SE441448B - SET TO MAKE HEXAHYDRO-GAMMA CARBOL COMPOUNDS - Google Patents

Description

N 2 - (CH 2) 5 CO- -F where R 1 is methyl or ethyl and H 2 is hydrogen, methyl or ethyl.

The stereochemical ratio of the hydrogen atoms bonded to the carbon atoms in positions 4a and 9b is not stated in the patent specification, but the production process for the hexahydro-X 'carboline nucleus from the 4,2,3,4-tetrahydrocarbonoline by catalytic hydrogenation in the presence of platinum is expected to be in the cis ratio because it is a well known fact that by means of the said process one introduces hydrogen atoms in the cis position to the carbon-carbon double bond. The listed compounds are neuroleptic and can be used to treat schizophrenia. . U.S. Patent No. 5,994,199 discloses hexahydropyrimidoli, 5-§7indoles useful as analgesics and sedatives, some of which are of interest as tranquilizers, some as muscle relaxants and a number of exhibit hypotensive activity. The compounds are stated to fall under the formula X8 and xa and pharmaceutically acceptable salts thereof, in which formula the hydrogen atoms on the carbon atoms 4a and 9b are in trans relationship to each other. When in the above formula Ya is -H, Xa represents -H, -Cl, -Br, -CH 5, -t-CAHQ or -OCH 5; and when Ya is -CF5, X8 represents ~ H. Furthermore, in the above formula, Ra represents hydrogen, 5-chloro-2-butenyl; 2 7803625-e 2-bromoallyl; benzyl; a benzyl ring substituted with methyl, methoxy or chlorine; phenethyl; 3-phenylpropyl; a 5-phenylpropyl ring substituted with chlorine, bromine or methoxy; íurfuryl; 2-phenyl; alkyl of 1-5 carbon atoms; alkenyl having J-5 carbon atoms; alkynyl having 5-5 carbon atoms; cinnamyl; a cinnemyl ring substituted with chlorine, bromine or methoxy; 3-phenyl-2-propynyl; cycloalkyl having 5-7 carbon atoms; cycloalkylmethyl having 4-8 carbon atoms; (methylcyclopropyl) -methyl; (cis-2,5-dimethylcyclopropyl) -methyl; cycloalkenylmethyl having 6-8 carbon atoms; cycloalkadienylmethyl having 6-8 carbon atoms; (?, 5-dimethylcycloprop-1-en-1-yl) methyl; exo-7-norcarylmethyl; (ois-1,6-dimethylendo---norcaren-7-yl) methyl; (4-methylbicyclo [2.2.1] oct-4-yl) methyl; (bicyclo .2.2_7hept-2-y1) methyl; (bicyk10 _ / _ §.2. _2_7hept-e-en-5-y1 _) - methyl; 1-adamantylmethyl; or 2-adamantylmethyl.

The recently published Belgian patent 845 568 (Derwent No. OOO45Y) discloses 5-phenyl-hexahydro-6-carbolines optionally substituted in the 2- and 4-positions by methyl or ethyl and in the 3-position by alkyl by 1-5 carbon atoms, allyl or propargyl. He is useful as an antidepressant.

In a recently published West German Offenlegungsschrift with no. 3 651 856, Derwent No. O9? 58Y, describes structurally related octahydropyrido1É ', 5': 2, §7índolo¿T, 7-ab7ZfW_7benzene azepines, which fall under the above formula, wherein Ya is an ethylene bridge between the two benzene rings, Ka is hydrogen and Ra is -CH2CH2COCH3 or -CH2CH2COC6H5. They are stated to be useful as analgesics and tranquilizers.

U.S. Pat. No. 4,001,265 discloses tranquilizers, namely 5-aryl-4,5,4,5-tetrahydro-carboline of the formula .Kb b NR 7803625-8 L »where Xb and Zb may represent hydrogen or fluorine and Rb ~ have the same meaning as given below for R in formula I- It has now quite surprisingly been found that trans -?,?, 4, üa,, 9b-hexahydro-1H-pyrido The present invention has a markedly superior tranquilizing effect compared to the corresponding 4,3,5,4-tetrahydrocarbons.

The tranquilizers prepared according to the present invention are 2-substitutes fl the 5-aryl-2, š, 4,4a, 5,9b ~ her fl hydro-1H-pyrido-7f, 5¿§7indoles of the formula "\ Z 9 1 __" b _ Ûš ha Ä_ (LH2) “(| 'H 7 N 3 nu siz xÜßv (m2 L, cH-azn-Û -; Ä' VII IY och z .7 \ x -q- (cagnê-QÛ / m fl 0 'xiv i which formulas the hydrogen atoms attached to the carbon atoms in positions 4a and 9b, respectively, are in trans relation to each other, X and Y are the same or different and represent hydrogen or fluorine, n is 3 or 4, m is 2 or 3 and z is hydrogen, fluorine or methoxy, indole, 7803625-8 The compounds of the present invention have marked and unexpected, superior tranquilizing action in comparison with the above-mentioned prior art tranquilizers.

Particularly preferred tranquilizers obtained by the method of the present invention are the enantiomers and the racemic mixtures of: trans-8-fluoro-5- (p-fluorophenylD- ° ¿¿ï-hydroxy) (p_f1gor-feUY1) bU-yl7; 5,41 “”, 5,9b-heXabydro-4H ~ pyridQÅK, K-§7indnl, träHS-5 ~ f @ fl Y1 * ° “ŶLhYÖP0Xí -" - (D ~ metodXifany1) butyl7 ~ 3,5,4, 4a, 5,9b ~ heXahydro-1H-pyridoíï,? ¿§7indol, trans ~ 8-fluoro-5- (p-fluorophenyl) -? »¿¶Lby§yOqilu_ (p_ meÜ ° ïif @ fi Y1> bUÜyl7? 2, 5,4,4a, 5,9b-hewahydro-1H-pyridoline, 5-§7- __-, ___, .i _ _. __ -n ~. Trans-5-phenyl-2- (fl-hydroxy- & phenylbutyl) -7, §, fl, & a, 5,? b-hexehydro-1H-pyridyl, β-indo1, trans-8-fluoro-5- (p-fluorophenyl) - “- (Q-hydroxy-H -Peryl-bunyl) -2,5, a, u fl, 5,9 b-hexanyaro-1H-pyridyl-β E; - g71 »d @ 1, trans-5-phenyl-β-ÅÉÄ (p-fluorobenzoyl) prop3l7 -,,,,, 4, flfi, 5, Qb-hexahydro-1H-pyridoyl, 31§7indole, trins-8-fluoro-5- (p-fluorophenyl) -? - 1ï- (p-fluorobenzoylI-propyl) 7 @ , 5,4, aq, 5, gb-nex fl hyaro- fl a-pyr: a0¿H, 3-g7ina01, trans-8-fluoro-5- (p-fluorophenyl) - „- ¿Ä ~ (p-fluorophenyl) - T »butenyl7; 2,5, u, aq, 5,9b-hexanyaro-1H-pyrrolo [5,5-g7 ina01, trans-8-fluoro-5- (p-fluorophenyl} -β-LE- (p-methowiphenyl) -β-butenyl] -β, 5,4,4a, 5,9b-hexahydro-1H-pyridine, 5α-7-indole, trans-8-fluoro-5- (o-fluorophenyl) -α-hydroxy-U- (p-fluorophenyl) butyl7-2,5, u, u @, 5,9b-newanyaw0-1H- pyr1a @ 1H, 5-37-indole, trans-5-phenyl-2-ÅE-hydroxy-- (9-fluorophenyl) butyl7-2,5,4,4a, 5,9b-nexahydro-1H-pyretho E, 5-g7inaol, trans-8-fluoro-5- (O-fluorophenyl-β-β (p-fluorophenyl) -burenyl; 7-2,5,4, ua, 5,9b-hexahyuro-1H-pyrido Detailed Description of the Invention: The following reaction scheme illustrates the process by which the free bases of 4a, 9b-trans-2,3,4,4a, 5,9b-hexahydro-1H can be synthesized as starting compounds. -pyrido [β, 3-hfindoles of the formula X in which X and Y have the meanings given above: 7803625- 8 N-RQ (1) BH¿ / etheri ___ ï ___ §> N (ä) H (VIII) (ïx) (IX) (i) Clo02c HX ___ ¿¿____ ¿\ 2 Kon, - '' H () czaso fl / Hzo. For economic reasons, H2 preferably represents benzyl, but RÖ can also represent other substituents for this purpose, which is obvious to the person skilled in the art.

The reduction of the tetrahydro-X-carbolines VIII to more than 9b-trans-hexahydro compounds IX is carried out in ether, usually tetrahydrofuran. To ensure complete reduction, a molar excess of boron / tetrahydrofuran complex (BH.THF) and a 100-200% molar excess of said complex are usually used. Although the reaction can be carried out at -10 ° C and 180 ° C, 0 ° C and E5 ° C are preferred. Usually, at a temperature between a temperature of a solution of the starting material VIII in the tetrahyururan, an ice-cooled solution of BH5.THF is added. After the addition is complete, the reaction mixture is heated to reflux and maintained at this temperature for between about 1 and about 2 hours or longer.

The reaction is usually carried out in the presence of an inert gas, for example nitrogen. When the reaction is substantially complete, the solvent is evaporated and the residue is acidified with excess acid, for example hydrochloric acid in 2-12 molar excess. A preferred acidifier is a mixture of equal volumes of acetic acid and 5M-H01. The acidified mixture is usually heated under reflux for 1-2 hours or longer. The desired product can then be isolated, for example by evaporation of any remaining ether and a portion of the acidic mixture and the precipitated product filtered off and washed.

According to an alternative isolation method, the product (XI) is filtered off after the reaction mixture is refluxed for the indicated time, the filtrate is cooled and made alkaline by the addition of, for example, sodium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is extracted with a water-immiscible organic solvent, for example chloroform, methylene chloride or benzene, the extracts are evaporated and the evaporation residue is purified by chromatography on a silica gel column and eluting, for example with ethyl acetate or a mixture of hexane and ethyl acetate.

By reducing tetrahydro-X-carbolines with BH5.THF and subsequent acid treatment, hexahydro-carbolines are obtained, in which the hydrogen atoms bonded to the carbon atoms in positions 4a and 9b are in trans relationship to each other, see for example U.S. Pat. 991 l99.

Thereafter, the 2-benzyl compounds IX are converted to the corresponding 2-hydrogen compounds X. In general, this can be accomplished by treating the compound IX with a lower alkyl chloroformic acid ester in molar excess, for example methyl, ethyl, propyl or isobutyl ester, in the presence of a suitable anti-reaction inert organic solvent, which treatment is accompanied by alkaline hydrolysis. Preferred chloroformic acid ester is ethyl chloroformate due to its readiness and efficiency. By the term "suitable reaction-inert organic solvent" is meant a solvent which substantially dissolves the reactants under the conditions of the reaction without forming by-products. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene and xylene; chlorinated hydrocarbons such as chloroform and 1,2-dichloroethane, diethylene chloride dimethyl ether and dimethyl sulfoxide. An especially preferred solvent is toluene.

To the mixture of the starting material IX in said organic solvent inert against the reaction is added the chloroformic acid ester in an up to 10 molar excess. For economic reasons, a molar excess of between 3 and about 5 is preferred. The resulting mixture is then heated at a temperature between 80 and 150 ° C, typically at the temperature at which the mixture boils under reflux, for between about 6 and about 24 hours or longer. The reflux was usually carried out overnight for convenience. The reaction mixture is then evaporated in vacuo and the residue is taken up in a mixture of alcohol and water, whereupon an alkali, for example sodium hydroxide or potassium hydroxide, is added in a 10 to 50 molar excess based on the amount of starting material IX, whereupon the mixture thus obtained is heated under reflux. typically all night.

The solvent is then evaporated and the residue is partitioned between water and a water-immiscible organic solvent, for example chloroform, methylene chloride or ethyl ether, and the organic phase is evaporated to dryness. The evaporation residue, namely product X, can be used as such or subjected to further purification in accordance with standard procedures known in the industrial field in question, for example by column chromatography on silica gel.

Compounds IX, in which both X and Y represent hydrogen and R 2 benzyl, can be converted to the corresponding compound X by catalytic debenzylation using hydrogen and a catalyst consisting of palladium on carbon. The reaction is typically carried out using the hydrochloride of compound IX at a temperature of between 50 and 100 ° C, preferably 60-75 ° C, and a hydrogen pressure of between 140 and 690 kPa in the presence of a reaction-inert solvent. , for example methanol, ethanol, isopropanol, ethyl acetate or mixtures thereof with water. When hydrogen uptake is complete, the catalyst and hydrochloride are filtered off.

The BO 7803625-8 product, namely compound X, is precipitated by the addition of a non-solvent, for example ethyl ethers, benzene or hexane.

Alternatively, the Free Base X can be isolated by evaporation of the filtrate from the debenzylation to dryness, partitioning the residue between an alkaline aqueous solution, for example an aqueous solution of sodium hydroxide, and a solvent such as chloroform or ethyl ether. The free base is then isolated in accordance with standard methods, for example one of those described above.

The free bases X serve as precursors for the new compounds VI in the manner set forth in the following reaction scheme, in which X, Y, Z and n have the meanings given above: 0 _o Z uu X 'Q 0 C_ (CH2) 5: íC0H- ~ 9Ä? ”“ "“ “/ \“ Në- (CH) ~ ë- * m X (x) + ', \' Nk) 2 “~ 1 \} I7 (XII) (XIII) Z ß ssšä IX _____ / '\ (BH / \ (XIII) LIAIHÅ, N- (CH2) fi CH --- ~> va; - z The acylation of the compounds X to the intermediate XII] can be effected using acids XII or the corresponding acid chlorachides or acid bromides. used in the acylation, approximately equimolar amounts of the acid and the compound X are brought into contact with each other in the presence of an inert reaction, an organic solvent and certain known condensing agents for the formation of peptide bonds in relation to the reaction of LUUUTY 7803625. Carbodiimides are mentioned, for example dicyclohexylcarbodiimide and 1-ethyl-5- (3-dimethylaminopropylacarbodiimide hydrochloride, and alkoxyacetylenes, for example methoxyacetylene and ethoxyacetylene. , ethyl ether and benzene; Although the reaction with satisfactory results can be carried out at a temperature between -10 and + 50 ° C, it is preferred to apply a temperature between 0 and 2fi “C. At this temperature, the reaction is usually completed in a few hours. The product XIII is isolated, for example by filtration to remove insoluble material and evaporate the filtrate. The product thus obtained usually has such purity that it can be used in the subsequent step.

The whole product XIII is then reacted with lithium aluminum hydride in the manner indicated above to prepare 2-methyl compounds XI. The product VI is also isolated in the manner indicated above and purified, for example by column chromatography on silica gel.

An alternative method for the preparation of 4a, 9b trans compounds VI in admixture with the corresponding dihydrated compounds VII is shown in the following reaction scheme: Z ------- è x - (c112) n-

Claims (1)

1. 0 15 20 25 30 PATENT REQUIREMENTS Method for preparing hexahydro-Y-carboline compounds 1 - x- (UH) CH 9 “<Éïz X \ [::: I \ 5 ha 2 n '\ / VI 7 r: 3 ou e with the formula Z É X VII and <^ Z x -e- (C142) nšà \ _¶ / _ f; x xv and pharmaceutically acceptable salts thereof, in which formulas the hydrogen atoms bonded to the carbon atoms in positions 4a and 9b, respectively, are in trans relationship to each other, X and Y are the same or different and represent hydrogen or fluorine, n is 3 or 4 , m is 2 or 3 and Z is hydrogen, fluorine or methoxy, characterized in that a) a terahydro-Y-carboline of the formula _ Z - X reaction inert, organic solvent and then treated with acid to prepare compounds of formula (VI) and (VII) or (b) reduces a 4a, 9b-trans-hexahydro-7-carbonyl compound of formula 0 Y with lithium aluminum hydride in the presence of a reaction-inert solvent for the preparation of compounds of formula (VI) reactes a compound of formula (VI) obtained under (a) or (b) VI) with an oxidizing agent for the preparation of compounds of formula (XIV).