PL116944B1 - Process for preparing novel 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido/4,3-b/indoles,9b-geksagidro-1h-pirido/4,3-b/indolov - 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]indoIi of formula 1, where X and Y are fluorine atoms, which are the starting compounds in the synthesis of new 4a,9ib-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H pyrido [4,3-b]indo!i (hexahydrogen-ro-y-carboline) and pharmaceutically acceptable salts of these compounds, which have a calming effect. After the introduction of reserpine and chlorpromazine into psychotherapy in the early 1950s, considerable effort was directed to the search for other treatments. calming agents with a better biological profile. Several active compounds have been found in the group of pyrido[4,3-b}indoles, called γ-carbolines. In the St. patent description United No. 3,687,961 discloses 8-fluoro-2-[3-/4-fluorophenylanilino/propyl]-1,2,3,4-tetrahydro-y-carboline as a useful sedative for warm-blooded animals. In the United States patent description No. 3,755,584, it was found that related compounds with fluorine atoms in positions 6 or 8 have similar activity, especially compounds substituted in position 2 with a phenylalkyl radical with a para substituent on the phenyl ring. In the patent description St. . United No. 3,983,239 describes hexahydrogen-y-carbolines of the formula 8, in which 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 interdependence of hydrogen atoms bonded to carbon atoms in positions 4a and 9b. However, it can be expected that these atoms are in a cis position to each other, because the compounds were obtained by catalytic hydrogenation of the corresponding 1,2,3,4-tetrahydrogen-y-carbolines in the presence of platinum, and as is known, atoms hydrogen introduced in this way into the carbon-carbon double bond are in a mutual cis position. Compounds of formula 8 are claimed as neuroleptics, useful in the treatment of schizophrenia. In US Patent No. U 3 991 199 hexahydropyrido[4,3-b] indoles are presented, useful as analgesics and psychotropic agents. Some of them are interesting as sedatives, while others as agents releasing muscle tension. Many of them have hypotensive activity. in the described compounds, hydrogen atoms at the carbon atoms in positions 4a and 9b in the mutual trans position. The compounds are represented by the general formula 9, in which when Ya is -H, Xa is -H, -Cl, -Br, -CH3, -III .25 G4H9 or -OCH3, and when Ya=-OF3, then Xa=-H; and Ra represents a hydrogen atom or a 2-(3-chloro)butenyl, 2-bromoallyl, benzyl, benzyl radical substituted with a methyl radical, a methoxy group or a chlorine atom, phenylethyl, 3-phenylpropyl, 3-phenylpropyl, substituted 944116 644 3 in the ring with a chlorine or bromine atom or a methoxy group, furfuryl, 2-thienyl, C1-C8-alkyl, C8-C6-alkenyl, C8-C5-alkynyl, cinnamyl, cinnamyl substituted in the ring with a chlorine atom , 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-norkarylmethyl, [7-/cis-1j6-dimethyl-endb *3*noTkaTen7yl]methyl, 1-(4-methylbicyclo[2.2.2]octyl/rhetyl 1-(4-methylbicyclo]2.2.2[octen-2-yl)methyl, 5-(bicyclo[2.2. 2.1-repten-^-ylmethyl, 1-adamah*tylmethyl or 2-adamantylmethyl. In Belgian patent No. 845,368 (Derwent No. 00043Y) depicts 5-phenylsixhydrogen-y-carbolines, optionally substituted in the 2- and 4-positions by methyl or ethyl radicals, and in the 3-position by an alkyl radical with 1-3 carbon atoms, an allyl radical or a propargyl radical. These compounds are useful as antidepressants. German patent advertisement No. 2,631,836 (Derwent No. 0988Y) describes the structurally related octahydropyrido[4',3':2,3] indolo [1,7-ab] [l ]benzazepines, which can be represented by the formula 9, in which Ya is an ethyl bridge between two benzene rings, X* is a hydrogen atom, and Ra is a -CH2CH2COCH8 or -CH2CH2COC6H5 group. These compounds are useful as analgesics and sedatives. In Patent Specification 5t; United America No. 4,001 fttil, the calming 5*arylO*I,2M*e^terohydrofo*^carT3olin^ of the formula 1 is presented, which consists of a hydrogen or fluorine atom, and Rb is a methyl radical, a group, - CH^M-C^Z or */Gtt8/nl-CH=CH- -C6H4Z, in which formulas n is equal to 3 or 4, m jdst is equal to 2 or 3, M is -CO- or -CH/OH/-, and Z is hydrogen, fluorine or methoxy group, it has been found that it has a significantly higher antioxidant effect than l^^^-CKt^twater-o^- carbolines have trans-2,3,4,4a,5,9b-hexa- -lH- #ifydO[4,3-b]i*ldole with a general chip 3, in which gfujfc fflctoxy and pharmaceutically acceptable salts of these compounds or of the formula Ó, in which X and Y fflafó excluding the given meaning, m stands for HOZbe 2 Ittb 3, and z stands for a fluorine atom or gfupe methoxyl otphase, pharmaceutically acceptable salts of these compounds, in the mutual trans position there are hydrogen atoms in different compounds at the atom. It was found that compounds of the formula 3, in which X and thus limit your pits activity for at least 24 hours. The two bundles of formula I produced by the method according to the invention are the starting compounds for the production of compounds - WzófzG 3, which are unexpectedly active final compounds. The method according to the invention for the preparation of compounds of formula I, in which X and Y are the atoms of the fluid, is that the 4a,9b-trans-2,3,4, 4a,5,9b-hexas Odoro-1H-pyrido[4,3-b]-indole of the formula 2, in which X and Y are expressed given meaning, and R2 is a beniyl radical, is treated with hydrogen in the presence of palladium on WgglU. io The reactions are usually carried out on the hydrochloride of the compound of formula 2, at 50-100, preferably 00-75°C, under hydrogen pressure, 1.4-7 kG/cm2, in the presence of a solvent inert in the reaction, e.g. methanol, ethanol , isopropanol, ethyl acetate or mixtures of these solvents with water. After the hydrogen absorption is completed, the catalyst leaves the leaves and the compound of formula 1 is precipitated in the form of hydrohydride by adding e.g. ethyl ether, benzene or hexane. Alternatively, the compound of formula 1 can be isolated as the free base by evaporating the filtrate and debenzylation to dryness and partitioning the residue between an aqueous solution of alkali metal hydroxide, ftp. Sodium hydroxide and a solvent such as chloroform or ethyl ether. The free base is then isolated by known methods. The starting materials are prepared as follows: 2-benzyl-5-phenyl-1,2,3,4-tetrahydrogen-y-carboline is obtained in the synthesis of indoles in L dlUg Fischer from N,N-diphenylhydrazine and N-benzylpiperidone-4. The starting mono- or difluoro-tetrahydro-γ-carbolines of the formula 7, in which at least one of the substituents X, Y is a fluorine atom and Rf is a benzyl radical, M are obtained from the corresponding compounds of the formula 7, in which fe2 means a hydrogen atom reacted with a benzyl halide, such as benzyl bromide, used in an equimolar amount. Compounds of formula I, in which R£ = H, are obtained as described in the 40th St. patent. United Americas No. 4 0Ó1Z63. The following example illustrates the method of the Invention; EXAMPLE D,L-trans*8~fluoro^5-/p-fluoroferiyl-45/-2y3,4,4a,5,9b*s€Hiohydrogen-1H-pyrido[4/3- b]ihdol. In a glass cisrieftlowyrium there was 780 g of palladium on carbon, 18W.5 g (3.0 moles) of water, water, benzyl-S-flUoffd^^/p ^lttórdfehyló/^^^,^^,^ s^s* 5o ciówdofÓ*lti-plryaó[4,3^b]indólU and 86.1 liters of methanol. The reactor is flushed with nitrogen, then with hydrogen, then it is filled with hydrogen, then with 84S.10* Pz, and the reaction is carried out in a temperature of 25-4 l°C for about 2 hours. The reactor is heated, rinsed with kyotttt, after the reaction is filtered, in order to extract the catalyst, the catalytic converter is washed with water, the rinsing water is evaporated and evaporated. fifó 80 residues are added 28 liters of methylene chloride and 87 liters of water, containing 852 g of hydrophoxide sddd. Obtain ^h^ friieszlaniri^ mixed. for 10 minutes, the layers are separated and the water layer is extracted with 28 liters of methylene chloride, the organic layers are washed and washed with 26.5 liters of water. The organic extracts are dried over anhydrous magnesium sulfate and concentrated after adding 95 liters of hexane. The obtained slurry is cooled to 8°C, filtered, washed with hexane and dried. 1446 g (yield 67%) of product with a melting point of 115-118°C are obtained. Elemental analysis: for C17H16F2N2: Calculated: C - 71.31, H - 5.63, N - 9.79, F - 13 .27 Found: C - 71.25, H - 5.50, N - 9.76, F - 13.28. Mass spectrum M/e: 286 (100, m+) 257(50), 256(72), 243(61), 242(57), 148(32), 135(36), 57(79). Patent claim Method for producing new 4a,9b-trans-5-aryl-2,3,4,4a,5 ,9b-hexahydrogen-1H-pyrido[4,3-b]indole of the formula 1, in which X and Y are fluorine atoms, characterized in that at 4a,9b-trans-2,3,4,4a, 9b- hexahydrogen-1H-pyrido[4,3-b]indole of formula 2, in which X and Y have the meanings given above and R2 is a benzyl radical, is treated with hydrogen in the presence of palladium on carbon. rxX7 Pattern 1 *XXXT! « -c- OH I ¦CH- Formula and Formula 5 '^CQHCH2,mCH-CH^y^ Y Formula 2 ¦(CH2)n-MH0' 1 Formula 6 N-R^ Formula 7 Y Formula 3116 944 9b.N R' N -(CH2)3CO-^y-F Pattern 8 X H k^N-Ra N- Yc H X Pattern 9 ~N-Rb N Pattern 10 Bltk 844/82 80 copies A4 Price PLN 100 PL PL PL

Claims (1)

1. Patent claim 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 1, wherein and Y represent fluorine atoms, characterized in that 4a,9b-trans-2,3,4,4a,9b- hexahydrogen-1H-pyrido[4,3-b]indole of formula 2, in which X and Y have the meaning given above, and R2 is a benzyl radical, reacted with hydrogen in the presence of palladium on carbon. rxX7 Pattern 1 *XXXT! « -c- OH I ¦CH- Formula and Formula 5 '^CQHCH2,mCH-CH^y^ Y Formula 2 ¦(CH2)n-MH0' 1 Formula 6 N-R^ Formula 7 Y Formula 3116 944 9b. N R' N-(CH2)3CO-^y-F Pattern 8 X H k^N-Ra N- Yc H X Pattern 9 ~N-Rb N Pattern 10 Bltk 844/82 80 copies A4 Price PLN 100 PL PL PL