JPS59507B2 - Method for producing novel heterocyclic compounds - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing novel heterocyclic compounds.

The present invention represents a cyclic group represented by the general formula, where w is a naphthyl group or an indolyl group that can be substituted with benzyloxy, A is a lower alkylene group, R is a phenyl group, and R1 is hydrogen. and R2 is a lower alkyl group or a benzyl group] and acid addition salts thereof.

The present invention also includes anhydrides and hydrates of the above compounds. "Alkylene" used in the present invention includes linear and branched groups, and when "lower" is placed in front of the group,
The radical is meant to have from 1 to 6 carbon atoms (but radicals containing from 1 to 4 carbon atoms are preferred).

[Aryl] means a group having aromaticity.
Compounds having 1) exhibit one or more of the following pharmacological activities when tested in mixed-breed animals:

namely effects on the heart and vascular system (eg hypotensive and/or antihypertensive activity), antihistamine activity and sometimes central nervous system activity (eg sedative or anticonvulsant activity). Compounds other than those mentioned above having formula (1) are intermediates of the corresponding compounds of formula (1). In addition to possessing useful pharmacological activities as described above, the active novel compounds of the present invention have the formula (1
) is an intermediate for the production of other compounds having

Examples of A are methylene, ethylene, propylene and butylene.

Examples of R2 are lower alkyl groups such as methyl, ethyl, propyl or butyl.

Examples of acid addition salts are those formed from inorganic and organic acids;
In particular pharmaceutically acceptable acid addition salts, such as sulfates, hydrochlorides, hydrbromides, hydroiodides, nitrates, phosphates, sulfonates (e.g. methanesulfonate, and p-toluenesulfonate), acetates, Among the quaternary ammonium salts of compounds having formula 1, which are maleates, fumarates, tartrates and formates, those in which the quaternization group can be removed under mild conditions, such as hydrolysis, are: Formula 1
It is an important intermediate for the production of compounds with

Preferred quaternary ammonium salts have the formula (where W, .A, .R, .Rl and R2 are as defined for formula 1, and the dotted line represents any double bond; =
4L? 1,? There are things that have the power of God, which is actually a halide ion.

Compounds of general formula 1 can be prepared in a number of ways by building up the molecules from appropriate starting materials in known manner. The above methods applied to the preparation of novel compounds of formula 1 are within the scope of the present invention. A preferred method of preparing compounds of formula 1 is to prepare compounds of formula 1 with reactive derivatives of acids of general formula RCOOH (formula It consists of becoming

As reactive derivatives of acids with the formula RCOOH used in the above process, halides (for example chlorides or bromides) or anhydrides are preferred. Other examples of reactive derivatives of the acid RCOOH that can be used are acid azides, mixed anhydrides and active esters. Furthermore, equation 1
Compounds having the formula are activated by treating a compound of formula with acid RCOOH in the presence of a known condensing agent (e.g. a carbodiimide) or by first activating the amino group (e.g. forming a phosphazo derivative). ), which can then be produced by reacting with the acid RCOOH. Regarding the introduction of the group -COR into compounds of the formula, "Che
mistryOftheAnllnOAcidl, Gr.
eenstein and Winitz [JOhnWi
ley & Sons Publishers, 1961], P. 782
-883 and P. 943-1108. The starting materials for the formula when [w] is a group other than indolyl group are described in British patent application 42090/70 by the applicant.
No. 34376/71.

Compounds in which [w] is substituted or unsubstituted indolyl can be prepared by methods analogous to those for preparing other compounds having the formula. An advantageous method for preparing compounds of the formula in which [W] is a substituted or unsubstituted indolyl group consists in reducing the corresponding compound in which R2 is an acyl group. For example, a compound of the formula where R2 is benzoyl is R2
can be reduced to a compound of the formula where is benzyl and a compound of the formula where R2 is carboethoxy (CO2Et) can be reduced to a compound where R2 is CH3. A suitable reducing agent is lithium aluminum hydride. A second method for producing a compound having formula 1 comprises the general formula (wherein,
R, R1 and R2 are as defined above) A compound having the general formula: or a similar substitutable atom or group, such as an organic sulfonyl group such as a tosyl group).

Compounds having the general formula are known compounds or can be made by methods known for making compounds of such type. Starting materials having general formula c are typically prepared by acylating the corresponding amino compound having general formula (wherein R1 and R2 are as defined above) and reducing the ring system to the corresponding piperidine ring. It can be manufactured by Nyoto.

Furthermore, a compound having the general formula 1 (wherein c is a cyclic group, W, .R, .Rl and R2 are as defined with respect to formula 1, and A is a lower alkylene group) One method of preparation consists of reacting a compound having the general formula, where W and A are as defined above, with a compound having formula c.

The reaction is preferably carried out in the presence of a catalyst such as Raney nickel.

Organic solvents which are inert under the reaction conditions, such as xylene, toluene or benzene, are usually used. Preferably, the reaction is carried out in a water-immiscible organic solvent such as xylene by heating the reactants under reflux and removing the water formed during the reaction by azeotropic distillation. If desired, reactive substituents may be protected and later removed in the reaction. Certain compounds having formula 1 can also be prepared by treating a compound of formula as defined above under mild conditions to remove the group R4.

Preferably R4 is removed by hydrogenolysis under standard conditions using a suitable catalyst such as a palladium-on-carbon catalyst, a platinum catalyst or a nickel catalyst. Instead of compounds having the formula 1, where R4 is as defined above, other starting materials may be used in which R4 is an organic group that is easily removable under mild conditions.

Other conditions effective to remove the group R4 are treatment with an acid such as acetic or hydrochloric acid to remove the trityl group, or removal of the alkali metal* (wherein R.Rl,
R2 and A are as defined above) can also be prepared by carrying out fissure indole synthesis.

The starting materials are of the formula Phenylhydrazine with the general formula H (XXI) {().

Preferred radicals R4 in the starting compounds of the formula are arylmethyl groups, such as benzyl, diphenylmethyl, trityl or naphthylmethyl.

Compounds of formula 1, for example where R, .Rl, R2 and A are as defined for formula 1, have the general formula (wherein R.Rl, R2
and A are as defined above).

Compounds having the formula (wherein [W] is a substituted or unsubstituted indolyl group) can be prepared by the same fissure indole synthesis described above. The above reaction may be carried out using solvents which are inert under the reaction conditions, such as alcohols such as methanol, ethanol or propan-2-ol, ethers, dioxane, dimethylformamide, pyridine, water, dimethoxyethane, methylene chloride, tetrahydrofuran and acetic acid or these. It is usually carried out in a mixture of solvents. The most suitable solvent system will vary depending on the particular reactants used. If desired, the reactants can be heated to reflux in solution;
Heating under high pressure can also be carried out if desired. Once a compound of general formula 1 has been prepared, one or more of the substituents in the molecule can be converted into another substituent within the meaning specified with respect to formula 1, if desired.

is a pyridinium ring system of formula a, which can be selectively reduced to one of the other ring systems in the lower oxidation state.

For example, when reduced with an alkali metal borohydride, the formula b-
A tetrahydropyridine ring system with N7i is produced.

On the other hand, careful reduction using catalytic hydrogenation or a hydride transfer agent (eg lithium aluminum hydride) in the presence of a Raney nickel or platinum catalyst, for example, produces a piperidine ring system having formula c. Similarly, when preparing compounds of formula 1 in which piγ-cho is a tetrahydropyridine ring system of formula b, it can also be reduced to a piperidine ring system of formula c. As mentioned above, the novel piperidine compounds provided by the present invention contain a basic nitrogen atom and are therefore suitable for use in acids (particularly pharmaceutically acceptable acids).
can produce acid addition salts. Acid addition salts can be formed in situ during the above process and then separated;
Alternatively, the free base can be treated with a suitable acid in the presence of a suitable solvent and the salt then isolated. Quaternary salts can be prepared by treating the free base with a suitable halide in the presence or absence of a solvent. The invention also encompasses pharmaceutical compositions containing as active ingredient an active compound having formula I as defined above.

The active compound can be pulverized if desired. In addition to the active ingredient, the compositions of the invention also contain a non-toxic carrier. Any suitable carrier known in the art can be used in preparing pharmaceutical compositions. In the above compositions, the carrier can be solid, liquid or a mixture of solid and liquid. Solid form compositions include powders, tablets and capsules. The solid carrier can be one or more substances that are also active as flavoring agents, lubricants, solubilizers, suspending agents, binders or disintegrants, and that serve as encapsulating agents. You can also do it.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the desired binding properties in appropriate proportions and compressed into the desired shape and size. Powders and tablets preferably contain from 5 to 99% active ingredient, preferably from 10 to 80% active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, and cocoa butter. The term "composition" refers to the active ingredient being formed with an encapsulating agent as a carrier to produce a capsule, surrounding the active ingredient (with or without other carriers) by the carrier, and co-acting with the active ingredient. It means to include what one does. Similarly, force sets are included. Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.

The active ingredient can be dissolved or suspended in a sterile pharmaceutically acceptable liquid carrier such as sterile water, sterile organic solvent, or a mixture of both. Preferably the liquid carrier is one suitable for parenteral injection. If the active ingredient is sufficiently soluble, it can be dissolved in normal saline as a carrier.
Alternatively, if the active ingredient is poorly soluble in normal saline, it can often be dissolved in a suitable organic solvent such as propylene glycol or aqueous polyethylene glycol. Aqueous propylene glycol containing 10 to 75% by weight of glycol is usually suitable. In other cases, the composition comprises finely divided active ingredient in an aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oily substance such as Arachis oil.
It can be produced by dispersing it in oil). Liquid pharmaceutical compositions that are sterile solutions or suspensions can be used by intramuscular, intraperitoneal or subcutaneous injection. In many cases, the compounds are orally active and can be taken orally in liquid or solid composition form.
Preferably, the pharmaceutical composition is in unit dosage form.

In such form, the composition is subdivided into unit dosage forms containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, the package containing a specified quantity of the composition, eg, a packaged powder or pill pin or ampoule. The unit dosage form can be a capsule, a tablet, or a tablet itself, or it can be the appropriate number of any of these in package form. The amount of active ingredient in a unit dose of the composition can be varied or adjusted from 5η or less to 500η or more depending on the particular need and the activity of the active ingredient.
The invention also includes carrier-free compounds when the compound is in unit dosage form. The following examples are intended to illustrate the invention, but are not intended to limit it. Example 13-[2-(4-ethoxycarbonylamino-1
-piperidyl)monoethyl]methylene dichloride (25
Dissolve 4-amino-1-[2-(3-indolyl)ethyl]piperidine (1.3t) in 0ml) and add ethyl chloroformate (0.54y) methylene chloride (15d) solution to this stirred solution. was added over 5 minutes.

Stirring was continued for 2 hours. The mixture was extracted with water (2x50ml) and the organic phase was separated, dried (MgSO4) and evaporated to yield an oil. Dissolving this product in ether gives the title compound as a hydrate (0.87 f) as a cream solid which, when recrystallized from aqueous ethanol, gives colorless needles, M. p. 8O-82 re was produced. Measured value 2 Cl 63.34; Hl 8.35; Nll 2. O4Cl8
Calculated value for H25N3O2・1-FH2O: Cl6
3. l3; H, 8.24: Nll2.27% Example 23-[
2-(4-methylamino-1-piperidyl)ethyl]indole 3-[2-(4-ethoxycarbonylamino 1
-piperidyl)ethyl]indole, hydrate (7.96
f7) was added in several portions to a stirred suspension of lithium aluminum hydride (10.0 V) in 1,2-dimethoxyethane (250d), and the mixture was refluxed for 4 hours.

Water (30ml) was added dropwise to destroy the unchanged hydride, the mixture was filtered and evaporated to yield the desired product as an oil which solidified upon trituration in ether ( 1.21t). A portion of this was converted into hydrochloride (recrystallized from ethanolic hydrochloric acid/ether, needle crystals), M.I.
p. 25l. Converted to lte. Measured value: Cl57. lO
;Hl7.6l;N, 12.20C1,H23N,・2
Calculated value for HC1.-F-H2O: C, 57.40
; Hl 7.68; Nll 2.55% Example 33-[2-(4
-N-methylbenzamido-1-piperidyl)ethyl]
Indole 3-[2-(4-methylamino-1-piperidyl)ethyl]indole (free base from Example 2) (5
．． 05r) was dissolved in chloroform (100110), and potassium carbonate (2.72?) dissolved in water (100m0) was added.

A solution of benzoyl chloride (2.76 ml) in chloroform (50 ml) was added dropwise to the stirred mixture.
Stirring was continued for 1 hour, the chloroform phase was separated and the aqueous phase was re-extracted with chloroform (50ml). The combined organic phases were dried (MgSO4), treated with activated carbon,
Filtration and evaporation produced an oil that crystallized on standing. Dissolve this in ethanol-HCl,
Ethyl acetate was added until crystallization occurred. Filtration produced the title compound in the form of the hydrochloride salt as colorless needles (
6.43V), m-P. Measured value of 2l6-218: Cl69.27; Hl7. O8; NllO. 33C23
Calculated value for H27N3O・HCl: Cl69.4l
;Hl7. O9; NllO. 56% Example 45-Benzyloxy-3-[2-(4-[N-benzylbenzamide]
5-benzyloxindole-3-glyoxyl chloride (23.2y) was dissolved in anhydrous 1,2-dimethoxyethane (1200mi) and stirred. was added in several portions.

After 1 hour, the resulting solid was collected, suspended in water (11) and stirred for 1 hour.

The product was filtered off, washed and dried to yield 4-benzamido-1-(5-benzyloxindole-3-glyoxylol)piperidine (34.49y), M.I. p926
4H was produced. Measured value: Cl7l. 85; Hl5.67; Nl8.66C29H
Calculated value for 27N3O4 2Cl72, 33; Hl5
．． 65; Nl8,73%B Above product (33.887
) was added in several portions to a suspension of lithium aluminum hydride (20y) in anhydrous tetrahydrofuran (850a), which was refluxed with stirring.

Stirring and refluxing were continued for 4 hours, then water (20a) and 2N sodium hydroxide solution (40m0) were carefully added dropwise. After stirring was continued for a further 20 minutes, the mixture was filtered and the inorganics were removed with fresh tetrahydrofuran. The combined filtrate and washings were evaporated and the remaining oil was dissolved in hot ethanol and ethanolic HCl.
and acidified with 3-[2-(4-benzylaminopiperidino)ethyl-5-benzyloxindole-2HC.
1. -FH2O (31.037), M. p. 2lO. was generated.

Measured value: Cl66.75: Hl6.7l; Nl7.95
Calculated value for C29H33N3O.2HC1-FH2O 2Cl66.78: Hl6.96; Nl8. O6%C
The above product (2.61'I7) and potassium carbonate (2.76t) were stirred with water (50TIII) and methylene chloride (50a) until dissolved.

Add benzoyl chloride (850η) dropwise and stir for 1 hour.
It lasted for hours. The aqueous phase was separated and re-extracted with methylene chloride and the combined organic phases were dried and evaporated.
Treatment of the remaining oil with ethanolic HCl yields H
Described compound as Cl・-FH2O(2.52y)・
M. p. 265 ((decomposition) was produced.

Measured value: Cl73.64; Hl6.78, Nl6.98
Calculated values for C36H3,N3O2.HCl-FH2O: Cl73.39; Hl6.67; Nl7. l3% Example 52-[2-(4-N-Methylbenzamido-1-piperidyl)ethyl]naphthalene Under the conditions of Example 1, 4-amino-1-[2-(2-naphthyl)ethyl]piperidine was converted into ethyl chloro Acylation with formate produces the ethoxycarbonylamino derivative, which is reduced by the conditions of Example 2 to the corresponding N-methylamine.

Benzoylation according to the conditions of Example 3 then yields the title compound, M. p. 283.2.
Measured value: C, 73.44; Hl7. l7;Nl6.9C25l[
Calculated value for 28N20-HCl: C, 73,41;
H, 7.15; N, 6.85% Example 63-[2-(4-N
-ethylbenzamide-1-piperidyl)ethyl]indoleA. By the conditions of Example 2, 4-acetamide-1
When 1[2-(3-indolyl)ethyl]piperidine is reduced using lithium aluminum hydride, 3-[2-[2-
-(4-ethylamino-1-piperidyl)ethyl]indole is produced.

B. Benzoylation of the above amine under the conditions of Example 3 produces the hydrochloride salt of the title compound. Example 73-[2-(
4-N-methylbenzamido-1-piperidyl)ethyl]indole 3-(2-bromoethyl)indole (2
．． 24y), N-methyl-N-4-piperidylbenzamide (2.187) and triethylamine (1.11
A solution of 7) in dimethylformamide (200 ml) was stirred at room temperature for 3 days.

Evaporation of the solvent and recrystallization from ethanolic hydrochloric acid gave the above compound as a hydrochloride salt (M.p. 216-218°C).
Example 8 3-[2-(4-N-methylbenzamido-1piperidyl)ethyl]indole drift hole (1.617)
, N-4-piperidyl-N-methylbenzamide (2.
18 t) and Raney nickel (W2, approx. 27) are suspended in xylene (150 mO) and boiled under reflux with stirring for 5 hours.

The released water is removed by a Dean & Stark device.
The hot mixture is filtered to obtain a solution from which the title compound crystallizes. Reconsolidated from ethanolic HCl,
This hydrochloride compound M. p. Obtain 2l6-218°C. Example 9 Acetonitrile (25TIL) of 3-[2-(4-N-methylbenzamido-1-piperidyl)ethyl]indole 3-(2-bromoethyl)indole (2.24y)
1) Add the solution dropwise to a solution of 1-benzyl-4-(N-methylbenzamido)piperidine (3.10y) in refluxing acetonitrile (50wLI!).

Stirring under reflux is continued for 72 hours, then the mixture is cooled and filtered to yield 4-(N-methylbenzamido)-1-benzyl-1-(2-indol-3-ylethyl)piperidinium bromide. This quaternary salt (1.12y) was dissolved in methanol (100ml) and hydrogenated for 30 minutes at 50°C in the presence of 10% palladium on charcoal (100ml).
Filter and evaporate the filtrate to obtain the title compound. Reconsolidation from ethanolic HCl gives this hydrochloride compound M. p.
Obtain 2l6-218°C. Example 103-[2-(4-N-
Methylbenzamide-1-piperidyl)ethyl]indole (a) 4-(N-methylbenzamide)-1-(
2-indole-3-ylethyl)pyridinium bromide (3.15y) (3-(2-
(produced by refluxing bromoethyl)-indole and 4(N-methylbenzamido)pyridine) in 91% ethanol (300ml) containing triethylamine (0.8y).
Dissolve the freshly prepared W-J nickel catalyst (
Add about 3y).

This mixture was placed in an autoclave at a hydrogen pressure of 400 psi.
Hydrogenate at 50°C/4 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. Shake the residue with a mixture of chloroform and 2N NaOH solution. The insoluble substances formed are removed by filtration,
Reconsolidation from ethanolic HCl gives the hydrochloride salt of the title compound M
．． p. 2l6-218°C was obtained. (b) in a similar manner;
3-[2-(4-N-methylbenzamide-1, 2, 5
・6-tetrahydropyrid-1-yl)ethyl]indole (4-(N-methylbenzamide)-1-(2-
(prepared by reducing indol-3-ylethyl)pyridinium bromide with sodium borohydride in methanol solvent) to give the title compound M. p. (Hydrochloride) obtained at 216-218°C. 3-[2-(4-N-Methylbenzamido-1-piperidyl)ethyl]indole 4-(N-methyl-4-benzamido)piperidine (66y) was dissolved in 300 mj anhydrous dioxane at 1.17 m
Add to a stirred suspension of copper acetate and 9.5r paraformaldehyde followed by propionaldehyde diethyl acemer (38.6y).

Continue stirring under nitrogen at 80° C. for 24 hours. The hot reaction mixture was filtered and the filtrate was evaporated. Ethyl acetate - petroleum ether (
B. p. The solid residue is reconsolidated from 4-(
N-methylbenzamido)-1-(4,4-diethoxybutyl-2-ynyl)piperidine was obtained. 1) Hydrogenate the above product (73y) in absolute ethanol (11?) in the presence of 10% palladium on charcoal (7V) at 50 Psi hydrogen pressure for 30 minutes.

After removing the catalyst, the filtrate was evaporated and dissolved in petroleum ether (B.p.
The residue was recrystallized from 60 to 80°C to obtain 4-(N-methylbenzamido)-1-(4,4-diethoxybutyl)piperidine. 2) 25% aqueous acetic acid (10ml) A4
A mixture of -(N-methylbenzamide)-1-(4,4-diethoxybutyl)piperidine (1.93y) and phenylhydrazine hydrochloride (0.72k) is stirred at 80°C for 3 hours.

The solution was evaporated and the residue was stirred with water, basified with potassium carbonate and extracted with chloroform. Anhydrous chloroform solution (15a) and polyphosphate ester (3.5V) were heated under reflux for 5 minutes, the cold solution was concentrated and the residue was stirred with ice water for 1 hour.

Claims (1)

[Claims] 1 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a cyclic group shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼II (c), W is a naphthyl group or indolyl group that can be substituted with benzyloxy , A is a lower alkylene group, R is a phenyl group, R^1 is hydrogen, R^2
is a lower alkyl group or a benzyl group] and its acid addition salt, a compound having the general formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ V (c) is a compound having the general formula [W] -A-Y(VI) (in the above formula, W, R, R^1, R^2 and A are as defined above, and Y is a halogen atom or an equivalent substitutable atom or group) react with an alkylating agent,
A process for the preparation of the above-mentioned compounds, characterized in that the compounds of formula (I) are isolated if necessary as acid addition salts. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ is a formula ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ Represents the cyclic group shown by II (c),
W is a naphthyl group or indolyl group that can be substituted with benzyloxy, A is a lower alkylene group,
R is a phenyl group, R^1 is hydrogen, and R^2 is a lower alkyl group or a benzyl group] In the production of a heterocyclic compound having the general formula ▲ mathematical formula, chemical formula, There are tables etc. ▼Compounds having V(c) are represented by the general formula [W]-A-OH(XV) (In the above formula, W, R, R^1 and R^2 are as defined above, and A is a lower alkylene group) and, if necessary, isolating the compound of formula (I) as an acid addition salt. 3 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼Represents a cyclic group shown by II (c), W is a naphthyl group or indolyl group that can be substituted with benzyloxy, A is a lower alkylene group, R is a phenyl group, R^1 is hydrogen, and R^2 is a lower alkyl group or a benzyl group] In the production of a heterocyclic compound having the general formula ▲ mathematical formula, chemical formula, There are tables etc. ▼ (wherein W, A, R^1 and R^2 are as defined above) as an acylating agent having a group RCO (R is as defined above) A process for the preparation of the above compounds, characterized in that the compound of formula (I) is isolated as an acid addition salt, if necessary as an acid addition salt. 4 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ represents the cyclic group shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. , A is a lower alkylene group, R is a phenyl group, R^1 is hydrogen, R^2
is a lower alkyl group or a benzyl group] and its acid addition salts, the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (III) (in the formula,
W, A, R, R^1 and R^2 are as defined above, X^■ is an anion, and R^4 is arylmethyl) under mild conditions. , the group R^4 is removed, and the compound of formula (I) is isolated, if necessary as an acid addition salt. 5 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a cyclic group shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, W is a naphthyl group or indolyl group that can be substituted with benzyloxy, and A
is a lower alkylene group, R is a phenyl group, and R
^1 is hydrogen and R^2 is a lower alkyl group or benzyl group] In the production of a heterocyclic compound having the general formula I (where ▲ mathematical formula, chemical formula, table, etc. Yes ▼ is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II (a) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II (b) (R, R^
1 and R^2 are as defined above and X^■ is an anion) and isolating the compound of formula (I) if necessary as an acid addition salt. A method for producing the above compound. 6 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ represents the cyclic group shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II (c), W is indol-3-yl, and A is a lower alkylene group. , R is a phenyl group, R^1 is hydrogen, and R^2 is a lower alkyl group or a benzyl group]
In the production of heterocyclic compounds having the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (wherein, ▲ mathematical formulas, chemical formulas, tables, etc. ▼, R, R^1, R^
2 and A are as defined above) under Fischer-indole synthesis reaction conditions and, if necessary, isolating the compound of formula (I). Method.