KR820000103B1 - Process for preparing trans-2-substituted -5-aryl-2,3,4,4a5,9b-hexahydro-1h-pyrido(4,3-b)indoles - Google Patents

Abstract

The title compds.(I; X,Y = H, F; Z = H, F, CH3O; n = 3, 4), useful as tranquilizer, were prepd. Thus, 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b indole was reduced in THF with borane, followed by hydrogenation to give 63% (±)-trans I(X,Y,Z = H; n =1; Z = bond)HCl which was debenzylated with H2 over Pd/C(87% yield) and the product isolated as the free base.

Description

Production method of trans-2-substituted-5-aryl-2,3,4,4a5,9b-hexahydro-1H-pyrido [4,3-b] indole derivative

The present invention provides trans-2-substituted-5-aryl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3b] indole derivatives and pharmacologically effective as neurostabilizer It relates to a process for preparing nontoxic salts.

Since the introduction of reserpine and chloropromazine as antipsychotics in the early 1950s, there has been much research on the development of other neurostabilizers with better physiological effects. Some of them are γ-carboline derivatives known as pyrido [4,3-b] indole derivatives.

U.S. Patent No. 3,687,961 describes 8-fluoro-2- (3- (4-fluorophenylanilino) propyl) -1,2,3,4-tetrahydro-γ-carboline as a neurostable agent in warm-blooded animals. It was announced that it is valid as. US 3,755,584 discloses that structurally related compounds having phenylalkyl groups substituted with fluorine at the 6- or 8-position and specific p-substituted at the 2-position have a similar effect.

US Patent Application No. 3,983,239 describes hexahydro-γ-carboline of the following general formula.

Wherein R ¹ is methyl or ethyl and R ² is hydrogen, methyl or ethyl.

Reference is not made to the stereochemical relationship of the hydrogen atoms attached to the 4a and 9b carbon atoms. However, hexahydro- is obtained by hydrogenating precursors 1, 2, 3 and 4-tetrahydro-γ-carboline, which are known methods for introducing hydrogen atoms into the carbon-carbon double bond in cis-coordination, in the presence of a platinum catalyst. Based on the method of producing gamma-carboline nuclei, they can be considered to be cis-related. The attached compound is a neuroleptic useful as a schizophrenic agent.

U.S. Patent No. 3,991,199 describes hexahydropyrimido [4,3-b] indoles and their pharmaceutically suitable salts, which are useful as analgesics and sedatives, some of which are of interest as muscle relaxants. Most of these have hypotensive action.

In the above formula, hydrogens bonded to carbon atoms at positions 4a and 9b are trans with each other, and when y ^a is -H, X ^a is -H, -C1, -Br, -CH ₃ , tertiary -C ₄ H ₉ or When -OCH ₃ and Y ^a is -CF ₃ , X ^a is -H,

R ^a is hydrogen, 3-chloro-2-burenyl, 2-bromo-allyl, benzyl, benzyl, methyl, methoxy or chloro substituted with chloro, phenethyl, 3-phenylpropyl, chloro, bromo or methoxy 3-phenylpropyl ring furfuryl, 2-tenyl, C _1-5 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, cinnamil, chloro, bromo or methoxy substituted cinnamil ring , 3-phenyl-2-propynyl, C _3-7 cycloalkyl, C _4-8 cycloalkylmethyl (methylcyclopropyl) methyl, (cis-2, 3-dimethylcyclopropyl) methyl, C _6-8 cycloal Kenylmethyl, C _6-8 cycloalkadienylmethyl, (2,3-dimethylcycloprop-2-en-1-yl) methyl, exo-7-nor-carylmethyl, (cis-1, 6-dimethyl Endo-3-norgaren-7-yl) methyl, (4-methylbicyclo- [2,2,2] oct-1-yl) methyl, (4-methylbicyclo [2,2,2] Oct-2-en-1-yl) methyl, (bicyclo [2, 2,2] hept-2-yl) methyl, (bicyclo [2,2,2] hept-2-en-5-yl) methyl, 1-adamantylmethyl, or 2-adamantylmethyl.

Recently patented Belgian Kingdom Patent No. 845,368 (Delwen 00043Y) discloses 5-phenyl-1 in which the 2 and 4 positions are optionally substituted with methyl or ethyl and the 3 position is substituted with C _1-3 alkyl, allyl or propazyl. Hexahydro-γ-carboline is described. These are useful as antidepressants.

Recently in Federal Republic of Germany Publication No. 2,631,836 (Delwent 09738Y), Y ^a is an ethylene bridge between two benzene rings, X ^a is hydrogen and R ^a is —CH ₂ —CH ₂ —COCH ₃ or —CH ₂ To structurally related octahydropyrido [4 ', 3': 2,3] indolo [1,7-ab] [1] benzazanes, which can be drawn with the above general formula of -CH ₂ -COC ₆ H ₅ And are effective as analgesics and neurostabilizers.

U.S. Patent No. 4,001,263 discloses 5-aryl-1, 2, 3, 4-tetrahydro-γ-carboline, a neurostabilizer of the following general formula.

또는

Wherein X ^b and Z ^b are hydrogen or fluorine, R ^b is CH ₃ ,

or

또는 이들의 혼합물 또는

이다)이다.Where n is 3 or 4, m is 2 or 3, and M is

Or mixtures thereof

Is).

The trans-2, 3, 4, 4a, 5, 9b-hexahydro-1H pyrido [4, 3-b] indole of the present invention has a corresponding 1, 2, 3, 4-tetrahydro-γ-carboline It has been found to have superior neurostable effects compared to Ryu.

Valuable neurostabilizers according to the preparation of the invention are the colon and racemates of the following general formula (II) and their pharmaceutically harmless salts.

이며 Z은 수소, 플루오르 또는 메톡시이다.Wherein hydrogens bonded to carbons at positions 4 _a and 9 _b are in trans relationship with each other, X and Y are the same or different and each is hydrogen or fluoro, n is 3 or 4, and M is

And Z is hydrogen, fluorine or methoxy.

Compounds prepared by the method of the present invention have a superior neurostable effect than any conventional neuro stabilizers.

In particular, the optically coarse and racemic mixtures of the following compounds exhibit good neurostable effects.

Trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (pfluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro- 1H-pyrido [4, 3-b] indole,

Trans-5-phenyl-2- [4-hydroxy-4- (p-methoxyphenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3- b] indole,

Trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (pmethoxyphenyl) butyl] -2,3,4,4a, 5,9b-hexahydro -1H-pyrido [4, 3-b] indole,

Trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl) -2, 3, 4, 4a, 5, 9b-hexahydro-1H-pyrido [4, 3-b] indole,

Trans-8-fluoro-5- (p-fluorophenyl) -2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4, 3-b] indole,

Trans-8-fluoro-5- ( o -fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2, 3, 4, 4a, 5, 9b-hexa Hydro-1H-pyrido [4, 3-b] indole,

Trans-5-phenyl-2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3- b] indole,

Trans-8-fluoro-5- ( o -fluorophenyl) -2- [4- (p-fluorophenyl) 3-butenyl] -2, 3, 4, 4a, 5, 9b-hexahydro- 1H-pyrido [4, 3-b] indole,

The following scheme shows 4a, 9b-trans-2-methyl-2, 3, 4, 4a, 5, 9b-hexa, wherein R is methyl and X and Y are the same or different and each is hydrogen or fluoro, useful for preparing the active compound. The synthesis process of the idro-1H-pyrido [4, 3-b] indole is illustrated.

The substituent R ² is benzyl best in economic terms, but may be of another kind.

For example, a benzyl group or benzhydryl substituted with one or more of methyl, methoxy, nitro and phenyl groups in the benzene ring and-(CH ₂ ) _n -CH (OH)-(C ₆ H ₄ ) z (Z Is hydrogen or fluoro or methoxy and n is 3 or 4).

The reduction reaction of tetraido-γ-carbolines of general formula (4) to 4a, 9b-trans-hexahydro of general formula (IV) is carried out in an ether solvent, usually tetrahydrofuran. In order to complete the reduction reaction, it is preferable to use an excess of borane / tetrahydrofuran mixture (BH-THF), in particular 100-200% mole of the mixture. As for reaction temperature, the temperature of -10-80 degreeC especially 0-65 degreeC is preferable.

Generally, a solution of the starting material of general formula in tetrahydrofuran is added to a BH ₃ ㆍ THF solution cooled with ice, and then the reaction mixture is heated to reflux and at about 1 to 2 hours or the same. Maintain over. This reaction is usually carried out in the presence of an inert gas such as nitrogen. After sufficient reaction, the solvent is evaporated and the residue is acidified with acid (2-12 moles of hydrochloric acid). A good acidifier is a mixture of acetic acid and 5 molar hydrochloric acid in the same volume. The acidified mixture is heated at reflux for at least 1 to 2 hours, and a portion of the ether solvent and acid mixture is evaporated to separate the desired product, filtered and washed.

Another method of separating the general formula is to filter the reaction mixture after reflux, cool the filtrate and add sodium hydroxide, potassium hydroxide or sodium carbonate to make the solution alkaline. The basic mixture is extracted with an organic solvent that is incompatible with water such as chloroform, methylene chloride, benzene, the extract is evaporated and the residue is purified by chromatography on a silica gel column (eluent: ethyl acetate or hexane / ethyl). Mixtures of acetates).

Tetrahydro-γ-carboline is reduced and acid treated with BH ₃ · THF to give hexahydro-γ-carboline, in which the hydrogens bonded to the carbon atoms of 4a and 9b are trans to each other. (See US Patent No. 3991199).

The 2-benzyl compound of general formula (v) is converted into the corresponding 2-hydrogen compound of general formula (v). The compound of formula (I) is generally treated with an excess of lower alkyl chloroformate esters such as methyl, ethyl, propyl and isobutyl esters in a suitable inert organic solvent followed by alkaline hydrolysis. Chloroformate esters are preferably ethyl chloroformate, which is readily available and effective.

Suitable reaction-inert solvents should be ones capable of dissolving the reactants sufficiently without producing byproducts under the reaction conditions. Such solvents include aromatic hydrocarbons such as benzene, toluene, xylene, chloroform, 1,2-dichloroethane, diethylene glycol, dimethyl ether and chlorinated hydrocarbons such as dimethyl sulfoxide, and toluene is particularly preferable.

A maximum of 10 molar excess of chloroformate ester is added to the mixture in which the starting material of general formula is dissolved in the reaction inert solvent. For economic reasons, 3 to 5 molar excess is preferable. The reaction mixture is usually refluxed at reflux for at least about 6 to 24 hours at a temperature of 80 to 150 ° C., in particular at the reflux temperature of the mixture. The reaction mixture is evaporated in vacuo and the residue is dissolved in a mixture of alcohol and water, and then alkali, such as sodium hydroxide and potassium hydroxide, is added at a molar ratio of 10 to 30 times the general formula of the starting material, and then the reaction mixture is mixed with water and water. In an organic solvent, chloroform, methylene chloride or ethyl ether, and the organic layer is evaporated to dryness. The product of formula (IV) is used as such or purified by column chromatography on silica gel.

In the case of compounds of formula (X) wherein X and Y are hydrogen and R ₂ is benzyl, debenzylation with hydrogen and a pd / C catalyst yields the corresponding compound of formula (VII).

The reaction was carried out using a hydrochloride salt of the general formula at a hydrogen pressure of 20 to 100 p.si (1.4 to 7 kg / cm ² ) at a temperature of 50 to 100 ° C., in particular 60 to 75 ° C., methanol, ethanol and isopropanol. , In the presence of a solvent such as ethyl acetate or a mixture of these and water. When the introduction of hydrogen is completed, the catalyst is filtered off, and non-solvent such as ethyl ether, benzene or hexane is added to precipitate the hydrochloride salt of the general formula (Ⅹ). Alternatively, the filtrate obtained from the debene disease is evaporated to dryness and the residue is partitioned between an aqueous alkali such as sodium hydroxide and a solvent such as chloroform on ethyl ether to separate the free base of the general formula. The organic base is separated by the standard method described above.

The free base of formula (VII) also acts as a precursor of the compound of formula (VI). This is shown in the following scheme where X, Y, Z and n are as described above.

To acylate the compound of formula (VII) to produce an intermediate of formula (XIII), an acid of formula (XII) or the corresponding acid chloride or acid bromide is used.

When an acid of the formula (XII) is used for the acylation reaction, an equimolar amount of the acid and the compound of the formula (X) are reacted in the presence of a condensing agent used to form a peptide bond with a reaction inert organic solvent. As such condensing agents, carbodiimides such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethyl-aminopropyl) carbodimide hydrochloride, and alkoxy acetylenes such as methoxyacetylene and ethoxyacetylene Dicyclohexylcarbodiimide is preferred. Solvents used also include dichlorometals, chloroform, tetrahydrofuran, ethyl ether and benzene. The reaction temperature may be carried out at about −10 ° to 50 ° C., but 0 ° to 30 ° C. is preferred to obtain satisfactory reaction results.

At this temperature, the reaction is complete within a few hours. The product of formula (VIIIII) is filtered to remove insoluble matters and separated by evaporation of the solvent. The product obtained at this time can be used as it is in the next step.

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

In this case, the reduction reaction is preferably carried out in the presence of an inert solvent such as nitrogen or argon under anhydrous conditions, and 2 to 10 molar excess of lithium aluminum hydride is suspended in an ether solvent such as ethyl ether or tetrahydrofuran and the mixture is Cool to 0 ° -10 ° C. The intermediate 2-alkoxy carbonyl obtained as described above is dissolved in the same solvent and the solution is added dropwise. The resulting mixture is allowed to react at room temperature for about 0.5 to 4 hours until the reaction is complete. Careful addition of water breaks down excess lithium aluminum hydride and the mixture is filtered and the filtrate is evaporated to dryness to afford the desired product. The product of formula (VI) is separated as above and purified by column chromatography on silica gel.

[Production of Starting Material]

2- benzyl-5-phenyl-1, 2, 3, 4-tetrahydro-γ-carboline was synthesized by Fisher indole synthesis using N, N-diphenylhydrazine and N-benzyl-4-piperidone. Manufacture. The starting or mono- or difluoro-substituted tetrahydro γ-carboline of general formula (at least one of X or Y is fluorine and R ₂ is benzyl) is the corresponding general formula wherein R ₂ is hydrogen. It is prepared by reacting the compound of (iii) with benzyl halides such as equimolar benzyl bromide.

Compounds of formula (VII, R ₂ = H) and tetrahydro-γ-carboline (V) are prepared according to US Pat. No. 4,001,263.

Other starting materials are readily available on the market and can be readily prepared according to the methods described in the chemical literature or known methods. For example, phenylhydrazine is either commercially available or prepared by reducing the phenyldiazonium salt as set forth in the following reference. (See: Wagner and Zook, "Synthetic Chemistry", John Wiley & Sons, New York, N.Y. 1956, chapter 26)

3-benzoylpropionic acid and 4-benzoylbutyric acid can be prepared according to the following references. [Reference: method of McElvain and Rorig, J. Am. chem, Soc., 70, 1826 (1948)]

1-Substituted 4-piperidones can be prepared by the following references. [Reference: "Organic Synthesis" Coll vol. 2, John Wiley and Sons, N.Y. 1943 p. 81]

As mentioned above, the basic compounds according to the invention can form acid addition salts. The basic compounds can be converted to acid addition salts by reaction with an acid in an aqueous or non-aqueous medium. In a similar manner, acid addition salts can be treated with equimolar amounts of basic aqueous solutions (e.g. alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates), or metal cations that react with acid anions to form insoluble precipitates. Converted to base. The base thus obtained can be converted back to the same or different acid addition salts.

In order to obtain a therapeutic effect of the salts of the compounds according to the invention, it is preferable to use them in the form of pharmaceutically harmless salts. Water insoluble, highly toxic or lacking crystallinity is not suitable for pharmaceutical applications, but water insoluble or toxic salts are converted to the corresponding pharmaceutically toxic bases by the decomposition of salts or to the desired acid addition salts. You can.

Acids that provide pharmaceutically harmless anions include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and gluconic acid. As noted earlier, the neurostable effect of the compound according to this name reduces human schizophrenia in the form of hallucinations, hostility, suspicion, atrophy, anxiety, excitement, tension, and the like. A standard process for testing and comparing neurostable actions is antagonism of the signs induced by amphetamines in rat testing. [Reference: A. Weissman et al. J. Pharmacol. Exp Ther. 151,339 (1966), Quinton et al. Nature, 200,178 (1963)]

These γ-carbolines and their pharmaceutically toxic salts, which are effective as neurostabilizers, may be administered as individual drugs or in combination. These may be administered alone, but are usually administered with a suitable pharmaceutical carrier depending on the method of administration.

For example, it can be administered orally in the form of tablets or capsules containing excipients such as starch, lactose, and certain clays, and the active ingredients can be mixed with emulsifiers and / or suspending agents to form elixirs or oral suspensions. It can also be administered. It may also be injected parenterally in the form of a sterile aqueous solution. Such aqueous solutions should be buffered and, if necessary, contain other solutes such as saline or glucose in order to obtain isotonic solutions.

Although the present invention is generally used for the treatment of mammals, the main purpose is for the treatment of humans. Ultimately, the physician will need to determine the dose that best suits the individual, which will vary depending on the age, body weight, response, and the nature of the drug being administered, the range of symptoms, and the pharmacodynamic properties. It is generally a good idea to start with a small amount initially and gradually increase the capacity until you reach the optimal level. When the composition is administered orally, a little overdose of the active ingredient should be reached to the level obtained when a small amount is administered parenterally.

In view of the various factors mentioned above, the single dose of the compound of the present invention is about 0.5 to 100 mg, in particular 1 to 25 mg is suitable for obtaining the effect as a neuro stabilizer. Each compound is administered once or twice in 5 to 125 mg per week to achieve lasting effects. However, this figure is only one example and can be added or subtracted in each case.

All compounds prepared by the process of the present invention have at least two sub-carbon neutralities obtained by reducing the 4a, -9b-double bonds to a trans-fusion system.

The present invention includes not only racemates but also the colon. In addition, if the 2-position substituent (R) includes a group which may exist as stereoisomer, all diasterio isomers are also included in the present invention because of this.

The following examples are merely to illustrate the invention and are not intended to limit the invention. Various anomalies may be possible without departing from the basic principles of the invention.

Example 1

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

In a three-neck round bottom flask equipped with a magnetic stirrer, a thermometer, a condenser, and a funnel, 150 ml of tetrahydrofuran solution containing 0.140 mol of borane was stirred in a nitrogen atmosphere at 0 ° C., and 23.9 g (0.071 mol) was added thereto. ), 460 ml of anhydrous tetrahydrofuran solution containing 2-benzyl-5-phenyl-1, 2, 3, 4-tetrahydropyrido [4, 3-b] indole is added. The rate of addition is good enough to maintain the reaction temperature below 9 ℃.

After the solution has been added, the reaction mixture is heated to reflux and held at this temperature for 1 hour. The solvent is evaporated in vacuo to give a white solid which is suspended in 40 ml of anhydrous tetrahydrofuran and heated together with 180 ml of acetic acid and 5N hydrochloric acid mixture (volume ratio 1: 1) (first slowly). The resulting suspension is heated and cooled at reflux for 1 hour. A portion of tetrahydrofuran and acetic acid is evaporated and the precipitate of white solid obtained is collected by filtration and washed with water.

This solid is suspended in tetrahydrofuran, filtered, washed with ethyl ether and air dried to yield 16.7 g (63%) of the desired trans-isomer. Melting Point: 256-260 ℃

Evaporation of the mother liquor gave more 7.2 g of product, which contained a small amount of cis-isomer.

When the above process is performed again using substituted 2-benzyl-5-phenyl-1, 2, 3, 4-tetrahydropyrido [4, 3-b] indole, the 4a, 9b-trans compound is in the form of a hydrochloride salt. Is obtained.

X Y X Y

H P-fluoro H O-fluoro

F H F m-fluoro

F P-fluoro F O-fluoro

Example 2

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

150 ml of anhydrous ethanol containing 4.17 g of dl-trans-2-benzyl-5-phenyl-2, 3, 4, 4a, 5, 9b-hexahydro 1H-pyrido [4,3-b] indole hydrochloride The suspension was removed by filtration of 1.0 g of 10% pd / C catalyst at 50 p.si and 60-70 ° C. and the filtrate was added to a sufficient amount of ethyl ether to precipitate the hydrochloride of the desired material. 2.76 g (87%), Melting point: 235 to 237 ° C

The hydrochloride salt is partitioned between ether and recovered sodium oxide solution to convert to organic base and the ether layer is dehydrated over sodium sulfate and evaporated to afford the title compound (97%).

Example 3

dl-trans-8-fluoro-5- (p-fluorophenyl) -2, 3, 4, 4a, 5, 9b- hexahydro-1H-pyrido [4, 3-b] indole

A. 5.6 g (12.4 mmol) and dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2, 5.3 ml (55.7 mmol) of ethyl chloroformate are added to 40 ml of toluene solution containing 3, 4, 4a, 5, 9b-hexahydro-1H-pyrido [4,3-b] indole. The mixture obtained is refluxed overnight and evaporated to dryness to obtain a mucus. To this mucus is added 200 ml of ethanol / water mixture (9: 1), the mucus is dissolved, 15 g of potassium hydroxide is added and the reaction mixture is refluxed overnight. The solvent is evaporated in vacuo and partitioned in water and chloroform. The organic extract is washed with water and dehydrated over sodium sulfate. The residual oil is dissolved in ethyl acetate and eluted first with ethyl acetate using a silica gel column to remove by-products and then the desired product is eluted with ethyl acetate / methanol (1: 1). The fractions containing the title compound were collected and evaporated to dryness to yield 1.5 g (43%) of yellow slime, which crystallized on standing.

(Melting point: 115 to 117 ° C)

B. In another method, dl-trans-2-benzyl-9-fluoro-5- (p-fluorophenyl) -2, 3, 4, 4a, 5, 9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride is refluxed in the presence of excess ethyl chloroformate or the corresponding methyl, isopropyl or n-butyl chloroformate ester, hydrolyzed and carried out as above to obtain the title compound.

Example 4

The following products are obtained following the procedure of Example 3B or 3A using suitable starting materials in each case.

dl-trans-5- (p-fluorophenyl) -2, 3, 4, 4a, 5, 9b- hexahydro-1H-pyrido [4, 3b] indole,

dl-trans-8-fluoro-5-phenyl-2, 3, 4, 4a, 5, 9b-hexahydro-1H-pyrido [4, 3-b] indole,

dl-trans-5- (0-fluorophenyl) -2, 3, 4, 4a, 5, 9b- hexahydro-1H-pyrido [4, 3-b] indole,

dl-trans-5- (0-fluorophenyl) -8-fluoro-2, 3, 4, 4a, 5, 9b- hexahydro-1H-pyrido [4, 3-b] indole,

dl-trans-5- (m-fluorophenyl) -8-fluoro-2, 3, 4, 4a, 5, 9b- hexahydro-1H-pyrido [4, 3-b] indole,

bl-trans-5- (m-fluorophenyl) -2, 3, 4, 4a, 5, 9b- hexahydro-1H-pyrido [4, 3-b] indole,

Example 5

dl-trans-2- (4-hydroxy-4-phenylbutyl) -5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] -indole Hydrochloride

A. 1.0 g (4.0 mmol) of dl-trans-5-5 at 0 ° C. in a 30 ml dichloromethane suspension containing 865 mg (4.20 mmol) of disacclohexyl carbodiamide and 748 mg (4.20 mmol) of 3-benzoylpropionic acid. A 10 ml solution of dichloromethane containing phenyl-2, 3, 4, 4a, 5, 9b-hexahydro-1H-pyrido [4, 3-b] indole is added. The resulting mixture is stirred and warmed to room temperature for at least 2 hours. Cooled again to 0 ° C., filtered the reaction mixture, washed with dichloromethane and evaporated the filtrate to dl-trans-2-((3-benzoyl) propionyl] -5-phenyl-2, 3, 4, 4a, 5, 9b-hexahydro-1H-pyrido [4, 3-b] indole is obtained, which can be used as is in the next step.

B. The residue is dissolved in 50 ml of tetrahydrofuran and heated to reflux. A filtrate solution of lithium aluminum hydride dissolved in tetrahydrofuran was added until the gas evolution ceased (molar excess), then the mixture was refluxed with stirring for 5 to 10 minutes and cooled, followed by 17 g of anhydrous sodium sulfate powder, followed by 0.5 ml of water is added. The mixture is stirred for 30 minutes at room temperature, filtered and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on 80 g silica gel column (eluant: ethyl acetate / methanol = 4: 1) and the solvent is evaporated to give the organic base of the title compound.

The organic base is dissolved in ether, converted to hydrochloride, and a saturated solution of anhydrous hydrogen chloride in ether is added until the precipitation is completed, followed by filtration and drying to obtain a compound having a melting point of 222 to 224 ° C of 1.04 g.

Infrared spectrum (KBr), μ: 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) λ max 245 (ε = 0.653 × 10 ⁴ ), 270 (ε = 0.914 × 10 ⁴ ).

Example 6

Using the starting materials suitable for each case selected from the free bases prepared in Examples 2 and 3, the following dl-trans-compound was prepared according to the process of Example 5. The product is separated in the form of hydrochloride unless otherwise indicated.

X Y Z Melting Point ℃ Yield%

F F H 220 to 223 18

H H F 239 to 245 39

HH CH ₃ O amorphous solid (a) 54

FF CH ₃ O 45 to 48.5 (b) 31

(a) mass spectrum M / e; 428, 411, 263 (100%), 220, 206, 204;

Infrared spectrum (KBr), μ: 2.98, 3.42, 4.07 (broad), 6.20, 6.26, 6.70, 6.88, 8.04, 8.54, 9.77, 12.05.

(b) Melting points and yields are for free bases.

Example 7

Example 5 using selected from the suitable dl-trans-hexahydro-1H-pyrido [4,3-b] indoles prepared in Examples 2, 3 and 4 and the appropriate substituted 3-benzoyl propionic acid or 4-benzoylbutyric acid By the method of the following compounds are prepared.

Claims (1)

4a and 9b of the following general formula (VII) -trans-hexoxide-γ-carboline free base are acylated with a carboxylic acid or its acid chloride or acid bromide of the following general formula (XII), and 4a of the following general formula (XIII) , 9b-trans-hexahydrocarboline compound, which is then reduced to lithium aluminum hydride, characterized in that the trans-2-substituted-5-aryl-2, 3, 4, 4a of the following general formula (VI) And 5, 9b-hexahydro-1H-pyrido [4,3-b] indole derivatives and a method for producing pharmaceutically nontoxic salts thereof.

Wherein hydrogens bonded to carbon at positions 4a and 9b are trans to each other, X and Y are the same or different, each is hydrogen or fluoro, n is 3 or 4 and Z is hydrogen, fluoro or methoxy.