JPH03223250A - New indole derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R1 is H, 1-6C alkyl, benzyl or indolylcarbonyl; R2 is 5- to 8-membered heterocyclic group (may be replaced with 1-6C alkyl or arylalkyl) containing one or more N atoms; (n) is 1-5; H atom in (CH2)n may be replaced with 1-4C alkyl, phenyl and/or OH; with the proviso that a case wherein n=1 and R2 is 1-methyl-2-pyrrolidinyl or 1-benzyl-2- pyrrolidinyl is omitted] and an acid addition salt thereof. EXAMPLE:1H-Indole-3-carboxylic acid 2-(1-pyrrolidinyl)ethyl ester. USE:An antagonist selectively effective against 5-HT in 5HT3 acceptor. Effective for treating insanity, neurogenic diseases, gastrointestinal function incompetence and gastrointestinal disorder. Also effective for suppressing vomiting induced in cancer chemotherapy. PREPARATION:An indole-3-carboxylic acid shown by formula II is condensed with a compound shown by formula III to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel indole derivative and a method for producing the same.

Furthermore, the present invention relates to 5-BT, a novel indole derivative that is a selectively effective antagonist to 5-HT at the receptor. The indole derivatives of the present invention act on 5-HT receptors in the central nervous system, causing mental disorders (e.g. schizophrenia, chronic illness, depression, anxiety, dementia, cognitive disorders,
It is effective in treating drug dependence, etc., and is also used in the treatment of nervous system diseases (eg, migraine, etc.). It also acts on peripheral 5-HT3 receptors, causing symptoms of gastrointestinal dysfunction (e.g. delayed gastric emptying, indigestion, flatulence, esophageal reflux, etc.) and gastrointestinal disorders (e.g. gastritis, peptic ulcer, Crohn's disease, ulcerative colitis). , diarrhea due to various causes). It is also effective in treating vomiting and nausea, especially those induced during cancer chemotherapy and radiation therapy.

[Prior art and problems to be solved by the present invention]

Vomiting is a serious problem frequently seen in patients receiving cancer chemotherapeutic agents and radiation therapy, and management of emesis is an extremely important adjunctive therapy for adequate anticancer treatment. Since it was reported that large-dose intravenous administration of metoclopramide is effective in suppressing this vomiting (Grade A,
R,J.

et al., N. Engl., J. Med.
305.905-909 (1981)), it has become possible to manage vomiting better, although it is not perfect. However, it has become clear that existing antiemetics, especially compounds with a benzamide structure, have undesirable side effects such as sedation, ataxia, diarrhea, and akathisia due to their dopamine blocking and central nervous system depressing effects. Ta.

Recently, a specific antagonist of 5-HT3 receptor was reported to suppress emesis induced during cancer chemotherapy (Cun
ningham, D. et at, The L.
ancet.

1, 1461-1463 (1987)), 5-HT
, antagonists are thought to be drugs that suppress vomiting at lower doses than existing antiemetic drugs and have no undesirable side effects.

The previously known 5-)IT antagonist was disclosed in Japanese Patent Application Laid-open No. 589.
78, No. 59-106486, No. 59-67284, No. 60-226858, and JP-A No. 1-106882i, which have an azabicyclic partial structure, or JP-A No. 64-22870, It had an imidazole ring moiety as disclosed in JP-A-1-131178.

From this situation, it has a chemical structure different from that of known compounds, and therefore the 5-)IT at the 5-HT3 receptor.
It is desired to develop selectively effective antagonists.

[Means to solve the problem]

The present inventors have conducted extensive research to solve the problems described above, and have synthesized a compound having a novel indole ring.
The present invention was completed by discovering that this compound has a selectively effective antagonistic effect on 5-)IT at the 5-HT3 receptor.

That is, the present invention relates to the following general formula (I) [wherein R1 is a hydrogen atom, C4-C, alkyl, benzyl or indolylcarbonyl, and R2 contains one or more nitrogen atoms as a hetero atom] 5 members who do ~
an 8-membered saturated or unsaturated heterocyclic group (this heterocyclic group may be substituted with Cl to C, alkyl or arylalkyl), n is an integer of 1 to 5,
One or more hydrogen atoms in -(cuz)n- may be substituted with C3-C, alkyl, phenyl and/or hydroxyl group. provided that n is 1 and R8 is 1-methyl-2-pyrrolidinyl or 1-benzyl-2-pyrrolidinyl), and a pharmaceutically acceptable acid addition salt thereof. , and its quaternary ammonium salts and N-oxide derivatives.

Specific examples of the substituent R1 at the 1-position on the indole ring in the above general formula (I) include hydrogen atom, methyl, ethyl, n-propyl, 1so-propyl, n-butyl, 1
C1-C such as so-butyl, tart-butyl, n-pentyl and n-hexyl.

Alkyl, benzyl, or indol-3-ylcarbonyl.

Specific examples of the heterocyclic group R1 in the group -(CHz)n-Rz bonded to the carbonyloxy group on the indole ring in the above general formula (1) include l-pyrrolidite, 2-pyrrolidinyl, 3-pyrrolidinyl, l-pyrrolidinyl, -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, ■-imidazolyl, 2
-imidazolyl, 4-imidazolyl, 5-imidazolyl, ■-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,
5-pyrazolyl, l-piperidyl, 2-piperidyl, 3
-piperidyl, 4-piperidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, l-piperazinyl, 2-piperazinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, hexahydroase Examples include pinyl, hexahydroazepinyl, octahydroazosinyl, octahydrdiazosinyl, and the like.

These heterocyclic groups include methyl, ethyl, n-propyl,
1so-propyl, n-butyl, iso-butyl, t
C such as ert-butyl, n-pentyl, n-hexyl
1 to C1 alkyl group or benzyl, phenethyl,
It can be further substituted with arylalkyl groups such as phenylpropyl groups.

The group -(cnx)n- is methylene, ethylene, propylene, butylene, or bentylene, in which one or more of the hydrogen atoms is methyl, ethyl, n-propyl,
1so-propyl, n-butyl, 1so-butyl, te
It may be substituted with rt-butyl, n-pentyl, n-hexyl, phenyl and/or hydroxyl group.

This compound of formula (I) can be produced by various methods, but for example, indole-3 represented by the following general formula (II) 1 (wherein R is defined in formula (I)) - a carboxylic acid or a reactive derivative thereof, such as an indole-3-carboxylic acid halide, in particular an indole-3-carboxylic acid chloride, of the general formula (III) HO-(CJ)n-Rz (DI
) (wherein R2 and n are defined in general formula (1)) by condensation reaction with a compound represented by the formula (1).

This reaction can be carried out under various reaction conditions, but when using an acid halide such as indole-3-carboxylic acid chloride, organic solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, .4-Dioxane or dimethylformamide at a temperature ranging from -20°C to the boiling point of the solvent, optionally with an inorganic or organic acid binder such as triethylamine, tri-n-butylamine,
The reaction mixture is reacted with a compound of general formula 1) in the presence of pyridine, dimethylaniline, tetramethylurea, metallic magnesium, n-butyllithium, lithium diisopropylamide, sodium amide, metallic sodium, sodium hydride, etc., and the reaction mixture is washed. , extraction and purification steps to obtain the desired product.

In the above reaction, when the compound of general formula (I[I) is a basic compound, this compound can be used in excess to replace the acid binder.

The acid addition salts of the compound represented by formula (I) above are:
General formula (1) having a group capable of forming acid addition salts in the structure
) refers to the acid addition salt of the compound. Among these salts, physiologically acceptable salts are preferred, such as inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and oxalate, maleate, fumarate, lactate, malate, citrate, tartrate,
Examples include organic acid salts such as benzoate and methanesulfonate. Further, the quaternary ammonium salts of the compound of general formula (I) specifically include lower alkyl halogenides such as methyl iosito, methyl bromide, ethyl iosito, and ethyl bromide; lower alkyl sulfonates such as methyl methanesulfonate and ethyl methanesulfonate;
Examples include quaternary ammonium salts such as lower alkylaryl sulfonates such as methyl p-toluenesulfonate. The compound of general formula (1), its acid addition salt, quaternary ammonium salt and N-oxide derivative may exist in the form of a hydrate or solvate, so these hydrates and solvates Also included in the compounds of the invention are compounds.

Among the compounds of general formula (I), those having at least one asymmetric carbon atom may exist in several stereoisomers. These stereoisomers, mixtures and racemates thereof are included in the compounds of the present invention.

Specific examples of the compound of general formula (I) mentioned above include the following compounds.

IH-indole-3-carboxylic acid, 2-(1-pyrrolidinyl)ethyl ester IH-indole-3-carboxylic acid, 2-piperidino)
Ethyl ester IH-indole-3-carboxylic acid, 2-hydroxy-
3-piperidinopropyl ester IH-indole-3
-carboxylic acid, (1-methyl-2-piperidyl)methyl ester IH-indole-3-carboxylic acid, 2-
(1-methyl-2-pyrrolidinyl)ethyl ester 1-(IH-indol-3-ylcarbonyl)indole-3-carboxylic acid, (1-benzyl-2-pyrrolidinyl)methyl ester IH-indole-3-carboxylic acid, 1-(4-Methylpiperidino)-2-propyl ester 1-(IH-indole-3-carbonyl)indole-3-carboxylic acid, 1-(4-methylpiperidino)-2
-Propyl ester LH-indole-3-carboxylic acid, 1-(2-methylpiperidino)-2-propyl ester 1-(IH-indol-3-ylcarbonyl)-indole-3-carboxylic acid, 1-(2-methylpiperidino) )-2-propyl ester IH-indole-3-carboxylic acid, 1-(3-methylpiperidino)-2-propyl ester 1-(IH-indol-3-ylcarbonyl)-indole-3-carboxylic acid, 1-( 3-Methylpiperidino)-2-propyl ester 1-methylindole-3-
carboxylic acid.

(1-Methyl-2-piperidyl)methyl ester IH-indol-3-carboxylic acid, 1-(4-methyl-1-piperazinyl)-2-propyl ester 1-(IH-indol-3-ylcarbonyl)-indole -3-carboxylic acid, 1-(4-methyl-1-piperazinyl)-2-propyl ester 1,1-dimethyl-2-(IH-indole-3-carbonyloxymethyl)piperidinium, iositoIH-indole-3- Carboxylic acid, l,6-dimethyl-2-piperidyl)methyl ester IH-indole-
3-carboxylic acid, 1,6-dimethyl-1.2.5.6-
Tetrahydro-2-pyridylmethyl ester IH-indole-3-carboxylic acid, (1-ethyl-2
-piperidyl) methyl ester IH-indole-3-
Carboxylic acid, (1-ethyl-6-methyl-2-piperidyl)methyl ester IH-indole-3-carboxylic acid, (1-methyl-2
-piperidyl)-1-ethyl ester -pentylindole-3-carboxylic acid.

(1-methyl-2-piperidyl)methyl ester 1-benzylindole-3-carboxylic acid.

(l-Methyl-2-piperidyl)methyl ester IH-indole-3-carboxylic acid, (1-benzyl-
2-Piperidyl) methyl ester IH-indole-3
-carboxylic acid, (1-(2-propyl)-2-piperidylcomethyl ester 1H-indole-3-carboxylic acid, (1-7enethyl-2-piperidyl)methyl ester IH-indole-
3-carboxylic acid, (1-pentyl-2-piperidyl)methyl ester IH-indole-3-carboxylic acid, (1
-methyl-2-piperidyl)-1-ethyl ester IH-indole-3-carboxylic acid, (1-methyl-2
-piperidyl)-1-ethyl ester (highly polar diastereomer) IH-indole-3-carboxylic acid, 1-(1-methyl-2-piperidyl)-1-7z-nylmethyl ester IH-indole-3-carboxylic acid , 1-(1-methyl-2-piperidyl)-2-phenylethyl ester IH-indole-3-carboxylic acid, 2-(1-methyl-2-piperidyl)-2-propyl ester IH-indole-3-carboxylic acid Acid, 1-(1-methyl-2-piperidyl)-1-propyl ester IH-indole-3-carboxylic acid, 1-(1-methyl-2-piperidyl)-2-methyl-1-propyl ester IH-indole -3-ty Lupo/#, 1-(1-methyl-2-piperidyl)-1-hexyl ester IH-indole-3-carboxylic acid, (1,4-dimethyl-2-piperidyl) methyl ester IH-indole- 3-carboxylic acid, (1,3-dimethyl-1,2,5,
6-tetrahydro-2-pyridyl)methyl ester IH-indole-3-carboxylic acid, (1,5-dimethyl-2-piperidyl)methyl ester IH-indole-3-carboxylic acid, (1,3-dimethyl-2- piperidyl) methyl ester IH-indole-3-carboxylic acid, (1-methyl-2-hexahydroazepinyl) methyl ester IH-indole-3-carboxylic acid, 2-pyridylmethyl ester IH-indole-3-carboxylic acid acid, 3-pyridylmethyl ester IH-indole-3-carboxylic acid, 4-pyridylmethyl ester (-)-1H-indole-3-carboxylic acid, (1-methyl-2-piperidyl)methyl ester (+)-1H −
Indole-3-carboxylic acid, (1-methyl-2-piperidyl)methyl ester (-')-1H-indole-
3-carboxylic acid, (1-methyl-2-piperidyl)-1
-ethyl ester (+)-1H-indole-3-carboxylic acid, (1-methyl-2-piperidyl)-1-ethyl ester 1,1-dimethyl-2-(IB-indole-3-carbonyloxymethyl)hexa Hydroazepinium iosito 1,1-dimethyl-2-(IH-indole-3-carbonyloxymethyl)piperidinium bromide 1,1-dimethyl-2-(IH-indole-3-carbonyloxy-1-ethyl) Piperidinium iosito 1,1-dimethyl- -(IH-indole-3 carbonyloxy- monoethyl) Piperidinylampromide 1,1-dimethyl- -(]H-indole-3 carbonyloxy- monoethyl) Pipe Lysinylampromide 1,1-dimethyl-1(IH-indole-3 carbonyloxymethyl) Piperidinium iodide(-')-1,1-dimethyl-(IH- Indole- Carbonyloxy- ethylpiperidinium bromide 1,1-dimethyl-2-(1-methylbindole-carbonyloxymethyl)piperidinylampromide The compounds of the present invention may be administered orally or parenterally, usually in the form of a pharmaceutical preparation.

Forms of pharmaceutical preparations include tablets, capsules, layers, troches, syrups, creams, ointments, patches, poultices, granules, powders, injections, and suspensions. It can also be made into double-layer tablets or multi-layer tablets together with other drugs.

In addition, tablets may be coated with a conventional coating if necessary.
For example, sugar-coated tablets, enteric-coated tablets, and film-coated tablets can also be used.

When preparing a solid preparation, additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, hydroxypropylcellulose, glycerin, polyethylene glycol, stearic acid, Magnesium stearate, talc, etc. are used.

In the case of semi-solid preparations, vegetable or synthetic waxes or fats are used.

When preparing a liquid preparation, additives such as sodium chloride, sorbitol, glycerin, olive oil, almond oil, propylene glycol, and ethyl alcohol are used.

The amount of active ingredient in these formulations is from 0.1 to 100% by weight of the formulation, suitably from 1 to 50% by weight in the case of formulations for oral administration, and in the case of injectable formulations. 0
．． 1 to 10% by weight.

The administration method and dosage of the compound of the present invention are not particularly limited, and are appropriately selected depending on various formulation forms, patient age, sex, degree of disease, etc., but the daily dosage of the active ingredient is l ng ~1000++g.

Specific examples of methods for synthesizing the compounds of the present invention and their pharmacological effects are shown below as examples, and methods for producing compounds that are raw materials used to synthesize the compounds of these examples and are not yet published in literature are shown below. This is shown as a reference example.

Reference example 1 2-(tert-butyldimethylsilyloxymethyl)
Piperidine 2-Piperidine methanol (1,009,8,7m+*
off) and imidazole (1,489,21,7m+i
t-butyldimethylchlorosilane (1,579,IO, 4mmol
12) was added. After stirring for 30 minutes, the reaction solution was poured into water, extracted with diethyl ether (ab, 30 mQ), washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain L61 g of the title compound.

(Yield 81%) Reference Example 2 1-Benzyl-2-(tert-butyldimethylsilyloxymethyl)piperidine 60% sodium hydride (0.21g, 5.2mi+
off) in DMF (4+xff) solution.
t-Butyldimethylsilyloxymethyl)piperidine (
1,0h, 4.41111012) DMF (4mf
f) The solution was added dropwise at room temperature. Then, after stirring at room temperature for 30 minutes, benzyl bromide (0.75 g, 4.4
A solution of mmoQ) in THF (1iQ) was added dropwise.

After stirring at room temperature for 30 minutes, the reaction solution was poured into water, extracted with diethyl ether (301IIQ), washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound 1.30e. (Yield 96%) Reference Example 3 THF solution of J-benzyl-2-piperidine methanol tetrabutylammonium fluoride (IM, 3
．． l-benzyl-2-(tert
-butyldimethylsilyloxymethyl)piperidi7 (
1,00g, 3-2+11moff) of THF (2r
a(2) solution was added dropwise. After stirring at room temperature for 2 hours,
It was poured into water and extracted with ethyl acetate (30+Q). water,
After sequentially washing with saturated brine, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (SiOx: 209.
C) ICL) to obtain 0.419 of the title compound. (Yield 62%) Reference Example 4 l-(2-propyl)-2-piperidinemethanolPyridine-2-methanol (3.27g, 30IIIl
Oa) and 2-iodopropane (3,59+lIQ, 3
6mmoQ) was heated at 120° C. for 20 hours in a stainless steel sealed tube. The reaction product was dissolved in methanol-water (10:l) mixture (23i12), and sodium borohydride (
1,149,30 mmoff) was added. After stirring at room temperature for 3 hours, the reaction solution was concentrated to dryness, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was filtered with silica gel.
Column chromatography (Sin,: 90g, CH
CQs) to obtain 0.619 tetrahydropyridyl compound (yield 13%). This was then catalytically reduced to C2.7ky/cm" in ethanol (20Tn+2) using platinum oxide (0.07g) as a catalyst at room temperature.
l h) was performed. Filter the catalyst, remove the solvent under reduced pressure,
0.589 of the title compound was obtained.

(Yield 94%) Reference Example 5 Phenyl(2-pyridyl)methanol φ 2-pyridinecarboxaldehyde (0,509°4.
A 3.0M phenylmagnesium bromide ether solution (2,6+IL 7.8+*moQ) was slowly added dropwise to a THF (low (1) solution of 7+1off) at room temperature. After stirring for 1 hour, diluted hydrochloric acid was slowly added. It dripped.

The organic layer was separated, and the aqueous layer was extracted with ether.

The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (Sins
: 50g, separated and purified with ethyl acetate:hexane-1:l), and then the desired fraction was distilled under reduced pressure to obtain the title compound (
0,849,97%) was obtained. This material crystallized at room temperature.

b, p, 104-109℃ (0,25mmHg) +n
, p, 63-54 °C 'H-NiJR (CDCQs) δ 5.31 (br, s
, IH), 5.75 (s.

IH), 7.1-7.4 (m, 7H), 7.61 (d
d, J-8Hz, J'-1Hz, IH), 8.5
6 (d, J-5Hz, IH).

Reference example 6 1-Methyl-2-piperidyl)phenylmethanol Phenyl(2-pyridyl)methanol (6.24g).

33.7 mmol12) and iodomethane (8.0 (h,
56.3mmoI2) was mixed and placed in a stainless steel sealed tube.
The reaction was carried out at 10°C for 1 hour. The product was dissolved in methanol (100
mQ) and sodium borohydride (7,659
,0,20moQ) were gradually added. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. Water was added to the residue and extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the reduced product as a brown wave-like substance. Next, this was mixed with ethanol (10
0m12), add platinum oxide (0,239), and catalytically reduce it at room temperature (hydrogen pressure: 3719/cll")
did. The reaction solution was filtered and the filtrate solution was concentrated under reduced pressure to obtain the title compound (2,009, yield 29%)! child.

Reference Example 7 ■-Preparation of a double mirror body of methyl-2-piperidine methanol I-Methyl-2-piperidine methanol (48.8 g,
0.378i+o(1) and dibenzoyl-D-tartaric acid l hydrate (130,09°0.363io12) were mixed and dissolved in ethanol (200mQ) by heating. ethanol(
50+1l12) was added and stirred under water cooling to perform crystallization. After stirring for 3 hours, the precipitated crystals were filtered, washed with cold ethanol, and air-dried. The resulting pale brown solid (73,
4g) was dissolved in ethanol (160mff) under heating, and recrystallization was performed by stirring at room temperature. The precipitated crystals were filtered, washed with cold ethanol, and then dried in vacuum (50°C) to obtain single yellow crystals (52.3 g, 59%). The specific optical rotation of this product is [α]. +90' (c=1.02°MeOH)
Met. The crystals were dissolved in 3N hydrochloric acid (200 mff) and washed with ethyl acetate (C20C20O2).

After adjusting the aqueous layer to pH>10 with sodium carbonate powder, the aqueous layer was concentrated under reduced pressure and the residue was dissolved in chloroform (300 Il
+12X 2 ) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the (+) form of the title compound (8.68 g, 64%) as a single yellow oil.

[α) o +33.4” (cJ, 67, MeOH).

The (-) form was obtained in the same manner using dibenzoyl-tartaric acid. (Yield 41%) (a) o-34
, 7° (cml, 47.MeOH).

Reference Example 8 Preparation of both mirror bodies of 1-methyl-2-piperidine-1-ethanol Oxalyl chloride (3,04++12.33.9ii
of dichloromethane (75ml)
After cooling to °C, DMSO (5,2 mff, 67
．． A solution of 8m+*o12) in dichloromethane (15mQ) was slowly added dropwise. Next, the compound obtained in Reference Example 7 (
-)-1-methyl-2-piperidinemethanol (3,0
49,23,81111012) dichloromethane (3
011111) solution was added dropwise and stirred at -78°C for 30 minutes. Triethylamine (22m<1.150+moQ
) was slowly added dropwise, and the mixture was stirred for 15 minutes. After raising the liquid temperature to about 10° C., water (65 m4) was added. The organic layer was separated, and the aqueous layer was diluted with chloroform (10011 (2X 2
), the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the crude product was reduced to a brown oil (3,009
) was obtained. The obtained crude aldehyde was immediately used in the next reaction.

The crude aldehyde (3-009,33,8 mmoj2) was dissolved in ether (100 mff) and 1.0 M methylmagnesium iodide in ether solution (25 NL2) was dissolved in ether (100 mff).
5 m off) was added dropwise under water cooling. Thereafter, after stirring at room temperature for 2 hours, a saturated ammonium chloride aqueous solution (50
mQ) and extracted with chloroform (100X 2 ).

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crude product was distilled under reduced pressure to obtain the (-) form of the title compound (1.04 g).

A yield of 17%) was obtained.

b, p, 95-96°C (18 mHg).

Ca)o-18,5° (c-2-05,CHC(I
s).

by HPLC) Example 1 IH-indole-3-carboxylic acid.

pyrrolidinyl) ethyl ester (79% e, e.

(l 2-(l-pyrrolidinyl)ethanol (1.10 g.

9.611111O(2) 1.5M in anhydrous THF solution
n-BuLi hexane solution (6,412,9,6iio
ff) was added dropwise over 10 minutes under water cooling, and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with anhydrous THF (20++
+12) was added. Indole-3-carboxylic acid chloride (1,00 g, 5.6++1o(
1) (1) Anhydrous THF (5m+2) solution was added dropwise at room temperature over 10 minutes while stirring. - After stirring overnight,
The reaction solution was concentrated under reduced pressure, and the residue was extracted with diluted hydrochloric acid and washed with ether. The aqueous layer was brought to pH>10 with saturated aqueous sodium bicarbonate solution and extracted again with ether.

The obtained organic layer was washed with water and saturated saline, and then dried (
MgSO*) L, concentrated under reduced pressure to 1. The title compound was obtained as 10g of colorless platelets.

Melting point 145-146℃; IRy wax (KBr)
3425(w), 281O(1m), 1695(s)
, 1530 (m), 1452 (+a), 1312 (m)
, 1190 (s), 1055 (+)
, 758 (+o) cm -S; H-NMRδ
(CDCffs) 1.82 (4H, m), 2.71 (
4H, br, s), 2°96 (2H, t, J□5.
9 Hz), 4.50 (2H, t, J-s, a Hz
), 7.14-7.19 (2H, m), 7.21-7.
33 (2H, m), 7.70 (IH, d, J=2.9
Hz), 8.08 (IH, m); MS (m/z)2
59 (M”+1.0.4), 144 (100), 116
(68), 97(92).

Example 2 1H-indole-3-carboxylic acid, 2-biperidinoethyl ester H Prepared according to the method of Example 1.

Columnar crystal; melting point 123-125°C; 1RvIllax
(KBr) 3260(S), 2940(s), 16
70(s), 1538(m), 1450(s), 132
0(m), 1192(s), 101060(,1010
42(,735(s) cm-'; H-NMRδ(CD
C(is) 1-46 (2B, m), 1.62 (4H.

m), 2.59 (48, m), 2.82 (2) 1.
t, J=5.9 Hz), 4.49(2B, t,
J・5.9 Hz), 7.10 to 7.36 (4H, m
), 7.67(1)1. d, J=2.9)1z)
, 8.05-8.10(l)1. m); MS(m/z
) 271 (M” 1.0.2), 144 (26), 1
12(80), 98(100).

Example 3 IH-indole-3-carboxylic acid, 2-hydroxy-
3-Biperidinoprobyl ester Prepared according to the method of Example 1.

Foamy solid; I Ry +nax (KBr) 330
0(m), 2940(m), 1704(s), 153
0(m), 1440(s), 1315(m), 118
2(S), 101048(,750(m)cm-';
H-NMRδ (CDCff3) 1.48C2H, m)
1. L63 (4B, m), 2.45-2.75 (
6)].

+o), 4.15-4.40 (6H, m), 7.22-
7.26 (2H, m), 7.41-7.46 (2H, m
), 7.99 (1B, s), 8.11-8.16 (I
L m); MS (m/z) 302 (M", 0-2)
, 144(20), 116(8), 98(100).

Example 4 IH-indole-3-carboxylic acid, (1-methyl-2
-piperidyl) methyl ester l-methyl-2-piperidine methanol (1,70 g,
13.2mmoQ) (7) THF (17mff)
To the solution: Cool to -5°C in an ice-salt bath and add 1.5M
n-BuLj hexane solution (8,7N2.13.On+
moQ) was added dropwise over 5 minutes.

After stirring for 30 minutes under water cooling, indolecarboxylic acid chloride (1,509,8-35m off) f) T
HEC5mQ) solution was added dropwise over 5 minutes. Thereafter, the mixture was stirred at room temperature for 5 hours, and the reaction solution was poured into diluted hydrochloric acid solution to separate the organic layer, and the aqueous layer was extracted with EtOAc. The pH was then brought to >10 with saturated aqueous sodium bicarbonate solution and extracted again with EtOAc. The basic extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained single yellow solid was recrystallized from a chloroform:methanol mixture to obtain 1.20 g of the title compound as columnar crystals.

Melting point 168-170"O; JRy wax (XBr)
2930 (m), 286° (w), 1698 (s
), 1532(w), 1455(+n), 1345(W
), 1310 (m), 1179 (s), 1025
(s) cta-': H-NMRδCCDCl2s)
1-25 to 1.90 (6H, m), 2-10 to 2-5
0C2H.

m), 2.40 (3H, s), 2-90 (IH, b
r, d, J=11.5Hz), 4.38(2H, d
q, J=4.6 Hz, J'□11.6 Hz),
7.21 (2H, m) , 7.45 (2H, m) , 8
．． 13 (IH, m), 11.5 (1B, br, s)
; MS (m/z) 144 (10), 116 (5),
98 (100).

Example 5 IH-indole-3-carboxylic acid, 2-(1-methyl-2-pyrrolidinyl)ethyl ester 2-(1 methyl-pyrrolidine)ethane (3.0 h, 23.2 m+*o (2) in anhydrous THF
Add 1.5M n-BuLi hexane solution (16, (hffi, 24.0in+oQ) to the (30mQ) solution at -1
The mixture was added dropwise over 10 minutes at 0 to 5°C. After stirring for 30 minutes, indole-3-carboxylic acid chloride (4,20
g, 24.01111012) of anhydrous THF (20
mff) solution was added dropwise over 45 minutes at -5 to 5°C.

After removing the cold bath and stirring overnight at room temperature, cold dilute hydrochloric acid was added to the reaction mixture, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH>10 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.91 g of the title compound as a yellow viscous substance.

Foamy solid; IRymax (KBr) 2960 (m)
, 1700(s), 1538(m), 1455(n
+), 1330(v), 1315(w), 1180(
s), 1050 (v), 755 (m) cm-'; H
-NMRδ (CDCQ3) 1.55-1.90 (4H,
m), 2.00-2.45 (4H, m), 2.40 (3
H, s), 3.12 (IH, br, t, J=7.
0 Hz), 4.40 (2H, t, J depth 7.9
Hz), 7.22 to 7-45 (4H, m), 7.91 (
IH, s), 8.18 (IH, m).

Example 6 l-(IH-indol-3-ylcarbonyl)indole-3-carboxylic acid, (1-benzyl-2-pyrrolidinyl)methyl ester Prepared according to the method of Example 1.

Pale yellow viscous substance; IRy,,ax(film) 32
80(w), 2954(w), 1710(s), 1
684(s), 1523(m), 1451(s), 13
71(s), 1195(s), 1172(s), 83
3(s), 750(S)c++-'; H-NMRδ(
CDCffs) 1.65-1.85 (3H, m),
1.9.3-2.15 (IH, m), 2-20-2.3
4 (IH, m), 2.86-3.08 (2H, m),
7.18-7.45 (12H, m), 8.05-8.1
3 (IH, m), 8.20-8.28 (IH, m), 8
．． 30-8.40 (IH, m), 9.02 (IH,
br, s) ; MS (m/z) 477 (M”
.

0.3), 333 (0,2), 234 (0,4), 16
0 (100).

Example 7 1H-indole-3-carboxylic acid, 1-(4-methylpiperidino)-2-propyl ester Prepared according to the method of Example 1.

Colorless viscous substance; IRy wax (film) 3290 (
o+), 1700(s), 1676(s), 1534
(s), 1453(s), 1377(m), 1177
(s), 788(S)C+I-'; H-NMRδ(
CDCL) 0.86 (3H.

d, J=5.9 Hz), 1.15-1.48 (3H
, m), 1.36 (3H.

d, J・6.4 Hz), 1.50-1.70 (2H
, m), 2.00-2.25 (IH, m), 2.48
(IH, dd, J-4, 4Hz, J=13.2H
z), 2.80 to 3.20 (3) 1. m), 5.40
-5.55 (IH, n+), 7.04-7.17 (2H
, m), 7.20-7.30 (IH.

m), 7.68 (IH, d, 2.4 Hz), 7.8
5-8.05 (IH, +i), 9.88 (IH, br,
s); MS (m/z) 301 (M"+ 1.2),
204(IO), 117(100).

Example 8 l-(IH-indol-3-ylcarbonyl)indole-3-carboxylic acid, 1-(4-methylpiperidino)
-2-Propyl ester Prepared according to the method of Example 1.

Pale yellow viscous substance; IRyll1ax (fth m) 17
10(s), 1689(s), 1525(+n),
1450(s), 1201(s), 1173(s), 1
01061(,833(s),790(vs),763
(vs) cm-'; H-NMRa (CDCffs)
0.85 (3H, d, J-5, 9Hz), 1.08
~1.48 (3H, m), 1.39 (3H, d, 1□6
．． 3 Hz), 1.50-1.68 (2H, m), 2
．． 00-2.20 (2H, m), 2.50 (IN.

cld, J・4-4 Hz, J=13-2 H
z), 2.74-3.12(3)1゜m), 5.4
0-5.55(l)I,m), 7.10-7.50(6
) f, Il+), 8.05-8.12 (2L m
), 8.18-8.30 (2J(,m), 10.3(1
)1. br, s) ; MS (m/z) 445 (
M''+2.0.4), 204(5), 146(1
00).

Example 9 1H-indole-3-carboxylic acid, 1-(2-methylpiperidino)-2-propyl ester Prepared according to the method of Example 1.

Pale yellow viscous substance; IRywax (film) 2992 (m), 167
6(s), 1535(m), 1443(m), 1377(m), 1178(s)
, 1126(m), 101041(,910(II+)
, 789(s), 753(s), 735(s) cm-'
; H-NMRa (CDCffs) 1.12-1
．． 16(3)f.

m), 1.20-1.30 (2H, m), l-36 (3
) f, dd, J=3.4Hz, 6.41(z), 1.
45-1.65C3H,m), 2.25-2.55(3
L m), 2-79 (lH, d, J-5, 9Hz),
2.90-3.18 (2L m), 5.30-5.4
8(IH, l11), 7.16-7.28C2H.

m), 7.29-7.40 (IH, m>, 7.69-7
．． 83CIH, rn), 8.09-8.19 (IL
m), 9.20-9.60 (IJ(,W); M
S (m/z) 302 (M”+ 1.15), 286 (2
0), 202 (40), 140 (100).

Example 10 1-(IH-indol-3-ylcarbonyl)indole-3-carboxylic acid, 1-(2-methylpiperidino)
-2-Propyl ester Prepared according to the method of Example 1.

Orange viscous substance; lRy +nax (film) 3296
(w), 1684(s), 1525(m), 1451
(s), 1440(s), 1383(m), 1201
(s), 1173(s), 834(s), 78B
(vs), 754(vs)c+m-'; H-NMR
a(CDC(Is) 1-07~1.11 (3H, m
), 1.18-1.30 (3H, m), 1.39-1.
41 (3B, m), 1.45 to l-80 (3H, +I
+), 2-20 to 2.51 (3H, m), 2.70
~2.80 (IH, m), 2.88-3.10 (2B,
m), 5.30-5.48 (IH, m), 7.20-
7.60 (6H, m), 8.07-8.12 (LH.

m), 8.21-8.26 (2H, m), 8.30-8
．． 35 (IH, m), 9-58 to 9.70 (IH, m)
; MS (m/z) 444 (M"+ 1.0.5), 4
31(1), 202(5), 139(100).

Example 11 1H-indole-3-carboxylic acid, 1-(3-methyl-1-piperidino)-2-propyl ester Prepared according to the method of Example 1.

Pale yellow viscous substance; IRy mix (film) 170
0(s), 1677(S), 1535(m), 14
60 (m), 1377 (m), 1178 (s), 101
038(,752(s)cm-'; H-NMRa(C
DCffs) 0-80-0.88 (3H, m), 1.
37 (3H, d, J=6.3 Hz), 1.45-1
．． 83 (5H, m), 1.89-2.13 (2H, m
), 2.46 (1B.

dd, J□4.4 Hz, J'=13.2)1z
), 2.77-3.18 (3H.

m), 5.38-5.53 (IH, +n), 7.01-
7.20 (2B, m), 7.21-7.30 (IH,
m), 7.69 (IH, d, J-2, 9Hz), 7.
96 (IH, br, d, J4.8 Hz), 9
．． 82 (LH, br.

s); MS (m/z) 302 (M”+2. 1.
5), 203(3,5), 145(100).

Example 12 1-(IH-indol-3-ylcarbonyl)-indole-3-carboxylic acid, 1-(3-methylpiperidino)-2-propyl ester Prepared according to the method of Example 1.

Orange viscous substance; IRy max (film) 1686 (
S), 1551 (m), 1526 (m), 1450 (
s), 1370(s), 1202(s), 1175(
S), 101060 (, 833 (m), 751 (s)
cm-'; H-NMRδ (CDCL) 0.79-0
-85 (3H, m), 1.40 (3H, d, J-6
,4Hz), 1.48-1.85(5H,m), 1.8
8-2.10 (2H.

m), 2.44-2.53 (IH, m), 2.70-3
．． IO (3M, m), 5.40-5.48 (IH, m)
,7. lO ~ 7-50 (6H, m), 8.00 ~ 8.1
5 (2H, +m), 8.18-8.30 (2H, m),
10.10 (IH.

br, s); MS (m/z) 444 (M”
+1. 0.5), 385(1), 203(3,5
), 145(100).

Example 13 1-Methylindole-3-carboxylic acid, (1-methyl-2-piperidyl) methyl ester e 60% sodium hydride (0,099,2,3 wealth chart.a
IH-indole-3-carboxylic acid, (1-methyl-2-piperidyl) methyl ester (0.5 h, 1.8 mmoff) (7) in DMF (10 mff) suspension of
A DMF (5ml) solution was added dropwise at room temperature over 5 minutes.

After stirring the reaction solution for 15 minutes, methyl iodide (0,29
A solution of 9,2,0 mm off) in THE (5 ml) was added and stirred overnight. Pour the reaction solution into water and dilute with EtOAc.
After extraction, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was subjected to silica gel column chromatography (20 g
, CH Off, ) to give the title compound as 0.43 g of a colorless oil. IRy,,x(file)
2940 (m), 2780 (m), 1700 (s), 1
540(s), 1470(m), 1382(a+), 1
268(m), 1226(s), 1105(s), 1
01018(,755(n+)cm-'; NMR
δ (CDC42s) l-25 to l-90 (H, m), 2
．． 06-2.35 (2) 1. m), 2.40 (3H
, s), 2.80-2.95 (2) 1. br, ), 2
．． 90 (2B, m), 3.80 (3H, s), 4.3
8(2)1. dq, J-11,5Hz, J'□5
．． 1Hz), 7.30 (4H, m), 8.20 (IH,
m), MS (n+/z) 287 (M”), 158, Il
1, 98° Example 14 1) 1-Indole-3-carboxylic acid, 1-(4-methyl-1-piperazinyl)-2-propyl ester Prepared according to the method of Example 1.

Melting point 165.5℃; IRy wax (KBr) 294
2(m), 1685(s), 1538(s), 145
4(s), 1369(m), 1325(s), 117
3(S), 1115(m), 779(m), 758(
m) cm-'; H-NMRδ(CDCL)l-39(
3H, d, J=6.4 Hz), 2.27 (3H, s
), 2.30-2.85 (10B, m), 5.3
2-5.48 (IH, m), 7.16-7.25 (2H
, m), 7-30 to 7.40 (1) 1. m), 7.8
1 (IH, d, J・2.9 Hz), 8.08-8.
18 (IH, m), 9.56 (IH, m); MS (m
/z) 303(M”+2.4), 202(2), 144
(100).

Example 15 1-(IH-indol-3-ylcarbonylindole-3-carboxylic acid.1-(4-methyl-1-piperazinyl)-2-probylester H Prepared according to the method of Example 1 .

H-NMRδ (CDCI2s) l-39 (3H, d,
J・6.4 Hz), 2.26 (3H, s), 2.3
0-2.80 (IOH, m), 5.30-5.45 (1
M.

m), 7.28-7.50 (5H, m), 7.68 (I
H, br, s), 8.09-8.13 (IH, m),
8.19-8.23 (I) I, m), 8.28 (IH
, s), 8.31-8.36 (IH, m), 9.65 (
IH, br, s); MS (m/z) 445 (M”+ 1
．． 0.2), 302 (0,3), 243 (0,6), 1
13 (100).

Example 16 1.1-Dimethyl-2-(LH-indole-3-carbonyloxymethyl)piperidinium iosito 1H-indole-3-carboxylic acid, (l-methyl-2
-piperidyl) methyl ester (0,109°0.37
mmo12) was heated and dissolved in benzene (10m12),
Then methyl iodide (0,149,0,99mmo4)
A solution of benzene (5 ml) was added thereto, and the mixture was reacted at 100° C. for 2 hours in a stainless steel sealed tube. The reaction tube was cooled, the reaction product was scraped out with spatyl, washed with IPE, and dried under reduced pressure (70°C) to form a foamy yellow solid of 0.11
9 of the title compound was obtained. Melting point 95-97℃; IRy w
ax (KBr) 3430 (s), 3200 (m), 17
05(s), 1530(m), 1432(s), 131
5(m), 1242(n+), 1170(s), 112
4(+o), 101042(,758(m)cm-';
H-NMRδ (CDC et al.-CD, 0D=1:5)
1.65-2.18 (6H, m), 3.21 (38, s
), 3.34 (3H, s), 3.50-3.62 (
2B, br, s), 3.80-3-96 (IH, br
, ), 4.62~4.86 (2H, +a), 7.22~
7.27 (2H, m), 7.47-7.51 (IH, n
+), 8.05-8.10 (2H, +o).

Example 17 IH-indole-3-carboxylic acid, 1,6-dimethyl-2-piperidyl methyl ester Prepared according to the method of Example 1.

Foamy solid; TRνwax (KBr) 2930(s)
, 2850(m), 1700(s), 1678(
s), 1530(m), 1450(s), 1310(
s), 1172(s), 101040(,750(s)
c+m-'; H-NMRδ(CDC(2x) 1.1
5 (3H, d, J=6.2 Hz), 1.30~2
-30 (8H, m), 2.45 (3H, s)
, 4.44 (2H, d, J=4.4Hz), 7.
15-7.38 (31, +m), 7.74 (IH, d,
J = 2.9Hz), 8.1 (IH, m), 9.8 (I
H, br, s); MS (m/z) 287 (M”, 1
．． 6), 144 (100), 116 (38), 89 (4
4).

Example 18 IH-indole-3-carboxylic acid, 1,6-dimethyl 1.2.5.6-tetrahydro-2-pyridylmethyl ester Prepared according to the method of Example 1.

Foamy solid; IRy max (KBr) 2960 (w
), 1698(s), 1530(m), 1450(
m), 1310(w), 1245(w), 1170(
s), 1042 (+11), 750 (s) cm-';
H-NMRδ (CDC4,) 1.07-1.20 (3
H, two d, J=6.8 Hz), 1.82~2
．． 40 (3H, m), 2-50-2.57 (3H, tw
o s), 3.1O-3-50 (IH, m), 4.30
-4.63 (2H, m), 5.51-5.96 (2) 1
．． m), 7.20-7.42 (3H, m), 7.
75 (IH, m), 8.14 (IH, m), 9.8
2(LH,br,s); MS(w+/z)284(
M+, 5.6), 144 (58), 110 (100).

Example 19 IH-indole-3-carboxylic acid, (1-ethyl-2
-piperidyl) methyl ester Prepared according to the method of Example 1.

Foamy solid; IRlmax (KBr) 3280(w)
, 2930 (m), 1700 (s), 1678 (s
), 1530(m), 1450(a+), 1410(
W), 1172(s), 101045(,750(s)
cm-'; H-NMRδ (CDC(23) 1.09
(3H, t+ J=7.0 Hz), 1.2 (1-2
,20(6H,m),2.38(l)I,br,
q) , 2.75 (2H, m), 2.90 (2H, m)
, 4.44 (2H, dd, J□9.OHz, J'□
4.7Hz), 7.21 (2H, m), 7.36 (IH
, m), 7.84 (IH, d.

J=2.9 Hz), 8.20 (IH, +n), 9.
40 (IH, br, s); MS (m/z) 287 (M
”+1. (L4), 144 (54), 112 (100
), 89(26).

Example 20 IH-indole-3-carboxylic acid, (1-ethyl-6
-Methyl-2-piperidyl) methyl ester Prepared according to the method of Example 1.

Foamy solid; IRy 1Ilax (KBr) 2930
(s), 1702(s), 1680(s), 153
0 (m), 1450 (m), 1315 (W), 117
5(s), 101042(,752(m)cm-';
H-NMRδ (CDC123) 1.00 (3H,t,
J・7.0 Hz), 1.15(3H,d, J□
6.2Hz), 1.20-2.35 (6H, ■), 2
．． 57 (IH, m), 2.85 (IH, m), 3.0
5 (2H, q, J=6.7 Hz), 4.34 (IH
.

dd, J□5.6 Hz, J'□11.4 Hz)
, 4.55 (In, ad, J-4,4Hz, J'□
11. OHz), 7.25 (2H, m), 7.40 (I
H.

m), 7.80 (IH, br, d, J 2.I Hz
), 8-19 (IH.

m), 9.45 (IH, br, s); MS (m
/z) 300 (M”, 0.2), 285 (76),
144 (90), 126 (100), 116 (38).

Example 21 IH-indole-3-carboxylic acid, (1-methyl-2
-Piperidyl)-1-ethyl ester Prepared according to the method of Example 1.

Foamy solid; IRy max (KBr) 3270 (w
), 2940(s), 2800(v), 1700(
s), 1682(s), 1538(s), 1455(
m), 1330(v), 1180(s), 10
1050(,758(s)cm-'; H-NMRδC
CDCQs) 1.20-1.95 (6H, m), 2
-22 (2H, m), 2.37 (3H, s), 2.90
(IH, br, d.

J”11.1 Hz), 4.40 (2H, m), 7.2
5 (2H, m), 7.45 (IH, m), 7.91 (I
H, s), 8.15 (IH, m), 9.85 (III.

br, s); MS (m/z) 286 (M”, 0.3
), 144 (36), 116 (35), 98 (100)
.

Example 22 1-Pentylindole-3-carboxylic acid, (1 methyl-2-piperidyl) methyl ester 60% sodium hydride (0-10 g, 2.5 mmol) in DMF (5
Tomi Q) IH-indole-3-carboxylic acid, (
1-Methyl-2-piperidyl) methyl ester (0,5
A DMF (7mff1) solution of 09,1,7IImoQ) was added dropwise at room temperature for 10 minutes. Stir for 45 minutes;
After that, l-iodopentane (0.38g, 1.9ms+
off) and stirred for 4 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (50 m<1), washed successively with water and saturated saline, and dried over anhydrous vLWa magnesium. The solvent was distilled off under reduced pressure to obtain pale yellow crude fR(0,5
2g) was obtained. This was subjected to silica gel column chromatography 4- (sio*: 209.CHCl25/MeO
The product was separated and purified using H-20/l) to obtain a clear compound (0.33 g, yield 56%) as a colorless oil.

'H-NMR (CDCl25) δ0.89 (t, J
□6.4Hz, 3H), 1.20-1.95 (m,
12H), 2.08-2.45 (m, 2H),
2.42 (s, 3B), 2.88 (br, d,
Jgll-2Hz, IH), 4.13(t, J.
7.1Hz, 2H), 4.30(dd, J=4.9
Hz, J□11.5Hz, IH), 4.46(dd
, J-4,9Hz, J'・11.5HzLH), 7
．． 23-7.38 (m, 3H), 7.84 (s, I
J(), 8.11(city, IH); IR(fil
n+) 2930. 1700. 1538.1470
゜1400.1225.1185.1112.752
cm-'; Mast (m/e) 343 (M", 3
), 214(55), 144(45), 11](
100).

Example 3 1-Henselindole-3-carboxylic acid, (l-methyl-2-piperidyl)methyl ester The title compound was obtained according to the method of Example 21.

'H-NMRCCDCQs) a 1-20 to 1-90
(v*, 6H), 2.05"2.35(m, 2)])
, 2-41 (s, 3H), 2.90 (d, J-13, 2
Hz, 4)1), 4.32 (dd, J・4.9
Hz, J'・11.2Hz, LH), 4.47
(dd, J=4.6Hz, J'=11.5Hz, IH)
, 5.33 (s.

3H), 7.12 to 7-16 (+a, 2H), 7.23
~7.35 (m, 6B), 7.88 (s, IH), 8.
21 (br, d, J=7.3Hz, IH); IR (f
ilm) 2940.1700. 1538.1462
．． 1395.1240.118011092.752
cm-"; Mass (m/e) 363 (M",
1), 234(27), 204(12), 1it(1
00).

Example 4 ■ H-Indole-3-carboxylic acid, (1-benzyl-2-piperidyl) methyl ester Using l-benzyl-2-piperidine methanol obtained in Reference Example 3, according to the method of Example 1 above. Prepared.

'H-NMR (CDCffs) J 1.30~l-
93 (1,5H), 2.04-22-19 (, IH),
2.7BCrs, 2H), 3-38(d, Jeg. 13
Hz1)1), 4.17 (d, J13Hz, IH)
, 4.50 (+a, 2B), 7.16-7.42 (m
, 8H), 7.90 (d, J=3Hz, IH),
8.21 (a+, 1B), 8.81 (br, s,
IH) ; IR (film) 3296.2934, ]
678.1534.1442.1313.1244.1
172.1126.1047.752 cm-'Example 25 1B-indole-1propyl) 3-carboxylic acid, (1-(2-piperidyl)methyl ester obtained in Reference Example 4 1-(2-propyl)2- Prepared according to the method of Example 1 using piperidine methanol.

'H-NMR (CDC12s) δ 0.99.1.17
(two d, Jl17Hz.

3HX2), 0.85-1.94 (br,, 5B),
2.20 (m, LH), 2.88 (br, s, 2
B), 3.47 (Il, IH), 4.33 (dd,
J=14Hz, J'=3H, IH), 4.51(dd
, J=14Hz, J'=3H.

IH), 7.15-7.46 (m, 3H), 7.91
(d, J-3Hz, lH), 8.20(+n, I
H), 8.90 (br, LH); IR (fil
fi) 3270°2932.1679.1533.1
444.1314.1174.1044.779, 75
20 votes-1 Example 26 1H-indole-3-carboxylic acid, (1-7enethyl-2-piperidinyl)methyl ester 1-(1-7enethyl)-2-piperidinemethanol obtained according to the method of Reference Example 4 It was prepared according to the method of Example 1 using.

'H-NMR (CDCI23) δ 1.30-1.
93 (m, 8) 1), 2.40-2.55 (m, I
H), 2.75-3.08 (m, 4B), 4.38 (d
d.

J=5.1Hz, 1) J), 4.57(dd, J=
5.1Hz, IH), 7.12-7.32 (+o,
8H), 7.38-7.42 (m, IH), 7.84
(d.

J=3Hz, IH), 8.13-8.23 (m, 1B)
, 8.83 (br, s.

IH) ; IR (KBr) 2934.1679.1
533.1444.1313.1173.1125.1
045.752 cm-'; MS (m/e) 363
(M+1), 252 (92), 146 (80).

Example 27 IH-indole-3-carboxylic acid, (1-pentyl-2-piperidyl)methyl ester The method of Example 1 was carried out using l-pentyl-2-piperidine)methanol obtained according to the method of Reference Example 4. Therefore it was prepared.

'H-NMR (CDCff,) δ 0.84 (t, J
=6.5Hz, 2H), 1.18-1.35(m,
3H), 1.43-1.93 (+a, 10H), 2.
25-2.42 (m, IH), 2.48-2.98 (
m, 4H), 4.43 (m, IH), 4.45 (m
, IH), 7.21-7.29 (m, 2H), 7.
35-7.43Ctrr, 1)f), 7.86(d,
J□2-9Hz, IN), 8.13-8.21(m
, IH), 9.32 (br, s, IH);
IR(KBr) 2934.1683.1536.12
17.1173.758 cm-' Example 28 IH-indole-3-carboxylic acid, (1-methyl-2
-piperidyl)-1-ethyl ester (l-methyl-2-piperidyl)-1-ethanol (1-methyl-2-piperidyl)-1-ethanol (
19.4g, 140mmof) and 1,3-dimethyl-
2-imidazolidinone (30mL 270mmoff
) in THF (300IIi2) solution under ice cooling, 1.6M
n-Butyllithium hexane solution (85mQ,
140+++ moIl) was added dropwise over 25 minutes. 30
After stirring for a minute, indole-3-carboxylic acid chloride (17-09,95m+to(2) and 1,3-dimethyl-2-imidazolidi/7(10m112.90■o1
The THF (loOmQ) solution of 2) was heated to 50°C below -5°C.
It was added dropwise over a period of minutes. After stirring for 30 minutes under cooling, the water bath was removed and the mixture was stirred for an additional hour. The reaction solution was diluted with water (500
mff) and extracted with ethyl acetate (500+4). The organic layer was washed with water, then transferred to dilute hydrochloric acid (500 mQ), and the acidic layer was washed with ethyl acetate. pH>10 with sodium carbonate and ethyl acetate (200m6x
3) was extracted.

The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product (9,59) as a yellow oil. This is about 5 from NMR.
:l was found to be a diastereomer mixture.

Therefore, crystallization was performed from a chloroform-isopropyl ether mixture to obtain the title compound (6,1 Oe), a low polar main product, as colorless crystals as a single diastereomer.

m, p, (HCl2 salt): 185°C'H-NMR (CDC(ig) δ 1.20-1.
97(-16H), 1.37(d, J□7Hz,
33(), 2.05-2.40(m, 2B), 2.3
8 (5°3H), 2.83~2.95 (o+, IH
), 5.56~5.68 (m, IH), 7.20~
7.34 (m, 2H), 7.35-7.46 (m,
IH), 7.93(d, J-3H, IH),
8.12-8.23 (m, IH), 8.60-8.
85 (br,, 1B); IR (KBr) 30
70.295012600゜1700.1520.14
40.1320.1180.1110.1030°78
0 c-1 Example 29 1H-indole-3-carboxylic acid, (1-methyl-2
-piperidyl)-1-ethyl ester The crystallization mother liquor in Example 28 was concentrated, and the residue (3,209) containing a large amount of highly polar diastereomers was purified by silica gel column chromatography (Sin: 609.chloroform). :methanol-20:1) to obtain a highly polar diastereomer as a single substance as a colorless oil.

'H-NMR (CDCQ,) δ 1.36 (d, J・
6.5Hz, 3H), 1, 20-1.50 (br.
va, 21), 1.60-1.85 (br., 2H
), 1, 85-2.05 (br. m, 2H), 2-
22 (br. d. J=IO.6Hz, 2H), 2
．． 54 (s. 3H), 3.03 (br. d. J=
10.9Hz, IH), 5.62(dd, J=6.
5Hz. J'=1-7H2. 11), 7, 00-7
．． 12 (m, 2H), 7.25 (m. 2H), 7.
71 (s.

3H), 7.94 (+a. IH), 10.8 (br.
, IH).

Example 30 1H-indole-3-carboxylic acid. 1-(1-Methyl-2-piperidyl)-1-phenylmethyl ester Prepared according to the method of Example 1 using (1-methyl-piperidyl)phenylmethanol obtained in Reference Example 6.

■． p. 252-253°C 1) 1-NMR (CDCff3) δ 1.20 (m.
2H), 1.54 (m.

4) 1), 2.40 (+w. IH), 2.60 (s,
3H), 2.80 (m. IB), 2-97 (+i,
IH), 6.39 (d, J-6Hz, IH), 7
．． 28 (m.

9H), 7.93 (m. LH), 8.20 (■, 1
B); IR (KBr) 3400, 3310, 31
30, 3100, 2940, 2800, 1700, 1
625, 1585, 1460, 1380, 1315,
1250, 1125, 1110, 1045, 760c
m-”Example 31 1H-indole-3-carboxylic acid.1-(1 methyl-
2-Piperidyl)-2-phenyl-■-ethyl ester Using l-(1-methyl-2-piperidyl)-2-phenyl-1-ethanol obtained according to the methods of Reference Examples 5 and 6, the method of Example 1 was prepared. Prepared according to.

So-called. p. 245-248°C 'H-NMR (CDC2s) δ 1.60 (br. m
, 6H), 2.17Cm.

2H), 2.53 (s, 3H), 2.94 (dd,
3□7Hz, J'I=14Hz.

2H), 3.15(dd, J-8Hz, J'□14
Hz. 1B), 5.85 (t.

J□7Hz. 1B), 6.90 (dd, J=7Hz
, J'=15Hz, LH), 7, 18(dd, J
=6Hz, J'=15Hz. IH), 7.25 (m
, 6H), 7-58 (d. J=3Hz, IH),
7.77(d, J=7Hz, IH); IR(fi
lm) 3300, 3030, 2940, 1860
11700, 1630, 1610, 1585, I5
40, I460, I380, I340, 1270, 12
20, 1180, 1125, 1090, 990, 750
C-1 Example 32 IH-indole-3-carboxylic acid, 2-(1-methyl-2-piperidyl)-2-probyl ester H 1-(1 -Methyl-2-piperidyl)-2-propatol according to the method of Example 1.

') l-NMR (00012m) 81.32(m,
2B), 1.57 (br, m.

2H), 1.65(s, 3H), 1.70(s, 3
H), 1.81 (m, 2H), 2.30 (m, I
H), 2.45 (s, 3H), 2.87 (m,
2H), 3.08 (m, IH), 7.26 (m,
2H), 7.37 (m, IH), 7.81 (d,
J=3Hz, IH), 8-18(+n, IH
), 9.78 (br.

s, IH); IR (film) 3300.30
20.1680.1540.1390.1340.12
65.1250.1195.1180.1150.10
40.755 cm-' Example 33 IH-indole-3-carboxylic acid, 1-(1-methyl-2-piperidyl) 1-propylethyl 1(l-methyl-2-piperidyl) obtained according to the method of Reference Example 5.6 Prepared according to the method of Example 1 using 2-piperidyl)-1-propatool.

'H-NMR (CDC12,) δ 1.00 (t, J
・7Hz, 3H), 1.20 (m, 2H), 1.5
8 (m, 2H), 1.80 (w+, 4H), 2.2
0 (m.

21), 2.39 (s, 3)1), 2.90 (m,
1B), 5.49 (m, IH), 7.26 (m, 2
H), 7.41 (m, IH), 7.92 (d, 3 to
Hz.

IH), 8.20 (m, IH), 9.30 (br,
s, IH); IR (KBr.

HCff salt) 3430.3180.1700.162
0. 1535.1440.1380.1320.12
50.1175.1130.1030.760 cm-' Example 34 1B-indole-3-carboxylic acid, 1-(1 methyl-
2-Piperidyl)-2-methyl-1-propyl ester Using 1-(1-methyl-2-piperidyl)-2-methyl-1-propyl ester obtained according to the method of Reference Example 5.6, Example 1 In the method, the reaction solvent is THF
:1. Prepared by changing to 3-dimethyl-2-imidazolidinone.

'H-NMR (CDCI28) 81.03 (d, J=
7Hz, 3H), 1.07(d, J□7Hz, 3
H), 1.50 (m, 6H), 2.17 (m, IH
), 2.40 (m, IH), 2.50 (s, 3H)
), 2.62 (m, IH), 2.96 (m, IH
), 5.37 (t, J□6Hz, IH), 7.15
(+s.

28), 7.30 (m, IH), 7.80 (d, J
=3Hz, IH), 8.05(m, IH); I
R(KBr, H(j2 salt') 3425.2970.
2700.1700.1530.1442.1376.
1342.131B, 1250.1170.1130.
1030.780 cra-'Example 35 1H-indole-3-carboxylic acid, 1-(1-methyl-2-piperidyl)-1-hexyl ester M・1-obtained according to the method of Reference Example 5.6 Prepared according to the method of Example 1 using (1-methyl-2-piperidyl)-1-hexanol.

'H-NMR (CDCI23) 80.84 (t, J.
6Hz, 3H), 1.3(br,'m, 8H), 1
．． 65 (m, 6H), 1.97 (m, 2H), 2.
43 (s, 3H), 3.00 (br, d, IH)
, 5.60 (m, IH), 7-28 (+, 2M)
, 7.40 (m, IH), 7-94 (d, J-
2Hz.

1B), 8.20 (m, IH), 9.10 (br,
s, IH); IR(KBr)341O53
150, 2960, 2860, 1720, 1530, 1
170,1040 cm = Example 36 IH-indole-3-carboxylic acid, (1,4-dimethyl-2-piperidyl)methyl ester 1,4-dimethyl-2- and veridine methanol according to the method of Example 1 The title compound was prepared.

Cabinet, p, (MCI2 salt): 185°C') l-NMR (CDCff3) δ 1.20-1.9
7 (m, 6B), 1.37 (d, J-7Hz, 3
)1), 2.05-2.40 (+s, 2H), 2.3
6 (s.

3H), 2.83-2.95 (n+, IH), 5.5
6-5.68 (m, IH), 7.20-77-34C
, 2B), 7.35-7.46 (m, 1)I), 7
．． 93(d, J・3H, IH), 8.12-8.23(
m, 11), 8.60-8.85 (br,, IH);
IR(KBr)3070.2950.2600.170
0%! 520.1440.1320.1180.January 0
．． 1030.780 cm, -' Example 37 1H-indole-3-carboxylic acid, (1,3-dimethyl 1.2.5.6-tetrahydro-2-pyridyl)methyl ester [1,3-dimethyl-2- (1,2,5,6-titrahydrobiridyl)] Prepared according to the method of Example 1 using methanol.

m, p, 172℃ 'H-NMR (CDCa3) a 214), 2.14 (m.

3B), 1.82 (s.

2.55 (s, 3H), 2.62 (t, J=6Hz, I
H), 2.79 (t.

J snow 8Hz, IH), 3.14 (m, IH), 4.39
(dd, J=5Hz.

J'□12Hz, LH), 4.63(dd, J-3Hz
, J'-12Hz, IH), 5.70 (br, t, IH
), 7.18 (m, 2H), 7.30 (m, IH), 7
．． 72 (d, J=3Hz, IH), 8.11 (m, 1B
), 9.87 (br.

s, 1B); IR (KBr) 3400, 1695
．． 1530, 1468.1453.1362.1314
．． Example 1 It was prepared according to the method of

"H-NMR (CDCff3) 80.99 (d, J・7
Hz, 3B), 1.13-2.00 (m, 5) 1), 2
．． 30-2.57 (+e, 2H), 2.48 (s.

3H), 2.78-2.95 (m, IH), 4.
40(dd, J=6Hz.

J'・1lHz, 1B), 4.56(dd, J-5Hz
, J'・1lHz, LH), 7.17~7.31(m,
2M), 7.31-7.46 (m, IH), 7.87-
7.93 (kaku, IH), 8.14-8.26 (m, IH)
), 8.75-8.98 (br,, IH).

Example 39 IH-indole-3-carboxylic acid, (1,3-dimethyl-2-piperidyl)methyl ester Prepared according to the method of Example 1 using 1,3-dimethyl-2-piperidine methanol.

'H-NiJR (CDC23) δ 1.06 (d.

J=7Hz.

3M), 1.35-2,16 (m, 5H), 2.16-2.32 (+w,
IH), 2.41 (S.

3H), 2.56-2.81 (m, 2H), 4.36 (
dd, J=5Hz.

J'=12Hz, IH), 4.53(dd, J□6Hz
, J'=12Hz, IH), 7.20-7.34(m,
2H), 7.34-7.46 (+a, IH), 7.90
(d, J=2Hz, LH), 8.15-8.24(
+m, IH), 8.75-8.93 (br,, IH
).

Example 40 1) Using 1-indole-3-carvone ml, (1-methyl-2-hexahydroazepinyl) methyl ester (l-methyl-2-hexahydroazepinyl) methanol, the procedure of Example 1 was carried out. Prepared according to the method.

'H-NMR (CDCQs) δ 1.35-2.00 (
m, 8H), 2.55 (s, 3H), 2.75-3.
07 (+a, 3H), 4.15 (dd, J-7Hz.

J'□11Hz, IH), 4.39(dd, JW=5H
z, J'=lIHz, IH), 7.18-7.32 (m
, 2H), 7.32-7.45 (m, IH), 7.87
(d, J=3Hz, IH), 8.13-8-24 (+a
, IH), 8.80-9.05 (br,, IH).

Example 41 IH-indole-3-carboxylic acid, 2-pyridylmethyl ester Prepared according to the method of Example 1 using 2-pyridylmethanol.

'H-NMR (CDCQs) δ 5.52 (s, 2H
), 7.20-7.30 (m, 3H), 7.32-7
．． 46 (m, LH), 7.51 (d, J・8Hz.

IH), 7.72 (dt, J=lHz, J'□8H
z, 1) I), 7.98 (d.

J=3Hz, IH), 8.17-8.26(m, 1
)l), 8.63(d, J-5Hz, IH), 9.1
3-9.30 (br,, IH).

Example 42 IH-indole-3-carboxylic acid.

methyl ester-bilin 4-pyridylmethanol according to the method of Example 1.

'H-NMR (DMSO-da-CDC(Is) 8
5.38 (s, IH), 7.10-7.27 (m,
IH), 7.44 (d, J・5Hz, 2H),
7.442-7-55 (, IH), 7.94-8.07
(m, IH), 8.13-8.21 (m, IH),
8.57 (d, J=5Hz, 2H), 11.90-
12.12 (br,, IH).

Example 43 (-)-1H-indole-3-carboxylic acid.

(1-Methyl-2-piperidyl) methyl ester Prepared according to the method of Example 1 using (-)-1-methyl-2-piperidine methanol obtained in Reference Example 7.

[α)D-34,8° (c-1-06, CHCQs) Example 44 (R')-(+')-18-indole-3-carboxylic acid.

(1-Methyl-2-piperidyl) methyl ester Using (+)-1-methyl-2-biveridine methanol obtained in Reference Example 7, the title compound was prepared according to the method of Example 1.

Ca )o + 36-0' (c=0.60.C
HCl25) Example 45 (ls, 2's) -(-) -1H-indole-3
-carboxylic acid, 1-(1-methyl-2-piperidyl)l
-ethyl ester Ct)o -18,4'(c=1.80.CHC
Q3) 97% e, e, (by high performance liquid chromatography) m, p, 143°C Example 46 (lR,2'R)-(+)-18-indole-3-
Carboxylic acid, l-(1-methyl-2-piperidyl)--
Ethyl ester (tr) D + 18.9° (c=1.68°CHC
ff 5) 100% e, e, (by high performance adult chromatography) m, p, 143.8°C Example 7 1.1-dimethyl- (IH-indole-monocarbonyloxymethyl) hexahydroazevinylam. Yoshito was prepared according to the method of Example 16 using the compound obtained in Example 40.

'H-NHR (DiJSO-d,) δ1.35-1.7
2 (m, 2H), 1.72-22-30 (,68), 3
．． 15 (s, 3H), 3.31 (s, 3H), 3.40
=3.80 (m, 2H), 3.81~4.00 (m, I
H), 4.47-4.66 (a+, IH), 4.6
6-4.83 (IH, m), 7.05-7.32 (+a
, 2H), 7.44-7.58 (m, IN), 7.93
~8.07 (■, IH), 8.07~8.22 (m,
IH), 11.90-12.08 (br,, IH)
.

Example 48 1.1-Dimethyl-2-(IH-indole-3-carbonyloxymethyl)piperidinium bromide Prepared according to the method of Example 16 using the compound obtained in Example 4.

va, p-209, 1-209, 6℃ IR (KBr) 3414.2954, l699.153
5, I473.1369.1227.1107.754
cm-'Execution f149 1.1-Dimethyl-2-(IH-indole-3-carbonyloxy-I-ethyl)piperidinium iosito Prepared according to the method of Example 16 using the compound obtained in Example 28 did.

IR(KBr) 3428.1698.1528.14
29.1312.1241, 1172.1057.10
23.780cm-'Example 50 1.1-dimethyl-2-(IH-indole-3-carbonyloxy-1-ethyl)piperidinium bromide H Using the compound obtained in Example 28, the compound of Example 16 was prepared. Prepared according to the method.

IR(KBr) 3436.2952.1698.15
25.1428.1310%117L 1102.10
26.752cm-'Example 51 1.1-dimethyl-2-(IH-indole-3-carbonyloxy-1-ethyl)piperidinium bromide Using the compound obtained in Example 29, the compound of Example 16 was prepared. Prepared according to the method.

m-p・ 236.1-237℃ IR (KBr) 3412. 3182. 1699. 1524. 1429. 1311. 1253. 1173. 1125. 1045. 782cN-” Example 2 1.1-dimethyl- 1 (IH-I Ndor- 3-ka (rubonyloxymethyl) piperidinium ・Yaw hmm de Using the compound obtained in Example 44, Example It was prepared according to the method of No. 16.

m-p・ 222-224℃ IR (KBr) 3396. 3162. 2918. 1707. 1532. 1430. 1325. 1254. 1150° 1118. 755cm-' Example 3 1.1-dimethyl- -(IH-i hmm Doll-3 Ichika (rubonyloxymethyl) piperidinium Professional de Using the compound obtained in Example 44, Example It was prepared according to the method of No. 16.

m-p・240.2-241.0℃ IR (KBr) 3420. 3134. 1706. 1533. 1436. 1329. 1152. 1124. 1041°745C! l-' Example 4 (-)-1,1-dimethyl--(IH-indole-carbonyloxy-ethylpiperidinium bromide) Using the compound obtained in Example 46, according to the method of Example 16 Prepared.

IR(neat) 3116, 2948, 1687, 1
621 1526, 143111314, l17L 1
029,920,757cm-”Ca)o 9,l
'(C-1.32, CHsOH).

Example 55 1,1-dimethyl-2-(l-methylindole-3-
Carbonyloxymethyl)piperidinium bromide e Prepared using the compound obtained in Example 13 according to method 16.

IR(KBr) 3414, 2954, 1699, 15
35, 1369, 1227, 1107, 754cm-
'Example 56 Example 1473 For each of the compounds produced according to the above examples,
The antagonism of 5-HT in 5-HT3 synapses was tested.

That is, when 5-HT (serotonin) is administered into the jugular vein of anesthetized rats, transient bradycardia occurs (van B
ezold Jarisch ReflexXPain
tal, As,.

Physiol, Rev., 53.159-227
(1973)), the main reflection by 5-HT is 5-
Richardso said that HT occurs through receptors.
It has been proven by N et al. (Nature, 316
．． 126131 (1985)), therefore the effective and selective antagonism of 5HT at the 5-HT receptor by the compounds of the invention can be demonstrated by the inhibitory effect on this reflex. That is, rats were exposed to urethane (1 g
/&gi, p), and blood pressure and heart rate were recorded from the left femoral artery. The inhibition rate was calculated from the bradycardia caused when 5-HT (30 μg/ks+) was administered jugularly and the bradycardia caused by 5-BT administration 5 minutes after the jugularly administered compound of the present invention. The inhibition rates are summarized in the table below.

In addition, in this test, except for the compound (quaternary ammonium salt) obtained according to the method of Example 16,
All were tested in the hydrochloride form.

Therefore, the concentration of the test drug is also the concentration of the compound obtained in Example 16 as a hydrochloride. The compound obtained in Example 15 was tested in the form of dihydrochloride.

5-His antagonism 1 6 6 6 7 2 3 4 Inhibition rate (%) 0 8 8 4 1 1 5 6 0 1 Inhibition rate (%) Formulation example 1 tablet (1 tablet) Milk Sugar crystalline cellulose corn starch Magnesium stearate 67111g 15 9 711g I hit 00mg Each component is mixed uniformly to form a powder for direct application.

This was processed using a rotary two-tablet machine to a diameter of 5 sum and a weight of 10.
Form into 0m+9 tablets.

Formulation Example 2 Granules (1 sachet) After the components of A are mixed uniformly, the solution of B is added and kneaded, sized by extrusion granulation, and then dried in a dryer at 50°C. The dried granules are sieved to a particle size of 297μ to 1460μ and made into granules. 1 packet amount 20011
9.

Formulation Example 3 Syrup White Sugar 30,0009 D-Solbi)-Lua 0W/V% 25.0
00g rose ethyl oxybenzoate 0.
030g Roseoxybenzoic acid globipro 0
．． 015g Flavoring 0.200g Glycerin 0.1509
96% ethanol 0.5
0h Distilled water Appropriate total amount 100m12 White sugar, D-sorbitol, methyl roseoxybenzoate,
Propyl paraoxybenzoate and the above active ingredients are dissolved in 60G of warm water. After cooling, a solution of flavoring dissolved in glycerin and ethanol is added. Water is then added to this mixture to bring it to 100 C.

Formulation Example 4 Injection Sodium Chloride Distilled Water 10m + 9 Appropriate Total Volume 1.0 vote a Sodium chloride and the active ingredient are dissolved in distilled water to make a total volume of 1.9m12.

Formulation Example 5 Suppository Polyethylene Glycol 4000 20g Total amount 100g Glycerin is added to the active ingredient and dissolved. Polyethylene glycol 4000 is added there, heated and dissolved, then poured into a layer mold, cooled and solidified, resulting in a layer of 1.59 per piece.

Claims (1)

[Claims] The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is a hydrogen atom, C_1 to C_6 alkyl,
benzyl or indolylcarbonyl, and R_2 is a 5- to 8-membered saturated or unsaturated heterocyclic group containing one or more nitrogen atoms as a heteroatom (this heterocyclic group is C_1 to C_6 alkyl or (optionally substituted with arylalkyl), n is an integer of 1 to 5, and one or more of the hydrogen atoms in -(CH_2)_n- is a C_1 to C_6 alkyl, phenyl and/or hydroxyl group may be replaced with . provided that n is 1 and R_2 is 1-methyl-2-pyrrolidinyl or 1-benzyl-2-pyrrolidinyl), and a pharmaceutically acceptable acid addition salt thereof. , and its quaternary ammonium salts and N-oxide derivatives.