FI63402B - PROCEDURE FOR FRAMSTATING AV THERAPEUTIC ANVAENDBARA D- OCH D1-TRANS-5-PHENYL-2,3,4,4A 5,9B-HEXAHYDRO-1H-PYRIDO (4,3-B) INDOLDERIVAT - Google Patents

Description

• Jato ».! ΓβΙ rt1, ICUULUTUS | UUCAISU / 7. AA

[bj (11) utlAggningsskrift 634 0 2 C Patent granted 10 06 1933> ιί '* 1¾ ^^ Patent moddolat ^ T ^ (51) Kv.lk.3 / lnta.3 C 07 D 471/04 FINLAND I - FINLAND ( 21) Pwnttlhukumm — Pwuntunietamt 761612- (22) Htk # ml »p« ly «—Aieöknlnnd.g 22.05-78 '' (23) AlkupUvl — GlMchmdag 22.05.78 (41) Tullut fulktokal - Whrtt effimtllf 2k 11 78

Ntmtl. J. nkimriMIItt »j. w »u. P.-

Patent and Regression Act AmSkin utlagd och utl. * Krlftun puMIcurad 28.02.83 (32) (33) (31) Pyy * «* r utuelkuui — Begird prtorttut 23. 05.77 USA (US) 799392 (71) Pfizer Inc., 235 East U2nd Street, New York, NY, USA (US) (72) Willard McKowan Welch, Jr., New London, Connecticut, USA (US) (7I +) Oy Kolster Ab '(5 * 0 Method for the development of new therapeutically useful d- and dl for the preparation of trans-5-phenyl-2,3, **, ** a, 5,9b-hexahydro-1H-pyrido [1,3-b] indole derivatives - for the preparation of therapeutic derivatives of d- and dl-trans- 5-Phenyl-2,3,3,4α, 5,9b-hexahydro-1H-pyrido-1,3-b] indole derivatives

The invention relates to a process for the preparation of novel d- and dl-trans-5-phenyl-2,3,4-4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole derivatives and their pharmaceutically acceptable salts.

The formula of the new compounds is I

^ ^ 4a J '' k

Y

0 2 63402 in which the hydrogen atoms attached to carbon atoms 4a and 9b are in the trans position relative to each other, X and Y represent hydrogen or fluorine, M is CHOH or C = O, n is 3 or 4 and Z is hydrogen, fluorine or methoxy.

These compounds have been found to be very effective sedatives.

The compounds of formula I and their pharmaceutically acceptable salts can be prepared by:

(a) tetrahydro-N-carboline of formula II

-f ^ N-, CH2, n-CH- ^ ^ I oh Vrr— /! wherein X, Y, Z and n are as defined above, is reacted with borane in an inert organic solvent at -10 to 80 ° C, followed by treatment with an acid to give a compound of formula I wherein M is CHOH, or

(b) 4α, 9b-trans-hexahydro-N-carboline of formula III

XcQ

V N V

Q

Y

wherein X and Y are as defined above, are acylated with a ketocarboxylic acid of formula IV

3 63402

-C- (CH2) .i-COOH

1 ^ 1 '· ^ “IV

2 — U I p

wherein Z and n are as defined above, or an acid chloride or acid brimide thereof to give a compound of formula V

\ - ~ n-l ~ co \ _ / λ1

Q

* Y

wherein X, Y, Z and n are as defined above, after which the compound of formula V obtained is reduced with lithium aluminum hydride in the presence of an inert solvent to give a compound of formula I wherein M is CHOH; and if desired, the compound obtained is oxidized in a manner known per se to a compound of formula I in which H is C = O, and / or, if desired, the racemic compound obtained is decomposed and the d-enantiomer is isolated.

Since the introduction of reserpine and chlorpromazine in psychotherapy in the early 1950s, extensive studies have been conducted to obtain sedatives with superior biological effects, several of which have been shown to be VXcarboline derivatives, also known in the art as pyrido / 4,3-b7indole derivatives.

U.S. Patent No. 3,687,961 describes 8-fluoro-2- [3- (4-fluorophenylanilino) propyl] -1,3,3,4-tetrahydro-N-carboline as a sedative useful in warm-blooded animals. Patent No. 3,755,584 describes the corresponding compounds of the above-mentioned activity having the fluorine atom in the 6- or 8-position and a certain p-substituted phenylalkyl group in the 2-position.

U.S. Patent No. 3,983,239 describes hexahydro-Y * carbolines having the structural formula 4 63402 r1v / \ / \

7Ί-äJT N- (CH ~), CO- (O

LlClj ^

N / \ N4a \ X

: i2 1 2 wherein R is methyl or ethyl and R is hydrogen, methyl or ethyl. The stereochemical position of the hydrogen atoms attached to the carbon atoms at positions 4a and 9b relative to each other is not mentioned in this publication. However, they could be inferred to be in the cis position, since the formation of a hexahydro-N * carboline backbone from a 1,2,3,4-tetrahydro-N-carboline precursor by catalytic hydrogenation in the presence of platinum is a well-known method in the art for attaching hydrogen atoms to carbon-carbon. double bond to the cis position. The required compounds are neuroleptic agents mentioned to be useful in the treatment of schizophrenia.

U.S. Patent No. 3,991,199 describes hexahydropyrimido / T, 3-b7indoles useful as analgesics and sedatives, some of which are of interest as sedatives, some as muscle relaxants, and several as antihypertensives. The structural formula of said compounds is as follows: 'Ocb' '

B

where the hydrogen atoms attached to the carbon atoms at positions 4a and 9b are in the trans position relative to each other and Xa is -H, "Cl, -Br, -CH3, -tert-C4H9 or -OCH3 when Ya is -H, and Xa is -H when Ya is -CF3, and Ra is hydrogen, benzyl ring substituted with 3-chloro-2-butenyl, 2-bromo-allyl, benzyl, methyl, methoxy or chloro, phenethyl, 3-phenylpropyl, chloro, bromo or methoxy substituted 3-phenylpropyl ring, furfuryl, 2-thienyl, C 1 -C 4 alkyl, C 3 -C 8 alkenyl, C 3 -C 5 alkynyl, cinnamyl, chloro, bromo or methoxy substituted cinnamyl ring, 3-phenyl -2-propynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, (methylcyclopropyl) methyl, (cis-2,3-dimethylcyclopropyl) methyl, exo-7-norcarylmethyl, (cis-1,6-dimethyl- endo-3-norcaren-7-yl) methyl, (4-methylbicyclo-1- [2,2,2 / oct-1-yl) methyl, (bicyclo [2.2.2] hept-2-yl) methyl, (bicyclo (1,2,2,2 (hept-2-en-5-yl) methyl, 1-adamantylmethyl or 2-adamanthylmethyl).

BE Patent No. 845,368 describes 5-phenylhexahydro-N-carbolines which may be substituted at positions 2 and 4 by methyl or ethyl and at position 3 by alkyl, allyl or propargyl having 1 to 3 carbon atoms. These compounds are useful antidepressants.

From DE-A-2 631 836 to octahydropyridino / 4 ', 3 1: 2,37indolo </ 1,7-ab7_ / l / benzazepines of the preceding structure, which can be represented by the above formula such that Ya is an ethylene bridge between two benzene rings, Xa is hydrogen and Ra is -CH2Cl2COCH8 or -Cl2Cl2COCl2g. The compounds are said to be useful analgesics and sedatives.

U.S. Patent No. 4,001,263 describes 5-aryl-1,2,3,4-tetrahydro-γ-carbolines having the structural formula as sedatives.

Yb ö zb _ 6 63402

L U

wherein X and Z ° may be hydrogen or fluorine atoms and R ° is the same as R in formula (I). It has now surprisingly been found that the d- and dl-trans-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the formula I have a considerably better sedative effect than the corresponding 1,2, 3,4-tetrahydro-y-carboline.

The starting material of formula III used in process variant b) can be prepared according to the following reaction scheme.

B

X X - tl N-R „(1) BH, / ether - '' '' 'XVsN-R0

Ml J i] λ X x <

(VI) (VII) Y

X H

(1) C1CO2C2H5 "[j 'NH

-> I Jl (2) KOH, C2H50H / H2O

B

Y

(III) 7 63402

For reasons of economy, the benzyl group is preferred as the group R 1, but other R2 groups are also possible in the above scheme. Such alternative R2 groups include e.g. benzyl groups in which the benzene ring is substituted by one or more methyl, methoxy, nitro or phenyl groups, and a benzhydryl group.

The reduction of tetrahydro-N-carbolines of formula (VI) to 4a, 9b-trans-hexahydro compounds of formula (VII) is carried out in ether, usually tetrahydrofuran. In order to ensure the completeness of the reduction, an excess of borane / tetrahydrofuran complex (BH 2 'THF) is usually used, in which case a molar excess of 100-200% is preferred. The reaction can be carried out at a temperature in the range of about -10 to + 80 ° C, but preferably in the range of 0 to 65 ° C. Usually a tetrahydrofuran solution of the starting material of formula (VI) is added to an ice-cold BH 2 -THF solution. After the addition, the mixture is heated to reflux and maintained at this temperature for about 1-2 hours or more. The reaction is usually carried out in the presence of an inert gas such as nitrogen. When the reaction is substantially complete, the solvent is evaporated and the residue is acidified with an excess of acid, e.g. 2-12 M hydrochloric acid. The preferred acid is a mixture of equal volumes of acetic acid and 5 M hydrochloric acid. The resulting acidic mixture is usually refluxed for 1-2 hours or more. The desired product can then be isolated, for example, by evaporating any remaining ether solvent and part of the acid mixture, collecting the precipitated product and washing. Alternatively, the product (VII) can be isolated by filtering the reaction mixture after reflux, cooling the filtrate and basifying by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is extracted with a water-insoluble organic solvent such as chloroform, methylene chloride or benzene, the extracts are evaporated and the residue is purified on a silica gel column using, for example, ethyl acetate or a hexane-ethyl acetate mixture as an eluent.

Treatment of the tetrahydro-N-carboline with a BH 2 -THF complex followed by acid treatment gives hexahydro-N-carbolines in which the hydrogen atoms attached to the carbon atoms in positions 4a and 9b are in the trans position relative to each other, cf. e.g., U.S. Patent No. 3,991,199.

The 2-benzyl compounds of formula (VII) are then converted to the corresponding 2-hydrogen compounds of formula (III). This can generally be achieved by treating a compound of formula (VII) with an excess of 1 mole of a lower alkyl chloroformate ester such as methyl, ethyl, propyl or isobutyl ester in the presence of a suitable reaction-inert organic solvent and then carrying out basic hydrolysis. Ethyl chloroformate is a preferred chloroformate ester due to its easy availability and efficiency. By a suitable reaction-inert organic solvent is meant one in which the reactants are substantially completely soluble under the reaction conditions and no by-products are formed. Such solvents include, for example, aromatic hydrocarbons such as benzene, toluene and xylene, chlorinated hydrocarbons such as chloroform and 1,2-dichloroethane, diethylene glycol dimethyl ether and dimethyl sulfoxide. Toluene is a very preferred solvent.

A mixture of up to 10 moles of chloroformate ester is added to the mixture of the starting material of formula (VII) and the reaction-inert organic solvent. For reasons of economy, it is preferable to use an excess of 3-5 moles. The resulting mixture is heated to a temperature between 80-150 ° C, preferably at the reflux temperature of the mixture, for about 6-24 hours or longer. For convenience, reflux is usually performed overnight. The reaction mixture is then evaporated in vacuo, the residue is taken up in an alcohol-water mixture, a base, e.g. sodium hydroxide or potassium hydroxide, is added in an excess of about 10-30 mol, based on the starting material of formula (VII), and the mixture thus obtained is usually refluxed overnight. The solvent is then evaporated and the residue is partitioned between water and a water-insoluble organic solvent such as chloroform, methylene chloride or ethyl ether, and the organic phase is evaporated to dryness. The residual product of formula (III) may be used as such or may be purified by methods known in the art, such as column chromatography on silica gel.

In the case where both X and Y in the compound of formula (VII) are hydrogen atoms and have a benzyl group, the corresponding compound of formula (III) can be obtained by catalytic removal of the benzyl group using a hydrogen palladium / carbon catalyst. The reaction is usually carried out using a compound of formula (VTI) as the hydrochloride salt at a temperature in the range of 50 to 100 ° C, preferably in the range of 60 to 75 ° C, and a hydrogen pressure in the range of about 138 to 690 kPa in a reaction inert solvent such as methanol, ethanol , in iso-propanol, ethyl acetate or a mixture of one of these and water.

9 63402

When the hydrogen uptake is complete, the catalyst is filtered off and the hydrochloride salt of the product of formula (III) is precipitated by adding an insoluble solvent such as ethyl ether, benzene or hexane. Alternatively, the free base of formula (III) may be separated by evaporating the filtrate obtained after removal of the benzyl group to dryness and separating the residue between a base such as sodium hydroxide and a solvent such as chloroform or ethyl ether. The free base is then separated by standard methods as described above.

Process variant b) can be described by the following reaction scheme.

/ C-tCHj ^ COH -! U ^ \ nC- (CH2) Y

I + (III) -> s'

H Z

(IV) (V)

Q

NY

? H / ^

LiA1H4 J \ - / n

N i (I, M = CHOH) Z

t

B

Y

6 10 63402

When acylating compounds of formula (III) to intermediates of formula (V), acids of formula (IV) or their acid chlorides or acid bromides may be used. When acids of formula (IV), about equimolar amounts of said acid and a compound of formula (III) are used in the acylation, the reaction is reacted with each other in the presence of an inert solvent and a condensation reagent known in the art for forming peptide bonds. Such reagents include e.g. carbodiimides such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and alkoxyacetylenes such as methoxyacetylene and ethoxyacetylene. Dicyclohexylcarbodiimide is the preferred condensing reagent. Useful solvents include e.g. dichloromethane, chloroform, tetrahydrofuran, ethyl ether and benzene. Although the reaction can be carried out with satisfactory results at a temperature in the range of -10 to + 50 ° C, it is preferable to use a temperature in the range of 0 to 30 ° C. At this temperature, the reaction usually takes place in a few hours. The product of formula (V) can be isolated, e.g. by filtering off the insoluble matter and evaporating the solvent. The residue is usually pure enough to be used in the next step.

The intermediate of formula (V) is then reacted with lithium aluminum hydride.

The reduction is preferably carried out in the presence of an inert gas such as nitrogen or argon, and under virtually anhydrous conditions. About 2-10 moles of excess lithium aluminum hydride is suspended in an ether solvent such as ethyl ether or tetrahydrofuran, and the mixture is preferably cooled to a temperature between 0-10 ° C. The compound of formula (V) obtained above is generally dissolved in the same solvent and the solution is added dropwise. The resulting mixture is then allowed to react, usually at about room temperature for about 0.5 to 4 hours, so that the reaction is substantially complete. Excess lithium aluminum hydride is decomposed, for example, by careful addition of water, and when the resulting mixture is filtered and the filtrate is evaporated to dryness, a compound of formula (I) is obtained.

The product is purified by column chromatography using silica gel.

Process variant a) can be described by the following reaction scheme.

63402 η ύ ^ τ — η ^ Γ (CH2 '-ch ^ C ™ 3 / eett-> I II J oh N—' (2> H +

Uf M = CHOH) (II)

Y

The reaction with borane in an ether solvent, preferably tetrahydrofuran, followed by treatment with an acid is carried out under the same conditions as described above for the preparation of the 2-benzyl compounds of formula (VII). The product is purified by column chromatography using silica gel.

Compounds of formula (I) wherein M is CHOH may act as a precursor to the free bases of formula (III). Free bases of formula (III) are obtained using, for example, ethyl chloroformate followed by basic hydrolysis as described above for the removal of the benzyl group from compounds of formula (VII) wherein R 2 is benzyl.

Compounds of formula (I) wherein M is CHOH may be oxidised using reagents and methods known to selectively convert secondary alcohols to the corresponding ketones to give compounds of formula I wherein M is C = O. Suitable oxidants for this reaction include e.g. potassium permanganate, potassium dichromate and chromium trioxide, of which it is preferred to use chromium trioxide in the presence of pyridine. This reaction is preferably carried out by adding an alcohol of formula (I) in a reaction-inert solvent, e.g. dichloromethane, chloroform or benzene, to a mixture of up to 10 molar excess of chromium trioxide and up to 10 molar excess of pyridine, and the resulting mixture is usually stirred. at room temperature until the reaction is complete. Usually ^ 15 minutes - one hour is enough. The product can be isolated, for example, by filtering off insoluble matter, extracting the filtrate with a dilute base such as sodium hydroxide solution, drying the organic layer and evaporating to dryness. If desired, the product obtained as a residue can be purified, for example, by column chromatography.

2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-N-carboline of formula (VI) is obtained by Fischer indole synthesis using N, N-diphenylhydrazine and N-benzyl-4-piperidone. Fluoro-substituted tetrahydro-N-carbolines of formula (VI) in which at least one of X and Y is fluorine and R 2 is benzyl can be prepared from the corresponding compounds of formula (VI) in which R 2 is hydrogen by reaction with a benzyl halide such as benzyl bromide in equimolar form. amounts. The required compounds of formula VI wherein R 2 = H are prepared as described in U.S. Patent No. 4,001,263. The tetrahydrocarbolines of formula (II) used as starting materials are described in the same publication.

Other starting materials are either commercially available or their preparation is well described in the chemical literature or can be manufactured by methods known in the art. For example, phenylhydrazines are commercially available or can be synthesized by reduction of the phenyldiazonium salt, as described by Wagner and Zook in "Synthetic Organic Chemistry", John Wiley & Sons, New York, N.Y., 1956, paragraph 26; 1-Substituted 4-piperidones are commercial reagents or can be prepared by the method of McElvain and Rorig, J. Am. Chem. Soc., 70, 1826 (1948); the required 3-benzoylpropionic and 4-benzoylbutyric acids are either commercially available or can be prepared by modifying the method described in "Organic Synthesis", Coll. Butter. 2, John Wiley and! Sons, New York, N.Y., 1943, p. 81.

The compounds of formula (I) obtained by the methods described above form mixtures of diastereomers. Separation methods for such diastereomeric mixtures include fractional crystallization and chromatography. Separation of the diastereomeric components of the compound of formula (I) by fractional crystallization is usually sufficient to obtain each diastereomer in very pure form. The diastereomers can, of course, be further purified by column chromatography. The above di-! solvent systems useful in the fractional crystallization of astereomers; are, for example, mixed solvent systems containing both polar and non-polar solvents. Examples of polar solvents are ethyl acetate, methanol, ethanol, acetone and acetonitrile. Examples of the non-polar solvents are hexane and its close homologues, ‘1 13! 63402 Benzene, toluene and carbon tetrachloride. The preferred mixture of such solvents is ethyl acetate and hexane. j

The resolution of the individual diastereomers of formula (I) into the d and 1 enantiomers can be carried out by known methods for the resolution of racemic amines, cf. e.g., Fieser et al., "Reagents of Organic Synthesis", Wiley & Sons, Inc., New York (1967), Vol. 1, p. 977 and references cited therein. But a particularly useful method of enantio-! to obtain mers from the racemates of formula (I) it is necessary to esterify the compounds of formula (I); wherein M is CHOH with an optically active acid and then separates the diastereomeric esters by fractional crystallization or K-chromatography. The enantiomeric ketones of formula (I) are then obtained by oxidation of the corresponding enantiomers of formula (I) wherein M is CHOH. Although several optically active acids are known in the art for such use, L-phenylalanine has proven to be particularly useful in the preparation of diastereomers of formula (I, R = CHOH). according to the following scheme, wherein (A) is a 5-aryl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole moiety and t-Boc is tert-butyloxycarbonyl. j dl- (A) - (CH2) n-CHC6H4Z1 + L -C6H5CH2CHCOOH | ^, OH NHt-BOC]]

dl- (A) - (CH2) nCHC6H4Z1 CF3COOH

OCO | H2C6H5 "L _> NHt-Boc (VII) diastereomeric mixture) dl- (A) - (CH2) nCH C6H4Z1 OCOOH CgH4 -L_ ^ (IX, one diastereomer): <3 h2o

V

(I M = CHOH, one enantiomer) (mixture of diastereomers IX) (I, M = CO, one enantiomer) 14 63402

In the first step of the above reaction scheme, one racemic diastereomer (I, M = CHOH) is esterified with t-Boc-L-phenylalanine by a known method to esterify such compounds. In a particularly preferred method, the diastereomer (FI, M = CHOH) is contacted with at least an equimolar amount of t-Boc-L-phenylalanine in the presence of an unreacted solvent and a condensing agent at low temperature, preferably from about 0 ° C to room temperature. Examples of suitable unreacted solvents include chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran and ethyl ether. The preferred solvent is chloroform and the preferred condensing agent is dicyclohexylcarbodiimide. The reaction is usually complete within a few hours. The resulting ester of formula (VII) is isolated by known methods and reacted in cold, preferably at -10 to 20 ° C with a molar excess of trifluoroacetic acid to remove the tert-butyloxycarbonyl protecting group to give the amino ester of formula (IV) as a mixture of diastereomers. The mixture is then separated by fractional crystallization or chromatography to give the separate daistereomers of formula (IV). A particularly suitable separation method is column chromatography on silica gel. The isolated individual diastereomers are then hydrolyzed by known methods in the presence of an acid or base to give the separated right and left rotating enantiomers of formula (I, M = CHOH). The latter enantiomers can be oxidized, e.g. as described herein, with chromic acid to give the corresponding enantiomeric ketones (I, M = CO).

Optical isomers of amine (III) are obtained by resolution of racemic mixtures. The decomposition is carried out with a salt of an amine (lii) and an optically active acid. Although several acids useful in the decomposition of amines are known in the art, cf. e.g., Fieser et al., supra. Preferred acids that readily separate the amine (III) are the optical isomers (D- and L-) of N-carbamoylphenylalanine. The latter is obtained by reacting isomeric phenylalanines with sodium cyanate by methods well known in the art. The decomposition is carried out by reacting one of the isomeric N-carbamoylphenylalanines, e.g. the L-isomer, with a racemic compound of formula (IV) in equimolar amounts in the presence of a suitable, unreacted solvent to give a homogeneous solution of salts. After cooling, the salt of the second optical isomer (III) is obtained as a crystalline solid which can be further purified if desired. The mother liquors containing mainly the salt of the second isomer are evaporated to dryness, the salt is decomposed with an aqueous solution of a base such as sodium carbonate, potassium hydroxide or calcium carbonate, the free base is extracted with a water immiscible solvent, typically ethyl acetate is obtained This residue is then dissolved in a reaction-inert solvent and treated with an equimolar amount of the second isomer of N-carbamoylphenylalanine, e.g. the D-isomer, and the solution is cooled to precipitate crystals of the N-carbamoylphenylalanine salt of the second isomer of formula (III).

Each salt of the amine (III) containing a single enantiomer is then resolved as described above to give near-pure dextrorotatory isomers of formula (III), respectively.

As mentioned above, the basic compounds of this formula I may form acid addition salts. Said basic compounds are converted into acid addition salts by contacting the base with an acid in either an aqueous or non-aqueous medium. Similarly, the free base is obtained when the acid addition salt is treated in the same manner with an equivalent amount of an aqueous solution of a base such as alkali metal hydroxide, alkali metal carbonate or alkali metal bicarbonate or with an equivalent amount of a cation which forms an insoluble precipitate with an acid anion. The bases thus regenerated can be reconverted into the same or other acid addition salts.

It is preferred to use pharmaceutically acceptable salts of the compounds of formula I. Although water insolubility, excessive toxicity, or non-crystallinity make certain salt species unsuitable or less desirable for certain pharmaceutical applications, water-insoluble or toxic salts may be converted to pharmaceutically acceptable bases by acidic disintegration as described above, or alternatively may be converted to any other form.

Pharmaceutically acceptable anions are obtained, for example, from the following acids: hydrochloric, bromic, iodine, jump, sulfuric, sulfuric, phosphoric, acetic, lactic, lemon, tartaric, succinic, malic and gluconic. -acid.

As mentioned above, the compounds of this invention may be used as sedatives in the treatment of mammals.

63402 16 The sedative drugs of this invention are characterized in that they alleviate human manifestations of schizophrenia such as hallucinations, hostility, suspicion, emotional or social withdrawal, anxiety, agitation, and tension. In A. Weissman et al., J. Pharmacol, Exp. Ther., 151, 339 (1966) and the test described by Quinton et al., Nature, 200, 178 (1963) for counteracting amphetamine-induced symptoms in rats is a common method for detecting and comparing the sedative effect of chemical compounds and also correlates excellent in relation to man.

Groups of five rats were placed in a covered plastic cage (26 cm x 42 cm x 16 cm). Rats were allowed to acclimate to the cage for a while and then treated subcutaneously (s.c.) with the test compound. After 1, 2 or 24 hours, they were administered intraperitoneally at a dose of 1 mg / kg of d-amphetamine sulfate. After one hour, amphetamine sulfate. One hour after amphetamine administration, each rat was observed for amphetamine-induced characteristic cage travel. Based on these findings, ED50 values could be calculated, i.e., the doses at which amphetamine-induced movements were antagonized or blocked in 50% of rats. The time of evaluation coincides with the strongest effect of amphetamine, which is 60-80 minutes after administration. The results are shown in Tables 1, 2 and 3.

table 1

The following results are for diastereomeric mixtures when M is CHOH and for individual diastereomers when M is C = O.

Compound of formula I ED50 ^ 9 / ^ 9) XY n MZ 1-5-24 hours HH 3 CHOH H 0.032-0.1 0.032-0.1 0.1-0.32 H (a) "" "pF 0 , 1-0.32 0.1-0.32 0.1-0.32 H "" CHOH P-CH3O 0.1-0.32 0.1-0.32 "1.0 v" "pF ' 0.32 0.1-0.32 "0.32 F-fluoro" CHOH H 0.1-0.32 0.1-0.32 <0.32 "o-fluoro" pF <0.32 <0.32 <0.32 "E-fluoro" "" 0.032-0.1 0.032-0.1 0.032-0.1 "" 2 CHOH p-CHgO 0.1-0.32 <0.1 <0 .32 "" 3 pF <1.0 <1.0 <continued ...

63402 17

Table 1 continues

Known compound (b)

B

B

__ / Y

EE »5o (mg / kg) X YM 1 ~ 5- 24 hours HHH 3.2-32> 3.2? 32" "C2H5" 1.0> '· ET (c) "" C6H5CH2- "10 3, 2-32> 3.2 "" C6H5 (CH2) 3 ~ 3.2-10 3.2-10> 10

Navane ^ 'po 0.32-1.0> 10> 32 a. The ED, -q of the corresponding 4a, 9b-cis analog was 56 mg / kg after one hour b. U.S. Patent 3,991,199 c. Not tested d. cis-9- [3- (4-methyl-1-piperazinyl) propylidene] -2- (dimethylsulfonamido) thioxanthene (US 3,310,553).

Table 2

The activities of the compounds of the formula I and the corresponding known o-s-substituted 5-aryl-1,2,3,4-tetrahydropyrido [4,3-b] indoles.

"~ j _______ X Y n M Z 1- 5- 24 48 hours Method of administration H H 3 CHOH H (a) 3.2-10 3.2-10> 10 - i.p.

(b) 0.032-0.1 0.032-0.1 0.1-0.32 P £ -E "CHOH pF (a) 0.1-0.32 0.1-3.2 1.0-3, 2 3.2-1.0 "(b) 0.032-0.1 0.032-0.1 0.032-0.1 0.1-0.32"

To be continued...

63402 18

Table 2 continued ED50 (mg / kg) X Y n M Z 1-5-24-48 hours Method of administration (a) 1-3.2 0.32-1.0 1.0-3.2 - p.o.

(b) 0.32-1.0 0.1-0.32 0.1-0.32 F £ -F 3 C = O p-F (a) 3.2-10> 10 ~ - i.p.

(b) <1.0 <1.0 <1.0 F oF "" "(a) 0.32-1 1-3.2> 10 (b) 0.1-0.32 ca.0.1 ca.0.1 (b) <1 <1 <1 - po

(a) A compound known from U.S. Patent 4,001,263 (b) A compound of formula I.

Table 3

The activities of the diastereomers άβ and ^ ^ and the enantiomers ei, β, v and 6 (prepared e.g. according to i). The formula of the compound is

N- (CH2) 3ch - \ / J

N! ^

B

O

_F_

Compound (e () D E ° 5o (nhkrog / fcg) ^ ___ 5-24 hours

Diastereomeric mixture - 32-100 32-100 32-100 θ (4 "il n λ + 32.2 ° 120" 33 '° A 000 000> 1,000 32-100 32-100 Y +3.1 180 ^ __ ~ 2 '7 1,000_ Ji60_320-1 000_ 19 63402 Inhibitor of dopamine receptor binding of H-spiroperidol

Experimental methods and results The relative propensity of drugs to dopamine binding sites has been shown to correlate with their relative pharmacological effects, possibly affecting dopamine receptor mediated behavior, cf. e.g., Burt et al., Molecular Pharmacol, 12, 800-812 (1976) and references therein. The neuroplastic receptor binding assay method has been developed by Leyson et al., Biochem. Pharmacol, 27, 307-316 (1978) using 1 H-spiroperidol (spiperone) as the marker ligand. The method used was as follows:

Rats (Sprague-Dawley CD dogs, 250-300 g, Charles River Laboratories, Wilmington, MA) were decapitated and the brain was immediately sectioned on an ice-cold glass plate to remove the corpus striatum (ca. 100 mg / brain). The tissue was homogenized in 40 volumes (1 g + 40 ml) of ice-cold 50 mM Tris-tris (hydroxymethyl) aminomethane, THAH.HCl buffer, pH 7.77 · The homogenate was centrifuged twice at 50,000 g (20,000 rpm). .) For 10 minutes, homogenize the intermediate pellet again in new THAM buffer (same volume). The final pellet was gently resuspended in 90 volumes of cold, freshly prepared (less than one week old) 50 mM Tris buffer, pH 7.6, with 120 mM NaCl (7,014 g / l), 5 mM KCl (0, 3728 g / l). 2 millimoles of CaCl 2 (0.222 g / l, 1 millimole of MgCl 2 (0.204 g / l), 0.1% ascorbic acid (1 mg / ml) and 10 micromoles of pargyline (100 [mu] l stock solution / 100 ml buffer, stock solution = 15 mg / 10 ml double-distilled water Ascorbic acid and pargyline were added fresh daily, the tissue suspension was placed in a 37 ° C water bath for 5 minutes to ensure deactivation of tissue monoamine oxidase and then kept on ice until the incubation mixture contained 0.02 ml of inhibitor solution. tissue homogenate and 0.10 ml of marker H-spiroperidol (New England Nuclear, 23.6 Ci / mmol) prepared in 0.5 millimoles of the final incubation medium (standard dilution 2.5 / hl of stock solution in 17 ml). The tubes were incubated sequentially for 10 minutes at 37 ° C in groups of three tubes and then 0.9 ml of each incubation tube was filtered through Whatman GF / B filters using a high vacuum pump. 10 ml of liquid scintillation fluorine was added and each tube was kept under vigorous vortexing for about five seconds. The samples were allowed to stand overnight until the filters were translucent, vortexed again, and the radioactivity was measured for 1.0 minute. Binding was calculated per milligram of protein as fentanyl (10 μmol) of bound β-spiroperidol. Controls (medium or 1-butaclamol, 10 m, 4.4 mg dissolved in 200 μl glacial acetic acid and then diluted to 2.0 ml with double distilled water to a 10 molar solution - stored in the refrigerator), blind (d- butaclamol, 10 -m, 4.4 mg / 2 ml -4-10 -m stock solution, same protocol as for 1-butaclamol, and inhibitor solutions were run in triplicate.The concentration that reduced binding by 50% (IC 2 q) was plotted. Insoluble drugs were dissolved in 50% ethanol (1% ethanol incubation).

Trans-8-fluoro-5- (p-fluorophenyl) -2-4-hydroxy-4- (p-fluorophenyl) butyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido] The results obtained with the different forms of 4,3-b / indole hydrochloride are shown in Table 4.

Table 4 3

Compound Inhibition of H-Spiroperidol Binding Example 1, Ri.0 millioles 1C ^ 1 4/9 and γ 6 mixed diastereomers 21 8 β-diastereomer 23 9 dextrorotatory oi-enantiomer 22 9 to the left ”β-enantiomer 1 800 8 Y <T diastereomer 23 9 dextrorotatory Y enantiomer 25 9 to the left "" enantiomer 350

The compounds of formula 5 and their pharmaceutically acceptable salts may be administered alone or in admixture with other drugs. They may be administered as such, but a pharmaceutical carrier selected according to the mode of administration and conventional pharmaceutical practice will generally be used. Administration can be, for example, orally in the form of tablets or capsules containing excipients such as starch, milk sugar, certain types of clay, etc. Oral administration can be in the form of elixirs or suspensions in which the active ingredient is mixed with an emulsifying and / or suspending agent. For parenteral injection, sterile aqueous solutions of the desired compounds can be prepared. These aqueous solutions should be suitably buffered, if necessary, and may also contain other solvents such as sodium chloride or glucose to make the solutions isotonic.

21 63402

The invention is illustrated by the following examples: Preparation of starting materials

Example I

dl-trans-2-benzyl-2,3,4,4a, 5,9b-hexahydro-5-phenyl-1H-pyrido [4,3-b] indole hydrochloride

To a 0 ° C solution of 0.140 moles of borane in 150 mL of tetrahydrofuran in a three-necked flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel under nitrogen was added a solution of 23.9 g (0.071 moles) of 2- 5-phenyl-1,2,3,4-tetrahydropyrido [1,3-b] indole in 460 ml of dry tetrahydrofuran. The addition was made at such a rate that the temperature of the reaction mixture remained below 9 ° C. After the addition, the reaction mixture was refluxed for one hour. The solvent was then evaporated in vacuo to a white residue which was suspended in 40 ml of dry tetrahydrofuran and then the suspension was heated, first slowly, with an acid (180 ml) of acetic acid and 5N hydrochloric acid in a volume ratio of 1: 1. The suspension thus obtained was refluxed for one hour and then cooled. Evaporation of tetrahydrofuran and some of the acetic acid gave a white precipitate which was collected and washed with water. When the resulting solid was suspended in tetrahydrofuran, filtered and washed with ethyl ether and air dried to give 16.7 g (63%) of the desired trans isomer.

Evaporation of the mother liquor gave a further 7.2 g of product containing some cis isomer as an impurity.

By repeating the above procedure, but using the correspondingly substituted 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido [3,3-b] indoles as starting materials, the following 4a, 9b-trans compounds are obtained as hydrochloride salts.

- ^^ - CH2C6H5

sN X Xi; J

»

B

Ύ 63402 22 x y x γ H £ -fluorine H o-fluorine F H F m-fluorine "£ -fluorine F o-fluorine

Example II

dl-trans-5-phenyl-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 [1,3-b] indole hydrochloride in 150 ml of absolute ethanol, was hydrogenated for two hours at 60-70 ° C under 345 kPa using a palladium / carbon catalyst (1.0 g, 10%). When the catalyst was filtered off and sufficient ether was added to the filtrate, 2.76 g (87%) of the hydrochloride salt of the desired product was obtained as a precipitate, m.p.

The hydrochloride salt was converted to the free base by separation between ether and dilute sodium hydroxide solution. The ether layer was dried over sodium sulfate and evaporated to give the title compound (97% yield), m.p. 74-76 ° C.

Example III

of dl-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-lH-pyrido%, 3 ~ b7indoli

To a solution of 5.6 g (12.4 mmol) of dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3 , 4,4a, -5,9b-hexahydro-1H-pyrido [3,3-b] indole in 40 mL of toluene, 5.3 mL (55.7 mmol) of ethyl chloroformate was added. The resulting mixture was refluxed overnight and then evaporated to a gummy residue. To the residue was added 200 ml of ethanol / water (9: 1 by volume). After the gum had dissolved, 15 g of potassium hydroxide was added and the resulting mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue partitioned between water and chloroform. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness, the oily residue was taken up in ethyl acetate and passed through a silica gel column eluting first with ethyl acetate and then with the desired product in ethyl acetate / methanol (1: 1 by volume). 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.

6 3 40 2 23

Alternatively, the title compound can be prepared such that dl-trans-2-benzyl-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4], The 3-b7indole hydrochloride is refluxed with an excess of ethyl chloroformate or a corresponding excess of methyl isopropyl or n-butyl chloroformate, then hydrolyzed and finally proceeded as described above.

Preparation of final products Example 1 dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b- hexahydro-1H-pyrido / 4,3-b7indoline hydrochloride

A 1,000 ml reaction vessel equipped with a magnetic stirrer and a dropping funnel under a nitrogen atmosphere was charged with 177 ml of a 0.94 M solution of borane in tetrahydrofuran. The solution was cooled in an ice bath, and a solution of 25 g (0.0555 mol) of 8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl)) was added to the cold solution over 30 minutes. butyl] -2,3,4,5-tetrahydropyrido [4,3-b] indole in 295 ml of tetrahydrofuran. The resulting mixture was first heated at ambient temperature for 20 minutes and then refluxed for two hours. When the reaction mixture was cooled and concentrated in vacuo, a liquid residue was obtained. When 50 ml of acetic acid and 50 ml of 5N hydrochloric acid were added to this mixture, a strong gas evolution began. The mixture was refluxed for one hour, cooled and filtered. The filtrate was cooled in ice and basified by the addition of 50% (v / v) sodium hydroxide solution. When the basic solution was extracted twice with 150 ml of chloroform, the combined organic extracts were dried over magnesium sulfate and evaporated to dryness in vacuo to give 25 g of a yellow foamy solid. When thin layer chromatography on silica gel using a hexane / ethyl acetate solvent system (1: 1 by volume) showed two products. The foamy solid was chromatographed on a silica gel column using hexane / ethyl acetate (1: 1 by volume) as eluent and the fractions were monitored by thin layer chromatographic analysis. When only a faster moving product, i.e. 8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido / 4,3- The fractions containing β-indole were evaporated to dryness, the residue was taken up in acetone and converted to the hydrochloride salt by the addition of anhydrous hydrogen chloride in acetone to give a white solid which was filtered and dried to give 1.5 g of 3-butenyl 63402 24, m.p. 270-273 ° C.

When only the slower moving 8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido- The fractions containing [4,3-b] indole were concentrated, stirred in ether and converted into the hydrochloride salt by the addition of anhydrous hydrogen chloride to give 10.8 g of product, m.p. 241-245 ° C.

The proportion of the more mobile 3-butenyl compound can be increased to up to 100% when the acidity is suitably added and the reflux time in the acetic acid / hydrochloric acid mixture is extended.

Example 2

When the procedure of Example 1 was repeated but starting from 8-fluoro-5- (o-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,5-tetrahydropyrido [4], 3-b7indole, the faster moving component trans-8-fluoro-5- (o-fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenyl] -2,3,4,4 -4a was identified by silica gel chromatography. 5,9b-hexahydro-1H-pyrido [4,3-b] indole, m.p. 141-142 ° C. The slower moving component was trans-8-fluoro-5- (o-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H- intended-do / 4,3-b7indoli, mp. 195-197 ° C.

Example 3 dl-trans-2- (4-hydroxy-4-phenylbutyl) -5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride 0 ° To a suspension of 865 mg (4.20 mmol) of dicyclohexylcarbodiimide and 748 mg (4.20 mmol) of 3-benzoylpropionic acid in 30 ml of dichloromethane was added 1.0 g (4.0 mmol) of dl -trans-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido-1H-pyrido [4,3-b] indole in 10 ml of dichloromethane. The resulting mixture was stirred for two hours while being allowed to warm to room temperature. When the reaction mixture was then cooled again to 0 ° C, filtered, washed with dichloromethane and the filtrates evaporated to give dl-trans-2- (3- (3-benzoyl) propionyl] -5-phenyl-2,3,4,4a, 5,9b -hexahydro-1H-pyrido [4,3-b] indole, which was used as such in the next step.

The residue obtained above was dissolved in 50 ml of tetrahydrofuran and the solution was heated to reflux. A filtered lithium aluminum hydride solution in the same solvent was added until gas evolution ceased (1 molar excess), and the resulting mixture was refluxed for 5-10 minutes and then cooled. Then, 17 g of powdered anhydrous sodium sulfate was added, followed by 0.5 ml of water. The mixture was stirred for 30 minutes at room temperature 63.402, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column (80 g) using ethyl acetate / methanol (4: 1 by volume) as eluent to give the title compound as the free base when the solvent was first evaporated. When the free base was dissolved in ether, an ethereal solution of anhydrous hydrogen chloride was added until precipitation was complete, filtered and dried to give 1.04 g of the hydrochloride salt, m.p. 222-224 ° C. Infrared Spectrum (KBr) / α: 2.97, 3.43, 4.00 (broad), 6.25, 6.68, 6.88, 7.51, 7.96, 8.18, 8.45, 9.82. Mass spectrum m / e: 398, 292, 263, 249, 220, 207, 192 (100%); UV (methanol) Δ 245 (ε = 0.653 x 104), 270 (ε = 0.914 x 104).

Example 4

Following the procedure of Example 3, the following dl-trans compounds were prepared using in each case the free base prepared in Example II or III and the corresponding 3-benzoylpropionic acid as starting material. Products were isolated as hydrochloride salts unless otherwise noted.

L \ -i / fo

V

y XYZ Yield (%) FFH 220-223 18 HHF 239-245 39 HH CH., 0 amorphous solid 54 (a) FF "45-48.5 (b) 31 (a) Mass spectrum m / e: 428, 411 , 263 (100%), 220, 206, 204, Infrared Spectrum (KBr), δ: 2.98, 3.42, 4.07 (broad), 6.20, 6.26, 2.60, 6, 88, 804, 8.54, 9.77 12.05.

(b) Melting point and yield mean free base.

63402 26

Example 5 dl-trans-5-phenyl-2- [3- (p-fluorobenzoyl) propyl] -3,4,4a, 5,9-hexahydro-1H-pyrido [4,3-b] indole hydrochloride to a magnetic stirrer and 0.828 mL (8.0 mg, 10.3 mmol) of dry pyridine and 10 mL of dichloromethane were placed in a 25 mL reaction vessel maintained under a nitrogen atmosphere. To the solution was added 517 mg (5.17 mmol) of chromium trioxide, and the resulting dark red suspension was stirred at room temperature for 15 minutes. A solution of 359 mg (0.862 mmol) of dl-trans-5-phenyl-2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b- was then added in one portion. hexahydro-1H-pyrido [4,3-b] indole as the free base in 5 ml of dichloromethane. The reaction mixture rapidly turned to a brown suspension. This was stirred for 30 minutes at ambient temperature. The insoluble material was filtered off and washed with dichloromethane, and the filtrate and washings were combined and extracted with 20 ml of 10% sodium hydroxide solution. When the organic layer was dried (MgSO 4) and evaporated to dryness in vacuo, a gummy residue was obtained. The residue was purified by column chromatography on silica gel using hexane / ethyl acetate (1: 1 by volume) as eluent. The fractions containing the desired compound were combined and evaporated to a gummy residue, and the gum was taken up in ether and treated with anhydrous hydrogen chloride. The resulting suspension was evaporated to dryness and the residue was taken up in 3 ml of cold dichloromethane. The resulting colorless solid was collected by filtration and dried to give 20 mg of the title compound, m.p. 224 to 246.5 ° C.

Example 6 dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [3- (p-fluorobenzoyl) propyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4 1,3-b7indole hydrochloride To a 100 mL flask containing 20 mL of dichloromethane and 1.76 mL (21.9 mmol) of pyridine was added 1.09 g of chromium trioxide and the resulting dark suspension was stirred for 15 minutes at ambient temperature. A solution of 824 mg (1.82 mmol) of dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] / 2 was then added in one portion. , 3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole as the free base (prepared from the hydrochloride salt by basifying the aqueous solution with sodium hydroxide, extracted with dichloromethane and the extracts evaporated to dryness) in 10 ml of dichloromethane. After stirring the red-brown suspension thus obtained at ambient temperature 27 63402 for one hour and then treating as described in Example 5, 25 mg of the desired product are obtained, m.p. 260-263 ° C. Example 7 dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H- pyridoZ4,3-b7-indole acetate

A mixture of 5 g of dl-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 hydrochloride in 75 ml of water, treated with 3 ml of water containing 1.0 g of sodium hydroxide and the liberated base extracted into 150 ml of diethyl ether. The ether layer was separated, dried over magnesium sulfate and treated with 1 mL of glacial acetic acid. The organic solvent and excess acetic acid were removed under reduced pressure, and the residue was triturated with hexane and filtered.

Example 8 dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H- separation of diastereomers of pyrido / 4,3-c7indoline

Five grams of the dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [T-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexane obtained in Example 3 a mixture of diastereomers of hydro-1H-pyrido, p-3-b7indole hydrochloride was converted to the free base by partitioning between methylene chloride and 10% aqueous sodium hydroxide solution. The organic phase was dried over sodium sulfate and evaporated to a foam which was dissolved in 12.5 ml of ethyl acetate and 45 ml of hexane at the boiling point of the mixture. After cooling overnight, the precipitated product was isolated by filtration to give 2.24 g of product, m.p. 126-129 ° C. This was recrystallized three times from ethyl acetate-hexane to give 1.22 g of one diastereomer, called the α-diastereomer, m.p. 132-134 ° C. This free base was converted to the hydrochloride salt by adding an ethereal solution of hydrogen chloride to a methanolic solution of the free base to give 1.30 g, m.p. 259-260 ° C. HPLC analysis showed that it was more than 99% pure diastereomer.

The mother liquor from the first crystallization above was evaporated to a resin which was dissolved in ethyl ether and converted into the hydrochloride salt by adding ethereal hydrogen chloride solution. The crystalline solid formed was recrystallized three times from a mixture of acetonitrile and methanol to give 1.03 g of the second diastereomer, which is called the γS diastereomer, m.p. 237-239 ° C.

f '/ Ϊ.

63402 28 High performance liquid chromatographic analysis of this product showed that it was about 95% by weight pure β diastereomer with about 5% vS diastereomer as an impurity.

Example 9 dl-trans-8-fluoro-5- (p-fluorophenyl) -2-Z4-hydroxy-4- (p-fluoro-phenyl) -butyl] -2,3,4,4a, 5,9b-hexahydro- Separation of diastereomers of 1H-pyrido [4,3-b] indole Separation of the α-β diastereomer into the β-enantiomer and the β-enantiomer. A solution of 2.40 g (5.3 mmol) of the racemic N, N-diastereomer obtained above and 2.0 g (7.5 mmol) of N-tert-butoxycarbonyl-L-phenylalanine in 80 ml of chloroform was cooled in an ice bath and under a nitrogen atmosphere. To the stirred solution was added 1.55 g (7.5 mmol) of dicyclohexylcarbodiimide, and the resulting mixture was stirred for one hour at 0 ° C and another hour at room temperature. The precipitated solid (urea) was isolated by filtration and washed with methylene chloride. The filtrate and washings were evaporated in vacuo and the residue was chromatographed on silica gel eluting with a 5: 1 mixture of methylene chloride and ethyl acetate. The fractions containing the desired esters of N-tert-butoxycarbonyl-L-phenylalanine were combined, evaporated in vacuo to give 2.5 g of a white, amorphous foam.

To this was added 30 ml of anhydrous trifluoroacetic acid at 0 ° C, and the mixture was stirred in an ice bath for 30 minutes, during which time dissolution occurred. Trifluoroacetic acid was removed by evaporation in vacuo on a rotary evaporator without external heating of the flask.

The solid residue was dissolved in cold methylene chloride and washed with cold 12% w / w aqueous sodium bicarbonate solution until the wash solution was neutral according to the pH test paper. The neutral organic layer was dried over magnesium sulfate, the solvent was evaporated to give 1.6 g of a pale yellow resin. This was purified by chromatography on 40 g of silica gel Merck 230-400 mesh eluting with a 35: 1 mixture of ethyl acetate and methanol. The fractions containing the L-phenylalanine ester of the β-enantiomer and the fractions containing the L-phenylalanine ester of the β-enantiomer were separated, evaporated to dryness in vacuo to give 636 mg and 474 mg, respectively.

A stirred solution at room temperature of 625 mg of the L-phenylalanine ester of the enantiomer in 10 ml of methanol was treated with 10% aqueous sodium hydroxide solution until the solution became cloudy and then stirred for 30 minutes at room temperature. Methanol 63402 29 was removed by evaporation in vacuo and 10 ml of water were added. The aqueous suspension was extracted with methylene chloride and the combined organic layers were dried over magnesium sulfate. Evaporation of the solvent gave a pale yellow resin which was dissolved in 5 ml of acetone and treated with an excess of ethereal hydrogen chloride solution from which the hydrochloride salt of the dextrorotatory enantiomer crystallized as flakes, 380 mg, mp 251-255 ° C, = + 32.2 ° C (c = 1.67 in methanol).

Similar hydrolysis of 474 mg of the L-phenylalanine ester of the β-enantiomer obtained above gave 8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-3- (p-fluorophenyl) butyl] -2,3,4 , 4a, 5,9b-hexahydro-1H-pyrido / 4,3-127 indole hydrochloride levorotatory enantiomer, m.p. 252-255 ° C, J = -33.0 ° C (c = 1.67 in methanol).

HPLC analysis showed that both the enantiomer and the β enantiomer were 99% or greater pure.

B. Separation of the> 6 diastereomer and into the 8 enantiomer

Trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-4 The? as described to separate the L-phenylalanine esters of the Y-enantiomer and the 3-enantiomer. The separated Y and S esters were then hydrolyzed separately and purified to give the dextrorotatory γ-enantiomer and the levorotatory γ-enantiomer as hydrochloride salts by the method described in Part A above.

The ^ enantiomer: m.p. 240-248 ° C (decomposes), = + 3.1 ° C (c = 1.67 in methanol).

The ^ enantiomer: m.p. 240-248 ° C (decomposes), Λ7β ° = -2.7 ° C (c = 1.67 in methanol).

HPLC analysis showed that the purity of the N-enantiomer was about 95% and that of the 8-enantiomer 97%. The lower purity of these enantiomers was expected in light of the γ-ε "diastereomer contamination of the above β-diastereomer.

Using the procedure described in Example 21 for the separation of diastereomeric mixtures and the methods for resolving the diastereomers in Parts A and B of the above example, the enantiomers of the compounds of formula (II) of Examples 3A, 4 and 9-11 were obtained, respectively.

Example 10 Decomposition of dl-trans-8-fluoro-5 - · (p-fluorophenyl) -2,3,4,4a, 5,9b-hexa-63402 30 hydro-1H-pyridoZ,4,3b7indole A. D - (-) - n-karbamoyyllfenyylialaniini

To a suspension of 16.52 g (0.10 moles) of D - (+) - phenylalanine in 75 ml of water was added 12.4 g (0.10 moles) of sodium carbonate hydrate. To the resulting solution was added 12.17 g (0.15 moles) of potassium cyanate with stirring, and the mixture was heated in a water bath (internal temperature 85-90 ° C) for 1.5-2.0 hours. After cooling in an ice bath, the reaction mixture was carefully acidified to pH 1-2 with concentrated hydrochloric acid. The precipitate was isolated by filtration, washed with ice water and then ethyl ether to give 15 g of crude product.

This was recrystallized by dissolving in 250 ml of warm methanol, diluting with 400 ml of water, allowed to cool slowly to room temperature and kept in a refrigerator until precipitation ceased. The product was obtained as white, opaque needles, yield 58%, after recrystallization, m.p. 203-204 ° C (decomposes), λ max - (-) 40.7 ° C (methanol).

B. L - (+) - N-carbamoylphenylalanine Using the procedure described above, L - (-) - phenylalanine instead of the D - (+) isomer, after recrystallization, L - (+) - N-carbamoylphenylalanine was obtained, yield 42%, m.p. 205-207 ° C (decomposes), = (+) 39.0 ° C (methanol).

C. Decomposition of Enantiomeric N-Carbamoylphenylalanine Salts 1. One equivalent of dl-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido / 4,3-b / indole as the free base dissolved in a minimum amount of ethanol, one equivalent of L - (+) - N-carbamoylphenylalanine was added. The mixture was heated on a water bath with more ethanol until a homogeneous solution formed. This was allowed to cool to room temperature and the precipitated white needles of the L - (+) - N-carbamoylphenylalanine salt of the free base (-) enantiomer were isolated by filtration and dried, m.p. 207-209 ° C, / o (7p0 = -5.9 ° C (in methanol)).

2. The mother liquor obtained above was evaporated to dryness, the residue partitioned between aqueous sodium carbonate solution and ethyl acetate, the organic layer dried over magnesium sulphate, evaporated in vacuo to give an oily residue, the oil dissolved in a small amount of ethanol and treated with one equivalent of N-carbyl. The mixture was heated on a water bath while adding more ethanol until dissolution was complete. The solution was cooled, worked up as above to give the crude D - (-) - N-carbamoylphenylalanine of the free base (+) enantiomer 63402 in 92% yield, recrystallized from ethanol (75 ml / g), total yield 65%, mp. 209-211 ° C, = + 6.6 ° C (in methanol).

D. Isolation of the hydrochloride salts of the enantiomeric free base 1. The enantiomeric N-carbamoylphenylalanine salt obtained in Part C1 was partitioned between aqueous sodium bicarbonate solution and ethyl acetate, the organic layer was dried over magnesium sulfate and evaporated in vacuo over anhydrous magnesium sulfate. hydrogen was passed over the surface of the solution with shaking to give a white precipitate. Excess hydrogen chloride and ether were removed by evaporation and at ambient temperature to give (-) - trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido / 4,3- b / indole hydrochloride in about 96% yield. This was recrystallized by dissolving in a minimum amount of boiling ethanol and ethyl ether was added until the solution became cloudy. The product was obtained as small white crystals, yield 75%, m.p. 258-260 ° C, m.p. = (-) 40.9 ° C (in methanol).

2. In a similar manner, (+) - trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [3,3-b] indole was obtained above. part of the salt of C2, crude yield 96% and after recrystallization 75%, m.p. 260-262 ° C, = (+) 39.2 ° C (in methanol).

Claims (1)

A process for the preparation of therapeutically useful d- and dl-trans-5-phenyl-2,3,4,43 / 5,9b-hexahydro-1H-pyrido [4,3-b] indole derivatives and their pharmaceutically acceptable derivatives. for the preparation of salts, 11 lia \ '-' »Y ___ in which the hydrogen atoms attached to the carbon atoms 4a and 9b are in the trans position relative to each other, X and Y represent hydrogen or fluorine, M is CHOH or C = O, n is 3 or 4 and Z is hydrogen, fluorine or methoxy, characterized in that (a) a tetrahydro-β-carboline of the formula II T1 in which X, Y, Z and n are as defined above is reacted with borane in an inert organic solvent at a temperature of -10 to 80 ° C, followed by treatment with an acid to give a compound of formula I wherein M is CHOH, or (b) 4α, 9b-trans-hexahydro-4'-carboline of formula III 33 63402 H ϋ y wherein X and Y are same as above, is acylated with a ketocarboxylic acid of formula IV O-C- < CH2) n.i-COOH wherein Z and n are as defined above, or with its acid chloride or acid bromide to give a compound of formula V1f-CO- (CH2) η-χ-CO- ^ [H '. . δ Ύ ___ wherein X, Y, Z and n are as defined above, after which the obtained compound of formula V is reduced with lithium aluminum hydride in the presence of an inert solvent to give a compound of formula I wherein M is CHOH; and if desired, the compound obtained is oxidized in a manner to be obtained per se to a compound of formula I in which M is C = O, and / or, if desired, the racemic compound obtained is decomposed and the d-enantiomer is isolated. 34 Patent 63402 For the preparation of therapeutically active compounds d- and dl-trans-5-phenyl-2,3,4,43,5,9b-hexahydro-1H-pyrido [4,3-b] indole derivatives with the formulation In the case of a pharmaceutical form of the same, H · IMY and a single formula are used in the form of a chelate 4a and 9b and a transducer in the form of a fluorine, X and Y are either fluorine, M CHOH or C = O, n 3 or 4 In the case of fluorine or methoxy, the reaction is carried out with (a) en tetrahydro-β-carboline in the form of II, Y, z and in the same manner as in the case of boron and inert organic solvents at a temperature of at -10-80 ° C, the mixture is prepared with the addition of the formulation of formula I, with M and CHOH, or (b) en 4a, 9b-trans-hexahydro-V-carboline with formula III 35 63402 QY for X and Y betecnar is sick with ovan, acyleras with ketocarboxyl-syrup with form In XV -c- (CH2) h ^ -COOH z-- 0 for Z and with betecnar sick with ovoc, or yachloride or syrabromide is obtained in the form of a mixture of V, ^, 11-CO- (CH2) r | Formula V reduces the amount of lithium aluminum hydride with a suitable inert solution for the formulation of Formula I, with M or CHOH; and in this case, the oxide of the same is used in the first and second part of the form of the form I, in which M is C = O, and / or, in the case of the same or more, the racemic formation and the d-enantiomers are isolated.