig in J. Am. Chem. Soc., 70, 1826 (1948).

The invention is illustrated by the following non-limiting example.

Example d1-tr ans-5-phenyl 1-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole

A suspension of 4.17 g of dl-trans-2-benzyl-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-bindole hydrochloride in 150 ml of absolute ethanol for 2 hours Hydrogenation was carried out at 60 psi and 60-70 ° C using 1.0 g of 10% palladium on carbon catalyst. The catalyst is filtered off and the hydrochloride of the desired product precipitates from the filtrate by addition of ethyl ether. Yield 2.76 g (87%), mp 235-237 ° C.

The hydrochloride is converted to the free base by shaking between ether and dilute sodium hydroxide solution. The ether layer was dried over sodium sulfate and evaporated to give the title compound 0 '(97%), mp 74-76 ° C.

Claims (1)

SUBJECT Process for preparing 4a, 9b-trans-hexahydro-γ-carboline derivatives of the general formula III SUMMARY OF THE INVENTION A hydroxy-γ-carboxylic acid derivative of the general formula IV wherein X and Y are hydrogen atoms, characterized in that the 4a, 9b-trans-hexane is hydrogen. X and Y are hydrogen and R2 is benzyl, reacted with hydrogen in the presence of palladium on carbon catalyst.