PL117107B1 - Process for preparing novel 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido/4,3-b/indoles-geksagirdid 1h-pirido 4,3-b ionidolov - Google Patents

Description

The subject of the invention is a method for preparing new 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of formula I, wherein one of the substituents X or Y is a fluorine atom and the other is a hydrogen or fluorine atom, which are starting compounds in the synthesis of new 2-substituted 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles (hexahydro-γ-carbolines) and pharmaceutically acceptable salts of these compounds, exhibiting sedative activity. After the introduction of reserpine and chlorpromazine into psychotherapy in the early 1950s, considerable effort was directed towards finding other Sedatives with a better biological profile. Several active compounds have been found in the pyrido[4,3-b]indole group, called Y-carbolines. U.S. Patent No. 3,687,961 describes 8-fluoro-2-[3-(4-fluorophenylanilino)propyl]-1,2,3,4-tetrahydro- for warm-blooded animals. U.S. Patent No. 3,755,584 states that related compounds with fluorine atoms in the 6- or 8-positions, and especially compounds substituted in the 2-position by a phenylalkyl radical with a substituent in the para-position of the phenyl ring, exhibit similar activity. U.S. Patent No. No. 3,983,239 describes hexahydrogen-Y-carbolines of the formula 7, wherein R1 is a methyl or ethyl radical and R2 is a hydrogen atom, a methyl radical, or an ethyl radical. The description does not mention the stereochemical relationship of the hydrogen atoms bonded to the carbon atoms in positions 4a and 9b. However, it can be expected that these atoms are in a cis position to each other, since the compounds obtained by catalytic hydrogenation of the corresponding 1,2,3,4-tetrahydro-Y-carbolines in the presence of platinum, and it is known that the hydrogen atoms introduced into the carbon-carbon double bond by this method are in a cis position to each other. Compounds of formula 7 are claimed as neuroleptics, useful in the treatment of schizophrenia. U.S. Patent No. 3,991,199 describes hexahydropyrido[4,3*-b] indoles, useful as analgesics and psychotropic agents. Some of them are interesting as sedatives, while others as muscle relaxants. Many of them exhibit hypotensive activity. In the described compounds, the hydrogen atoms at the carbon atoms in positions 4a and 9b are in a trans position with each other. The compounds are represented by the general formula 8, in which when Y a is -H, X a is -H, -Cl, -Br, -GHS, -Term.C 4 H 9 or -OCH 8 , and when Y « = -CF 8 , X a = -H; and R3 is a hydrogen atom or a 2-(3-chloro)butenyl, 2-bromoallyl, benzyl, benzyl substituted with a methyl, methoxy or chlorine atom, phenylethyl, 3-phenylpropyl, 3-phenylpropyl substituted in the ring with a chlorine or bromine atom or a methoxy group, furfuryl, 2-thienyl, C1-C8 alkyl, C3-C6 alkenyl, C3-C5 alkynyl, cinnamyl, cinnamyl substituted in the ring with a chlorine, bromine atom or methoxy group, 2-(3-phenyl)propynyl, C8-C7 cycloalkyl, C4-C8 cycloalkylmethyl, /methylcyclopropyl/methyl, /cis-2,3-dimethylcyclopropyl/methyl, C6-C7-cycloalkenylmethyl, C6-C8-cycloalkynylmethyl, [1-(2,3-dimethylcyclopropen-2/yl]methyl exo-7-norcarylmethyl, [7-(cis-1,6-dimethyl-endo-3-norcarene)methyl, 1-(4-methylbicyclo[2.2.2]octyl/methyl, 1-(4-methylbicyclo[2,2,2]-octen-2-yl)methyl, 5-(bidyllid^.^Jhepten-iZ-yl/methyl, 1-adamantyl) or 2-adamantylmethyl. In Belgian Patent No. 845 368 (Deiwerit No. 00043Y) presents 5-phenylhexahydroxycarbolines, optionally substituted in positions 2 and 4 with methyl or ethyl radicals, and in position 3 with an alkyl radical of 1-3 carbon atoms, an allyl radical or a propargyl radical. These compounds are useful as antidepressants. German patent publication No. 2 631 836 /Derwent No. 0938Y/ describes structurally related octahydropyrido[4,,3,:2,3]indolo[1,7-ab][1]benzazepines, which can be represented by formula 8, wherein Ya denotes an ethyl bridge between two benzene rings, Xa denotes a hydrogen atom, and Ra denotes a -CH2CH2COOH8 or -CH2CH2COC6H5 group. These compounds are useful as analgesics and sedatives. U.S. patent publication No. No. 4,001,263 describes sedative 5-aryl-1,2,3,4-tetrahydro-γ-carbolines of the formula 9, wherein Xb and Zb are hydrogen or fluorine atoms, and Rb is a methyl radical, a group of the formula -/CHa/n-M-C^Z or -/CH2/m-CH= =CH-C5H4Z, in which n is equal to 3 or 4, m is equal to 2 or 3, M is -CO- or -CH(OH)-, and Z is hydrogen, fluorine or a methoxy group. Surprisingly, it was found that trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles have a significantly higher sedative activity than 1,2,3,4-tetrahydro-γ-carbolines. of the general formula II, wherein X and Y have the above-mentioned meanings, n denotes a number, 3 or 4, M denotes a group of the formula V or VI, and Z denotes a hydrogen, fluorine or methoxy group, and pharmaceutically acceptable salts of these compounds. In these compounds, the hydrogen atoms at carbon atoms 4a and 9b are in a trans position to each other. The compounds of the formula I, prepared by the process according to the invention, are starting compounds for the preparation of compounds of the formula II. The process of the invention illustrates the second stage of the scheme, in which the substituents in the formulas have the above-mentioned meanings, and R2 is preferably a benzyl radical. It is, however, possible to use compounds in which R2 has other meanings. Examples of alternative meanings of R2 are a benzyl radical substituted in the ring, e.g., one or more methyl, methoxy, nitro or phenyl groups, a benzhydryl radical and a radical of the formula -/CH2/n-CH/OH/-/C6H4/Z, where Z is a hydrogen or fluorine atom or a methoxy group and n is 3 or 4. Reductions of tetrahydro-γ-carbolines of formula 3 to 4a,9b-trans-hexahydro compounds of formula 4 are carried out in an ethereal solvent, usually tetrahydrofuran. To ensure complete reduction, an excess of the boron hydride/tetrahydrofuran/BH3-THF/complex is used, typically 100 to 200%. The reaction can be carried out at -10°C to 80°C, and the preferred temperature range is 0°C to 65°C. Typically, a solution of the starting compound of formula III in tetrahydrofuran is added to an ice-cold solution of BH-THF. After the addition is complete, the reaction mixture is heated to boiling and refluxed for 2 hours or longer. The reaction is usually carried out in the presence of an inert gas, such as nitrogen. After the reaction is complete, the solvent is evaporated and the residue acidified with an acid permanganate, e.g., 2-12 molar hydrochloric acid. A preferred acidifying agent is a mixture of equal volumes of acetic acid and 5 molar hydrochloric acid. The acidified mixture is usually saturated within 1-2 hours. or longer is heated to reflux. The desired product can then be isolated, for example, by evaporating the remaining ether solvent and part of the acid mixture and filtering off and washing the precipitate. In an alternative method for isolating the product of formula 4, after heating under reflux, the mixture is filtered, the filtrate is cooled and made alkaline, e.g. with sodium hydroxide, potassium hydroxide or sodium carbonate. The alkaline mixture is extracted with a water-immiscible organic solvent, e.g. chloroform, methylene chloride or benzene, the extracts are evaporated, and the residue is purified by chromatography on a silica gel column, eluting with e.g. ethyl acetate or hexane/ethyl acetate mixtures. Reduction of tetrahydro-γ-carbolines with BH3*THF, followed by acid treatment, gives hexahydro-γ-carbolines in which the hydrogen atoms at carbon atoms 4a and 9b are in a trans position to each other, see, for example, U.S. Patent No. 3,991,199. The 2-benzyl compounds of formula 4 are then converted by the process of the invention to the corresponding 2-H compounds of formula 1. Generally, this can be accomplished by treating the compound of formula 4 with an excess of a lower alkyl chloroformate, e.g., methyl, ethyl, propyl, or isobutyl, in the presence of a suitable reaction-inert solvent. organic solvent, followed by basic hydrolysis. The preferred chloroformate is ethyl chloroformate because it is readily available and effective. A suitable reaction-inert organic solvent is one which dissolves the reactants under the reaction conditions 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 glycol dimethyl ether, and dimethyl sulfoxide. A particularly preferred solvent is toluene. To the mixture of starting material in the reaction-inert organic solvent, the chloroformate is added in about a 10-fold molar excess. For economic reasons, a 3- to 5-fold excess is desirable. The resulting mixture is then heated at 80-100°C, typically at reflux, for about 6-24 hours or longer. For convenience, heating is usually carried out overnight. The reaction mixture is then evaporated under reduced pressure, the residue is dissolved in an alcohol-water mixture, and an alkali metal hydroxide, e.g., sodium or potassium hydroxide, in a 10- to 30-fold molar excess, based on the starting material, of formula 4 is added, and the resulting mixture is then heated to reflux. usually overnight. The solvent is then evaporated and the residue is partitioned between water and a water-immiscible organic solvent such as chloroform, methylene chloride or diethyl ether. The organic phase is evaporated to dryness. The remaining product of formula I can be used crude or after further purification by standard methods, e.g. column chromatography on silica gel. The starting materials are prepared as follows: 2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-γ-carboline is obtained by the Fescher indole synthesis from N,N-diphenylhydrazine and N-benzyl-4-piperidone. The starting mono- or difluor- The tetrahydrogen-Y-carbolines of formula III, wherein at least one of the substituents X, Y is fluorine and R2 is benzyl, are prepared from the corresponding compounds of formula III, wherein R2 is hydrogen, by reaction with a benzyl halide, such as benzyl bromide, used in equimolar amounts. The compounds of formula III, wherein R2 = H, are prepared as in U.S. Patent No. 4,001,263. Other starting materials are commercially available or their preparation is fully described in the chemical literature or may be prepared by known methods. For example, phenylhydrazines are commercially available or may be prepared synthetically by reduction of a phenyldiazonium salt, as described in U.S. Patent No. 4,001,263. in Wagner and Zook's "Synthetic Organic Chemistry", John Wiley & Sons, New York, N.Y., 1956, chapter 26; 1-substituted 4-pipreridones are commercial reagents or are prepared by the method of McElvain and Rorig, J. Am. Chem. Soc., 70, 1826 (1948); 3-benzoylpropionic and 4-benzoylbutyric acids are commercially available or are prepared by a modification of the method of "Organic Synthesis", Coll, Vol. 2, John Wiley & Sons, New York, N.Y., 1943, p. 81. As previously mentioned, the basic compounds of the invention may form acid addition salts. Basic compounds are converted into addition salts by treating them with an acid in an aqueous or non-aqueous medium. In a similar manner, acid addition salts can be regenerated by treating them with an equivalent amount of an aqueous base, for example, an alkali metal hydroxide, carbonate or bicarbonate, or with an equivalent amount of a metal cation forming an insoluble precipitate with the acid anion. The invention is further illustrated by the following non-limiting examples. Example 1: D,L-trans-2-benzyl-2,3,4,4a,5,9b-hexahydro-5-phenyl-1H-pyrido[4,3-b]indole hydrochloride. To a solution of 0.140 moles of boron hydride in 150 ml of tetrahydrofuran, stirred at 0°C in a three-necked flask, A solution of 23.9 g (0.071 mole) of 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole in 460 ml of dry tetrahydrofuran is added to a round-bottomed flask equipped with a magnetic stirrer, condenser, and dropping funnel, and maintained under a nitrogen atmosphere. The dropwise addition is carried out at a rate sufficient to maintain the reaction mixture at a temperature below 9°C. After the addition is complete, the mixture is heated to boiling and refluxed for one hour. The solvent was evaporated under reduced pressure, leaving a white residue. This was suspended in 40 ml of dry tetrahydrofuran and heated, first slowly, with 180 ml of a 1:1 (v/v) mixture of acetic acid and 5 N hydrochloric acid. The resulting suspension was refluxed for 1 hour and then cooled. Evaporation of the chloroform and part of the acetic acid caused a white precipitate to form, which was filtered off and washed with water. The precipitate was resuspended in tetrahydrofuran, filtered off, washed with diethyl ether, and air-dried, yielding 16.7 g (63%) of the desired trans isomer. Melting point 256-260°C. Evaporation of the mother liquor gives an additional 7.2 g of product with a small admixture of the cis isomer. ' By the above-mentioned method, starting from appropriately substituted 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]-indoles, the 4a,9b-iranes isomers of the compounds of formula 4 are obtained, in which R2 is a -CH2C6H5 group and the substituents X Y have the following meanings: X Y X Y H p-F H o-F F H F m-F F o-F F o-F Example II. D,L-trans-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b] indole.A. To a solution of 5.6 g (12.4 mmol) D,L-trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-/p-fluorophenyl/butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 40 ml of toluene is added 5.3 ml (55.7 mmol) of ethyl chloroformate. The resulting mixture was refluxed overnight and then evaporated to dryness, leaving a gummy residue. To the above product was added 200 ml of a 9:1 ethanol/water mixture. After dissolving the product, 15 g of potassium hydroxide was added and the resulting mixture was refluxed overnight. The solvent was forcibly evaporated under reduced pressure and the residue partitioned between water and chloroform. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residual oil was dissolved in ethyl acetate and passed through a silica gel column, eluting first with ethyl acetate to remove the residue. by-products, then with a 1:1 mixture of ethyl acetate and ethanol to elute the desired product. The fractions containing the title compound were combined and evaporated to dryness to give 1.5 g (43%) of a yellow gum which crystallized on standing; m.p. 115-117°C. Alternatively, D,L-trans-2-benzyl-8-fluoro-[p-]-fluorophenyl]-2,3,4,4a,5,9b-hexahydro-[p-]-pyrido[4,3-b]indole hydrochloride was heated to reflux in the presence of an excess of ethyl chloroformate or the appropriate methyl, isopropyl or n-butyl ester, then hydrolyzed and processed as described above to obtain the title compound. Patent Claims 1. A method for preparing new 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of the formula 1, wherein X and Y are the same or different and represent hydrogen or fluorine atoms, characterized in that 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole of the formula 4, wherein X and Y have the above-mentioned meaning and R2 represents a benzyl, benzhydryl, benzyl radical substituted with a methyl, methoxy or phenyl radical or a nitro group. or a radical of the formula Z-C6H4CHOH/CH2/n-, in which Z is a hydrogen, fluorine or methoxy atom and n is 3 or 4, is treated with a molar excess of a lower alkyl chloroformate in the presence of a reaction-inert organic solvent and then subjected to basic hydrolysis. 2. A process according to claim 1, characterized in that the chloroformate is ethyl chloroformate. 3* A process according to claim 1, characterized in that the solvent is toluene and the reaction is carried out at the reflux temperature of the mixture. 4. A process according to claim 1, characterized in that the basic hydrolysis is carried out with sodium hydroxide or potassium hydroxide at the reflux temperature of the mixture; Formula 1 N-|CH2)rt.-MH0" Formula 2 N-Rr Formula 3117 107 X.~N N-R^ ^Y Formula A O II -c- OH I -CH- Formula 5 Formula 6 "Wjrif^^0^ R' Formula 7 H *N-R Yc H va X Formula X N N-Rc Formula 9117107 " ^ "N-Ro n DU.U.. ^l^T-^r "N-R Formula 3 Y XY Formula / D cico2c2h5 Tlr-^" 2) KOH,C2H5OH7H20 * ^N U Y Formula 1 Scheme Bltk 855/82 80 copies A4 Price 100 PLN PL PL PL PL PL PL PL PL PL PL

Claims (1)

1.