JPH04208263A - Indole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is phenyl which is not replaced or replaced with substituent group selected from halogen, NO2, lower alkyl, CN, lower alkoxy, lower alkylthio, etc.; A is lower alkylene) or a salt thereof. EXAMPLE:3-[4-{-4-(2-Fluorophenyl)piperazin-1-yl} butyl]indole-5-carboxylic acid. USE:A dopamine acceptor agonist, a 5-HT acceptor antagonist or an alpha1 acceptor antagonist. Effective for treating and preventing hypertension, other cardiovascular disorders (e.g. angina pectoris or congestive heart failure), Parkinson's disease, hyperprolalctinlemia, hyperchlolesterolemia, etc. PREPARATION:A compound shown by formula II (R<2> is protected carboxy) is subjected to carboxy-protecting group elimination reaction to give a compound shown by formula I. The compound shown by formula II is a new compound and is obtained by reacting a compound shown by formula III (X is eliminable group) with a compound shown by formula IV.

Description

[Detailed description of the invention]

[00011

[Industrial Application Field] The present invention relates to novel indole derivatives and salts thereof. More specifically, the present invention relates to novel indole derivatives and salts thereof that act on the central peripheral nervous system, methods for producing them, uses thereof as pharmaceuticals, and methods for treating diseases in humans or animals. [0002] Accordingly, one object of the present invention is to provide novel indole derivatives and salts thereof that act on the central and peripheral nervous system, particularly on the peripheral nervous system. [00031 Another object of the present invention is to provide a method for producing novel indole derivatives and their salts. [0004] Still another object of the present invention is to provide dopamine receptor agonists of the indole derivatives and salts thereof; 5
- HT receptor antagonists, especially 5-HT2 receptor antagonists; or use as α1 receptor antagonists and dopamine receptors in humans or animals; 5-HT receptors,
inter alia 5 HT2 receptors; α1 receptor-mediated diseases;
In particular, it is an object to provide methods for treating hypertension, other cardiovascular disorders (eg, angina pectoris, myocardial infarction, etc.), Parkinson's syndrome, etc. [0005]

DESCRIPTION OF THE INVENTION The indole derivatives of the present invention are novel and include compounds (I) represented by the following general formula [wherein R+ is unsubstituted or a halogen atom, a nitro group, a lower alkyl group, a cyano group, a lower alkoxy basis,
a phenyl group substituted with a suitable substituent selected from the group consisting of a lower alkylthio group, a mono- or polyhalo(lower) alkyl group, a mono- or polyhalo(lower) alkoxy group, and a lower alkoxy(lower) alkoxy group; Each represents an alkylene group. ] and their salts. [00061 Suitable salts of the object compound (I) are customary non-toxic salts, including salts with inorganic bases, such as alkali metal salts (e.g. sodium salts, potassium salts, etc.);
alkaline earth metal salts (e.g. calcium salts, magnesidium chloride salts, etc.), ammonium salts; salts with organic bases, e.g. organic amine salts (such as triethylamine salts,
Pyridine salt, picoline salt, ethanolamine salt, triphenolamine salt, dicyclohexylamine salt, N,
Inorganic acid addition salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); Organic acid addition salts (e.g. formate, acetate, trifluoroacetate, maleate, etc.); salts with bases or acid addition salts such as salts with basic or acidic amino acids (such as arginine, aspartic acid, glutamic acid, etc.); Vine. (00071 According to the present invention, the target compound (1) or a salt thereof can be produced by the following method. [0008] Process 1 In the formula, R1 and A are each as defined above,
R2 represents a protected carboxy group. [0009] Compound (II) used in Process 1 is novel and can be prepared, for example, by the method described below or by conventional methods. [00101 Method A In the formula, R1, R2 and A are each as defined above, and X represents a leaving group. [00111 Some of the starting compounds for Method A above are new and can be produced, for example, according to the Preparation Examples below or by conventional methods. [0012] In the foregoing and subsequent descriptions of this specification, preferred examples and examples of the various definitions encompassed within the scope of the present invention will now be described in detail. [00131r lower" means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified. [0014] Suitable "lower alkyl groups" include straight chain or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc., and particularly preferred among them are Methyl and ethyl. (OO15) Suitable "halogen atoms" mean chlorine, bromine, iodine and fluorine, with chlorine and fluorine being more preferred. [0016] Suitable "lower alkoxy groups" include straight chain or branched ones such as methoxy, ethoxy, propoxy, impropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc., especially Preferred are methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy. [0017] Suitable "lower alkylthio groups" include straight chain or branched ones such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, pentylthio, hexylthio, etc. Among them, particularly preferred are It is methylthio. [0018] Suitable mono- or polyhalo(lower)alkyl groups J include trifluoromethyl, trichloromethyl, triiodomethyl, tribromomethyl, trifluoroethyl, tetrafluoroethyl, trifluoropropyl, trifluoroisopropyl, trifluoro butyl,
Mention may be made of mono-, di-, tri- or tetrahalogenated straight-chain or branched (lower) alkyl groups such as trifluoro-t-butyl, trifluoropentyl, tonofluorohexyl. [0019] Suitable mono- or polyhalo(lower) alkoxy groups include trifluoromethoxy, trichloromethoxy, triiodomethoxy, tribromomethoxy,
mono-, di-, tri- or tetra-halogenated linear or branched (lower) alkoxy groups such as trifluoroethoxy, tetrafluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, tonofluorohexylnofluoropentoxy, trifluorohexoxy; Among them, particularly preferred are trifluoromethoxy and 1,1゜2.
．． 2-tetrafluoroethoxy. [0020] Suitable [lower alkoxy (lower) alkoxy groups J] may include the above-mentioned lower alkoxy groups substituted with the above-mentioned lower alkoxy groups, but the most preferred is 2-methoxyethoxy. [00211 Halogen atom, nitro group, lower alkyl group, cyan group, lower alkoxy group, lower alkylthio group,
Preferred examples of phenyl groups substituted with suitable substituents selected from the group consisting of mono- or polyhalo(lower) alkyl groups, mono- or polyhalo(lower) alkoxy groups, and lower alkoxy(lower) alkoxy groups include halophenyl ( For example, 2-fluorophenyl, 2.3-
or 4-chlorophenyl, etc.); Nitrophenyl (e.g., 2-nitrophenyl, etc.); Lower alkylphenyl (e.g., 2-methylphenyl, 2-ethylphenyl, 2,3-dimethylphenyl, etc.); Cyanophenyl (
lower alkoxyphenyl (e.g. 2-13- or 4-methoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 2-isopropoxyphenyl, 2-butoxyphenyl, 2-isobutoxyphenyl); ); lower alkylthiophenyl (e.g. 2-methylthiophenyl); mono, di, tri or tetrahalo(lower) alkylphenyl; mono, di, tri or tetrahalo(lower) alkoxyphenyl [e.g. 2-trifluoromethoxyphenyl, 2 - (1,1,2,2-tetrafluoroethoxy)phenyl, etc.]; lower alkoxy (lower) alkoxyphenyl [e.g. 2- (2-methoxyethoxy)
phenyl, etc.]. [0022] Suitable "lower alkylene groups" include linear or branched ones such as methylene, ethylene, trimethylene, tetramethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and particularly preferred ones. is tetramethylene. [0023] Suitable "protected carboxy groups" include esterified carboxy groups, where [
Examples of the "esterified carboxy group" include the following. [0024] Suitable examples of the ester moiety of the esterified carboxy group include lower alkyl esters which may have one or more suitable substituents (for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester) , isobutyl ester, [
butyl esters, pentyl esters, hexyl esters, etc.), such as lower alkanoyloxy (lower) alkyl esters [such as acetoxymethyl esters, propionyloxymethyl esters, butyryloxymethyl esters, valeryloxymethyl esters, pivaloyloxymethyl esters, Hexanoyloxymethyl ester, 1- (or 2-) acetoxyethyl ester, 1- (or 2- or 3-) acetoxypropyl ester, 1- (or 2- or 3- or 4-) acetoxybutyl ester, 1- (or 2-) propionyloxyethyl ester, 1- (or 2- or 3)
Propionyloxyprobyl ester, 1-(or 2
-) butyryloxyethyl ester, 1-(or 2-
) isobutyryloxyethyl ester, 1-(or 2
-) pivaloyloxyethyl ester, 1-(or 2
-) hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyl (lower) alkyl esters (such as 2-mesylethyl ester), mono (or di or tri) halo (lower) alkyl esters (such as 2-iodoethyl ester, 2,
2. 2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy (lower) alkyl esters [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2 -) methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1(or 2)
-) isopropoxycarbonyloxyethyl ester], phthalidylidene (lower) alkyl ester or (5-lower alkyl-2-oxo-1,3-dioxo-
4-yl) (lower) alkyl esters [e.g. (5-methyl-2-oxo-1,3-dioxo-4-yl)
-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxo-4-yl)methyl ester,
(5-propyl-2-oxo-1,3-dioxo-4-yl)ethyl ester, etc.]; lower alkenyl esters (e.g., vinyl esters, allyl esters, etc.); lower alkynyl esters (e.g., ethynyl ester, propynyl ester, etc.) ; Ar (lower) alkyl esters [such as mono- or di- or triphenyl (lower) alkyl esters] having one or more suitable substituents (such as lower alkoxy, nitro, hydroxy, lower alkyl, etc.), such as ( CI-
C4) Mono- or di- or triphenyl (CI C4) alkyl esters which may have alkoxy [e.g. benzyl ester, benzhydryl ester, trityl ester, phenethyl ester, 4-methoxybenzyl ester, 3,4-dimethoxybenzyl ester, bis( methoxyphenyl) methyl ester, etc.], nitrophenyl (CI C4) alkyl ester (e.g. 4-nitrobenzyl ester, etc.), [hydroxy] (CI C4) alkylphenyl (Ct
C4) alkyl esters (e.g. 4-hydroxy-
3゜5-di-t-butylbenzyl ester, etc.); aryl esters which may have one or more suitable substituents (for example, phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester,
(xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester, etc. [0025] A more preferred protected carboxy group as defined above is a (CI C4) alkoxycarbonyl group, and the most preferred is a methoxycarbonyl group. [0026] Suitable "leaving groups" may include acid residues, and examples of suitable "acid residues" include halogen atoms (e.g., chlorine, bromine, iodine, etc.), sulfonyloxy groups (e.g., (methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, etc.), among which a halogen atom is particularly preferred. [00271 The method for producing the object compound (I) of the present invention will be explained in detail below. [0028] (1) Process 1 Compound (I) or a salt thereof can be produced by subjecting compound (II) or a salt thereof to an elimination reaction of the carboxy protecting group of R3. [0029] A suitable salt of compound (II) is compound (II).
) are included. [00301 Usually, this reaction is carried out by a conventional method such as hydrolysis or reduction. [00311(i) Hydrolysis Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydrides (e.g., sodium hydroxide, etc.). , potassium hydride, etc.), alkaline earth metal hydrides (e.g., calcium hydride, etc.), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (eg, magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate, etc.), and the like. [0032] Suitable acids include organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). etc.) can be mentioned. Acidic hydrolysis using trifluoroacetic acid is typically accelerated by the addition of cation scavengers (eg, phenol, anisole, etc.). [0033] This reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as water, dichloromethane, alcohol (e.g., mechnol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, and the like, and mixtures thereof. . If the base or acid used is liquid, it can also be used as a solvent. [0034] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. [0035] (it) Reduction The reduction method used for this elimination reaction includes metals (e.g. zinc, zinc amalgam, etc.) or chromium salt compounds (
reduction using a combination of organic or inorganic acids (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.) and conventional metal catalysts, e.g. palladium catalysts (e.g. palladium sponge, Palladium black, palladium oxide, palladium on charcoal, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, palladium hydroxide on charcoal, etc.), nickel catalyst (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalyst (e.g. platinum plate, platinum sponge,
Examples include conventional catalytic reductions carried out in the presence of conventional metal catalysts such as platinum black, colloidal platinum, platinum oxide, platinum wire, etc.). [0036] In the case of catalytic reduction, the reaction is preferably carried out under conditions near neutrality. [00371 This reaction is usually carried out using conventional solvents that do not adversely affect the reaction, such as water, alcohols (such as methanol, ethanol, propatool, etc.), dioxane,
It is carried out in a solvent such as tetrahydrofuran, acetic acid, a buffer (eg, phosphate buffer, acetate buffer, etc.), or a mixture thereof. [0038] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. [0039] When the carboxy protecting group is an allyl group, it is deprotected by hydrogenation using a palladium compound. [00401 Suitable palladium compounds for use in this reaction include palladium on charcoal, palladium oxide on charcoal, palladium chloride, palladium ligand complexes such as tetrakis(triphenylphosphine)palladium (
0), bis(dibenzylideneacetone) palladium (0
), di[1,2-bis(diphenylphosphino)ethane]palladium(0), tetrakis(triphenylphosphite)palladium(0), tetrakis(triethylphosphite)palladium(0), etc. [00
41] The reaction involves a scavenger for allyl groups generated within the reaction system,
For example, amines (e.g. morpholine, N-methylaniline, etc.), active methylene compounds (e.g. dimedone, benzoyl acetate, 2-methyl-3oxovaleric acid, etc.), cyanohydrin compounds (e.g. α-tetrahydropyranyloxybenzyl cyanide, etc.) ), an alkanoic acid or a salt thereof (for example, formic acid, acetic acid, ammonium formate, sodium acetate, sodium 2-ethylhexanoate, etc.), N-hydroxysuccinimide, and the like. [0042] This reaction can be carried out in the presence of a base such as a lower alkylamine (eg, butylamine, triethylamine, etc.), pyridine, and the like. [0043] When a palladium ligand complex is used in this reaction, it is desirable to conduct the reaction in the presence of the corresponding ligand (eg, tonophenylphosphine, triphenylphosphite, tonoethylphosphite, etc.). [0044] This reaction is typically carried out using conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, etc., or mixtures thereof. carried out in a solvent. [0045] The elimination reaction may be selected depending on the type of carboxy protecting group to be eliminated. [0046] The target compound (I) obtained in Process 1 can be isolated and purified by conventional methods such as extraction, precipitation, fractional crystallization, recrystallization, chromatography, etc. [00471 Method A for producing the new starting material compound (II) or a salt thereof will be described in detail below. [00481(A) Method A Compound (I I) or a salt thereof is prepared from Compound (I I I
) or a salt thereof with compound (IV) or a salt thereof. [0049] Suitable salts for compound (IV) include the same salts as shown for compound (II). [00501 This reaction reacts with alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonates (e.g., sodium carbonate, carbonate, etc.). potassium, etc.), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, etc.), tri(lower)alkylamines (e.g. trimethylamine, triethylamine, etc.) , N, N-diisopropyl-N-ethylamine, etc.)
, pyridine compounds [e.g. pyridine, picoline, lutidine, N,N-di(lower)alkylaminopyridine, such as N,N-dimethylaminopyridine 1,
quinoline, N-lower alkylmorpholine (e.g. N-
methylmorpholine, etc.), N,N-di(lower)alkylbenzylamines (e.g. N,N-dimethylbenzylamine, etc.), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium butoxide, etc.); Preferably, the reaction is carried out in the presence of a base. [0051] This reaction is typically carried out using conventional solvents that do not adversely affect the reaction, such as dichloromethane, methanol, ethanol, propatool, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, acetonitrile, It is carried out in a solvent such as chloroform or a mixture thereof. [0052] The reaction temperature is not particularly limited, and the reaction is usually carried out with or without heating. [0053]

Effects of the Invention The target compound, the indole derivative (1), is a presynaptic (nervous) and/or postsynaptic compound that is involved in inhibiting the neurogenic release of catecholamines, dilating the renal vasculature, and remitting parkinsonism, respectively. (Vascular) Stimulates dopamine receptors. Indole derivatives (I) exert effects on the cardiovascular system as a result of the interaction of dopamine and adrenergic receptors. [0054] The object compound (I) of the present invention and its salts are novel and have a dopamine receptor stimulating effect, a 5-HT receptor antagonistic effect, especially a 5-HT2 receptor antagonistic effect, or an α
Dopamine receptor agonist; 5
- Useful as an HT receptor antagonist, especially a 5-HT2 receptor antagonist or an α1 receptor antagonist, and is useful for treating high blood pressure,
and other cardiovascular disorders (e.g., angina pectoris, congestive heart failure, myocardial infarction, etc.); Parkinson's syndrome; hyperprolactinemia; peripheral perfusion disorders such as Raynaud's phenomenon, Bersher's disease, and intermittent waves; percutaneous transluminal tubes It is useful for the treatment or prevention of thrombotic and/or smooth muscle cell proliferative diseases such as restenosis after coronary artery formation; hypercholesterolemia; urinary diseases, etc. [0055] The target compound (I) and its salts are also useful as anti-adrenergic agents, tranquilizers, sedatives, antiemetics, hypothermic agents, skeletal muscle relaxants, anti-inflammatory agents, hypoglycemic agents or antiviral agents. Seem. [00561 In order to demonstrate the usefulness of the object compound (I) of the present invention and its salts, test data regarding the dopamine receptor stimulating effect of representative compounds of the compound (I) of the present invention are shown below. [0057] Test 1 [Dopamine Receptor (DA2 Receptor) Binding Assay] Test Method 1: The DA2 receptor affinity of the test compound was determined by an in vitro receptor binding assay. Weight 150-300
G male rats were decapitated and the striatum was excised from the brain. This tissue was treated with 50mM Tris-HCl (pH 7.4 at 25°C).
120mM sodium chloride, 5mM potassium chloride, 1m
M calcium chloride, 1mM magnesium chloride, 10μM
The mixture was homogenized in 30 volumes of a buffer solution containing pargyline and 0.1% ascorbic acid. Homogenate for 15 minutes at 50.00. Centrifuged at Og. The pellet was resuspended in 30 volumes of buffer. The tissue suspension was centrifuged and resuspended similarly. During binding assays, incubation tubes contained 100 μM of [phenyl-4-3H]spiperone, test compound 10
0LL1 and 0.8 ml of tissue suspension were added. The concentration of [phenyl4-38]spiperone was 0.2 nM. The final tissue concentration in rat striatum was 160 ILg/ml. The incubation tubes were incubated at 37° C. for 10 minutes, then vacuum filtered through Whatman GF/B filters and washed three times with 3 ml of ice-water buffer. Filters were counted in a liquid scintillation counter. [Specific binding of 3H1 spiperone was determined in the presence of 1 μM butaclamol. The IC5o value of the test compound is 10
Calculated from [3H1 spiperone binding data in the presence of -9M, 10-8M, 10-7M, 10-6M test compounds. Test compound: Compound A (compound of Example 1) Test results: [0058] Test 2 [Suppression of reserpine-induced dopamine accumulation] Test method 2: Male SD rats weighing 300-400 g were used in this test. Rats were pretreated with reserpine (1 mg/kg, subcutaneously) 17-19 hours before sacrifice and then fasted. Test compounds were administered orally 2 hours before sacrifice. [m-Hydroxybenzylhydrazine (100 mg/kg, ip) was administered 30 minutes before sacrifice. ] Rats were exposed to microwaves for 15 seconds using a head focusing microwave applicator. Whole fat was removed and further separated into the striatum. Dopa was measured as follows. The striatum was treated with 9 volumes of O, IN perchloric acid (0,4% EDTA, 2
Homogenized in Na). Homogenate, 10.0
Centrifugation was performed for 1 minute at 0 Or pm. The supernatant was subjected to high performance liquid chromatography. Test results 2 [0059] Test 3 [Blood pressure lowering effect on spontaneously hypertensive rats] Test method 3: Mean arterial blood pressure approximately 160-200 mmHg,
Male spontaneously hypertensive rats, 15-25 weeks old and weighing 300-350 g, were used. A cannula was inserted into the left femoral artery, and mean blood pressure and heart rate were measured using a pressure transducer. The animals were fasted for about 18 hours before oral administration. The test compound was suspended in 0.5% methylcellulose and administered orally. Test result 3: The maximum rate of decrease in blood pressure (%) is shown in the table. [00601 For administration for treatment, the objective compound (I) of the present invention and its salts are used as active ingredients and administered orally,
They are used in the form of conventional pharmaceutical preparations containing them in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for parenteral administration or for topical use. The pharmaceutical preparation may be in a solid form such as a tablet, granule, powder, or capsule, or in a liquid form such as a solution, suspension, syrup, emulsion, or lemonade. [00611 If necessary, the above formulation may contain adjuvants, stabilizers, wetting agents, and other conventional additives, such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, Fallen beef oil, olive oil, cacao butter, ethylene glycol,
Tartaric acid, citric acid, formic acid, etc. may be added. [0062] The dose of compound (I) varies depending on the age and medical condition of the patient, the type of disease, the type of compound (I) used, etc., but in general, it is about 0.001 mg/day.
An amount ranging from mg to about 300 mg, preferably about 0.1 m
Amounts ranging from about 50 mg to about 50 mg may be administered to the patient. In the treatment of various diseases, the average single dose of the object compound (I) of the present invention is about 0.001 mg, 0.01 mg, 0.03 m
g, O, 1 mg, 0.3 mg, 0.6 mg, 1. O
mg, 3.0mg, 10.0mg, 50.0mg, 10
It may be used as 0.0 mg. [0063]

EXAMPLES The following Preparations and Examples are presented to illustrate the invention. [0064] Production Example 1 Methyl 3-(4-chlorobutyl)indole-5-carboxylate (0.53g), 1-(2-propoxyphenyl)piperazine (0.53g), sodium iodide (0.53g),
A mixture of 30 g), sodium carbonate (0.28 g) and anhydrous dimethylformamide (10 ml) is stirred at 80° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed successively with water and brine, dried over magnesium sulfate, and concentrated to give an oil. This was subjected to silica gel (30 g) chromatography, and a mixed solvent of methylene chloride and methanol (20:1, v/v) was used.
) and eluted with 3-[4-(4-(2-propoxyphenyl)piperazin-1-yl)butylcoindole-
5-carboxylic acid methyl ester (0.76 g) is obtained. IR (Nujol): 3250, 2950, 1700
゜1660crrr' NkiR (CDCI3, 6): 1.05 (3H
, t, J 8Hz), 1.65-L 85 (4
H, m), 1.78-1.95 (2H, m), 2.
51 (2H, t, J=sHz), 2
．． 55-2. 75 (4H, m),
2. 83 (2H, t, J=8Hz), 3. 1
0-3.22 (4H, m), 3.93 (3H,
s), 3.97 (2H. t, J=8Hz), 6.82-7.00 (4H, m
). 7.03 (LH, s), 7.34 (LH, d,
J=8Hz), 7.90 (LH, d, J=8Hz)
, 8.02 (LH, s), 8.40 (LH, s) [
[0065] Production Example 2 In substantially the same manner as Production Example 1, 3-[4-(4-(
2-fluorophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester is obtained. (Yield, 88.0%) IR (CHC13): 3500, 2950, 2800
゜700cm NMR (CDC13, δ); 1. 62-1.
85 (4H, m), 2. 50 (2H,t,
J=5Hz), 2. 67 (4H,t,
J=5Hz), 2. 87 (2H,t,
J=5Hz), 3. 18 (4H, t, J
=5Hz), 3°94 (3H,s), 6
．． 91-7. 10 (4H, m). 7, 35 (LH, d, J=8Hz), 7
．． 90 (LH. d, J=8Hz), 20 (IH, s), 8.3
9(LH,s) [0066] Production Example 3 In substantially the same manner as Production Example 1, 3-[4-(4-(2
-cyanophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester is obtained quantitatively. IR (Nujol): 3350.2200.1700c
NMR (CDC13, δ): 1. 60-1.
82 (4H, m), 2.50 (2H, t, J=
5Hz), 2.69 (4H, t, J=5Hz), 2
．． 80 (2H, t, J=5Hz), 3.27 (
4H,t, J=5Hz), 3°93 (3H,s)
, 6. 97-7, 07 (2H, m). 7.32 (LH, d, J=8Hz), 7.48
(LH. t, J=8Hz), 7.55 (LH, d, J=
8Hz), 7.90 (LH, d, J=8Hz), 8
．． 28 (LH, s), 8.40 (LH, s) [00
67] Production Example Scratches In substantially the same manner as in Production Example 1, 3-[4-(4-(
2-isopropoxyphenyl)piperazin-1-yl)
Butyl 1-indole-5-carboxylic acid methyl ester is obtained. (Yield, 8040%) IR: 3300.2900.280
0. 1700cm NMR (CDCI3, δ): 1.32 (
6H, d, J=5Hz), 1.60-1.83 (4
H, m), 2.50 (2H, t, J=8Hz), 2.6
2-2.72 (4H, m), 2.83 (2H,
t, J=8Hz), 3. LO-3,20 (4H, m)
, 4. 50-4. 70 (IH, m), 6.
82-6.97 (4H, m), 7.04 (LH, s
), 7.84 (LH, d, J=8Hz). 7, 90 (LH, d, J=8Hz),
8. 34 (LH. br s), 8.04 (LH, s) [0068] Production Example 5 In substantially the same manner as Production Example 1,
2nitrophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester is obtained. (
Yield, 64.2%) NMR (CDC13, δ): 1. 52-1
．． 85 (4H, m), 2. 48 (2H
, t, J=7Hz), 2. 61 (4H
, m), 2. 81 (2H, t, J=7
Hz). 3, 10 (4H, m), 3. 95 (3
H,s), 7. 01 (LH, t, J=8
Hz), 7. 03 (LH,s). 7.14 (LH, d, J==8Hz), 7.36
(LH. d, J=8Hz), 7.49 (LH, td, J=8
Hz, IHz), 7.76 (IH, dd, J=8H
z, IHz), 7.90' (LH, dd, J=8Hz,
IHz), 8. 30 (IH, br s)
, 8. 39 (IH.S) [0069] Production Example 6 In substantially the same manner as Production Example 1, 3-[4-(4-(4
-methoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester is obtained. (Yield, 73.6%) mp: 135-139°C IR (Nujol): 1700 cm NMR (CD Cl 3 , δ): 1. 7
0 (4H, m). 2,45 (2H,t, J==7.5Hz),
2. 51 (4H, m), 2. 82 (2H
,t, J=7. 5Hz). 3, 10 (4H, m), 3. 75 (3H,
S), 3.43 (3H,S), 6. 32
(2H, d, J=8Hz). 6, 39 (2H, d,, J=8Hz), 7
．． 01 (LH. d, J=IHz), 7.33 (LH, d, J=8H
z), 7.40 (, LH, dd, J=8Hz, IHz
). 8, 23 (LH, br s), 8. 370
H, d, J=IHz) [00701 Production Example 7 In substantially the same manner as Production Example 1, 3-[4-(4-(
4-chlorophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester is obtained.
(Yield, 70.5%) mp: 157-L5.9°C IR (Nujol): 3100, 1700, 1615c
NMR (CDCI3, δ): 1.70 (
4H, m). 2.45 (2H, t, J=7.5Hz), 2.60
(4H, t, J=6H2), 2°83 (2H,
4+ J=7°5Hz), 3.17 (4H,t,
J=6Hz), 3.91 (3H,s), 6. 82
(2H, d, J=8Hz). 7.02 (LH, d, J=IHz), 7.20
(2H.d, J=8Hz), 7.35 (LH,d,
J=8Hz), 7.91 (LH, d=, J=8
Hz, IHz). 8.26 (LH, br s), 8.39 (L
H, d, IHz) [00711 Production Example 8 Methyl 3-(4-chlorobutyl)indole-5-carboxylate (200 mg), 1-(2-methoxyphenyl)piperazine (180 mg) and triethylamine (
A warm mixture of 170 mg) of acetonitrile (10 ml) is refluxed for 5 days. After cooling, the mixture is concentrated to obtain a residue. This is dissolved in chloroform, and the organic layer is washed with water and then dried. The solvent was distilled off and the residue was subjected to silica gel chromatography. Elute with chloroform to obtain 3-[4
-(4-(2-methoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester (310 mg) is obtained as an oil. IR (Nujol): 3330, 1705, 1690° 1620.1590, 158.0cm-'NMR (CD
Cl 3. δ): 1. 75 (4H, m
). 2, 56 (2H, m), 2. 78 (2
H, m), 2. 85 (4H, t, J=7.5
Hz), 3.18 (4H. m), 3.85 (3H,s), 3.93 (3H.
,s). 6, 83-7. 06 (5H, m), 7.
34 (LH. d, J=10Hz), 7.90 (LH, dd, J=
2゜5Hz, 10Hz), 8.17 (LH, br
s). 8, 37 (LH,S) MS: m/z 422 (M+1) [0072] The following compound is obtained in substantially the same manner as in Production Example 8. [0073] Production Example 9 3-[4-(4-phenylpiperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester mp
: 125°C IR (Nujol): 3530, 1705, 1690° = 1620.1600 cm-' NMR (CDCl: l, δ): 1. 61-
1°84 (4H, m), 2. 47 (2H
,t, J=7. 5Hz). 2, 62 (4H, t, J=5.0Hz)
, 2. 83 (2H,t,' J=7.5H
z) , , 3. 22' (4H, t, J=5,
0Hz), 3. 92 (3H,s),
6. 81-6゜93 (3H, m), 7.03
(LH, d, J=2.5Hz), 7. 22-7.
2'9 (2H, m), 7. 34 (1H,
d, J=9.0Hz), 7.90 (LH, dd, J
=2.5Hz, 9.0Hz), 8.16 (LH,b
rs), 8.37 (LH, s) MS: m/z 392 (M+1) [0074]
Production Example 10 3-[4-(4-(3-methoxyphenyl)piperazin 1-yl)butylcoindole-5-carboxylic acid methyl ester IR (Nujol): 1700.1600 cmNMR (
CDC13, δ): 1. 60-1. 90
(4H, m), 2. 45 (2H, dd,
J=8Hz, 7. 5Hz), 2.60 (4
H, dd, J=7Hz, 5Hz), 2.70 (2H
, t, J=7Hz), 3.20(4H, dd, J=7H
z, 5Hz), 3.80 (3H, s), 3.
95 (3H,s), 6. 40-6. 5
0(2H,m), 6. 55 (LH, dd,
J=8Hz. 1.5Hz), 7.05 (LH, d, J=2Hz)
. 7.15 (LH, dd, J=9Hz, 8Hz), 7
．． 35 (LH, d, J=9Hz), 7.40 (
LH, dd. J=9Hz, 1. 58), 8. 25 (
LH, brs), 8. 40 (LH, d,
J=1. 5Hz) [0075] Production Example 11 3-[4-(4-(2-chlorophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester IR (Nujol): 1700, 1580 cm-'NM
R(CDC13, δ): 1. 60-1. 85
(4H, m), 2.50 (2H, dd, J=8
Hz, 7Hz), 2. 65-2. 75 (4
H, m), 2. 80 (2H, t, J=7
Hz), 3. 05-3. 15 (4H.m), 3. 95 (3H,s), 6.
95 (LH, td. J=7Hz, 1.5Hz), 7.05-7.10 (
2H, m), 7.20 (LH, dd, J=8Hz,
2Hz), 7. 35-7. 40 (2H,
m), 7. 90 (LH, dd, J=8.5
Hz, 1.5Hz), 8.25 (LH, br s)
, 8. 40 (LH, d, J=1.5Hz
) [0076] Production Example 12 3-[4-(4-(3-chlorophenyl)piperazin 1-yl)butyl 1-indole-5-carboxylic acid methyl ester IR (Nujol): 1700, 1590, 1240c
NMR (CDCI 3. δ): 1. 55-
1. 70 (4H, m), 2.50 (2H,
dd, J=8Hz, 7Hz), 2. 60-2.
70 (4H, m), 2. 80 (2H,t
, J=7Hz), 3. 20-3. 30
(4H.m), 3. 95 (3H,s), 6.
75-6. 85 (2H, m), 6. 85
-6. 90 (LH, m), 7. 05 (IH
, d, J=1. 5Hz), 7. 15 (
IH, dd, J=9Hz, 8Hz), 7.35 (LH
, d, J9Hz), 7.90 (LH, dd, J=8
Hz, 1.5Hz), 8. 15 (LH,br
s), 8.40 (LH, d, J=1.5Hz) [0077F Production Example 13 3-[4-(4-(2-ethoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid Methyl ester I R (CHC13, δ): 3250, 1690,
1500.1430.1120cm NMR (CDC13, δ): 1. 45 (3
H, t, J=7Hz), 1. 60-1.
85 (4H, m), 2. 50 (2H, dd
, J=8Hz, 6.5Hz), 3.103, 20
(4H, m), 3. 95 (3H,S),
4. 05 (2H, q, J=7Hz),
6. 80-6. 85 (LH, m), 6.
90-6. 95 (3H, m), 7. 0
5 (LH, d, J=1.5Hz), 7.
35 (LH, d. J=8.5Hz), 7.90 (LH, dd, J=8
Hz, 1. 5Hz), 8. 20 (L
H, br s), 8°40 (LH, d, J=
1.5Hz) [0078] Production Example 14 3-[4-(4-(2-Butoxyphenyl)piperazin-1-yl)butyl 1-indole-5-carboxylic acid methyl ester hydrochloride IR (Nujol): 1700crrr' [007
9] Production Example 15 3-[4-(4-(2-isobutoxyphenyl)piperazin-1-l)butyl 1-indole-5-carboxylic acid methyl ester hydrochloride IR (Nujol): 1700 cm [00801 Production Example 16 3 - [4-[4-(2-(2-methoxyethoxy)phenyl)piperazin-1-yl 1-butyl-1-indole-
5-Carboxylic acid methyl ester hydrochloride IR (Nujol): 1700 cm NMR (DMSOda, δ): 1. 75
(4H.m), 2. 80 (2H, m), 3.
10 (6H, m). 3, 32 (3H,S), 3. 55 (
4H, m), 3. 70 (2H, m),
3. 85 (3H, s), 4. 10 (2
H, m), 6. 95 (4H, m),
7. 82 (LH. d, J=1.5Hz), 7.45 (LH, d, J=
8Hz), 7.75 (LH, dd, J=8Hz, 1
．． 5Hz), 8. 23 (LH,s) [008
11 Production Example 17 3-[4-[4-(2-(1,l,2.2-tetrafluoroethoxy)phenyl)piperazin-1-yl 1-butyl 1-indole-5-carboxylic acid methyl ester IR
(CHC13, δ): 3350, 1700, 1490.
1430.1120cm NMR (CDC13, δ): 1. 60-1.
90 (4H, m), 2.45 (2H, t, J=
7Hz), 2.55-2.65 (4H, m), 2.
80 (2H, t, J=7Hz), 3.10 (4
H, t, J=5Hz), 3. ．． 95 (3H, s),
5.95 (IH, t, t, J=52Hz, 3Hz)
, 6.95-7.05 (3H, m), 7°20
(2H, td, J=7Hz, 1.5Hz), 7.35
(LH, d, J=8Hz), 7.90 (IH, d
d. J=9Hz, 1.5Hz), 8.25 (LH,
brs), 8.40 (LH,s) [0082] Production Example 18 3-[4-(4-(2-trifluoromethoxyphenyl)piperazin-1-yl)butylcoindole-5carboxylic acid methyl ester IR( Nujol): 1700 crrr l [008
3] Production Example 19 3-[4-(4-(2-methylphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester IR (Nujol): 3300,1700crrr'N
MR (CDC13, δ): 1.60-1.80
(4H, m), 2.30 (3H, s), 2.50
(2H, dd, J=9Hz, 7Hz), 2.60-
2.70 (4H, m), 2.85 (2H, t,
J=7Hz), 2.95-3.00 (4H, m),
3.45 (3H,S). 6.95-7.05 (2H, m), 7.10-7.
20 (2H, m), 7.35 (LH, d, J=8.
5Hz), 7.90 (IH, dd, J=8.5Hz
, 1.5Hz), 8. 25 (LH,br
s), 8. 40 (LH, brs) [0084] Production Example 20 3-[4-(4-(2-ethylphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester IR (CHCL3): 3350,1700 ,1610
゜1430.1110cm NMR (CDC13, δ): 1. 25 (3
H, t, J=7Hz), 1.60-1.85 (
4H, m), 2.50 (2H, m), 2.55-2.6
5 (4H, m), 2゜70 (2H, q, J=
7Hz), 2. 85 (2H, t. J=6.5Hz), 2.95 (4H, t. J=5H
z), 3.95 (3H, s), 7°00-7. 2
5 (5H, m), 7. 35 (IH, d
, J=8Hz), 7. 90 (LH, d
d, J=8Hz, 1.5Hz), 8.20(IH, br
s), 8. 40 (LH, d, J=
1. 5Hz) [0085] Type production 21 3-[4-(4-(2,3-dimethylphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester rR): 3300. 2950, 2800.
1700.1660. 1620cm NMR (CDCI3, δ): 1.58-
1.83 (4H, m), 2.21 (3H, S)
, 2.25 (3H. S), 2.41 (2H, t, J=8Hz), 2.6
2 (4H, t, J=8Hz), 2.81 (2H, t
, J=8Hz), 2. 90=2.93 (4H, m
), 3.92 (3H, s), 6.88 (LH, d,
J=5Hz). 6.92 (LH, d, J=5Hz), 7.01
(LH. s), 7.32 (LH, d, J=8Hz), 7.9
0 (LH, d, J=8Hz), 8.37 (LH, d
, J-=5Hz), 8.40 (LH,s) [0086] Production Example 22 Methyl 3-[4-(4-(2-methylthiophenyl)piperazin-1-yl)butylcoindole-5-carboxylate Ester hydrochloride NMR (CDC13, δ): 1. 70 (2
H, m). 2, 05 (2-H, m), 2. 40
(3H,S), 2. 85 (2H, m),
3. 03 (4H, m), 3. 30 (
2H, m), 3. 60 (4H, m),
3. 95 (3H.S), 7. 10 (5H, m), 7.
42 (LH, d, J=8Hz), 7.90
(LH, d, J=8Hz), 8°32 (IH, s)
, 8y55 (LH, br s) [0087] Bag production 23 3-[4-(4-(2-propoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid methyl ester hydrochloride mp: 185- 187°C NMR (DMSOda, δ): 1. 02
(3H, t. J-7Hz), 1. 75 (6H, m),
2. 80 (2H, m), 3゜07
(2H, m), 3. 20 (4H.m), 3. 53 (4H, m), 3. 8
5 (3H, s). 3, 92 (2H, t, J=7Hz),
6. 95 (4H.m), 3. 31 (LH,S), 7. 4
3 (LH, d, J=8Hz), 7.72 (L
H, d, J = 8 Hz), 8°23 (LH, s) [0088] Production example 24 3- [4-(4-(2-isopropoxyphenyl)piperazin-1-yl)butyl 1 indole-5- Carboxylic acid methyl ester hydrochloride mp: 210-211℃ IR (Nujol): 3200.1700cm-'NM
R(CDCl3, δ): 1. 36 (6
H, d, J=7Hz), 1°75 (2H, m)
, 2. 00 (2H. m), 3. 00 (4H, m), 3. 5
0 (6H, m). 3, 98 (3H,s), 4. 59 (
IH, sep, J=7Hz), 6. 8-7
．． 1 (5H, m), 7. 45 (LH,
d, J=8Hz), 7.87 (IH, d, J=8H
z), 8. 31 (LH,s), 9.
04 (LH,brS) [0089] Example 1 Methyl 3-[4-(4-(2-propoxyphenyl)piperazin-1-yl)butyl]indole-5-carboxylate (0,76 g), IN sodium hydroxide (8,4
1. ffl) and methanol (10 ml).
Stir under reflux for 5 Pi. Methanol is distilled off and the aqueous layer is adjusted to pH 4 with IN hydrochloric acid. Collect colorless crystals,
After sequentially washing with water and ether and drying, 3-[4
-(4-(2-propoxyphenyl)piperazine-1-
yl)butyl-1-indole-5-carboxylic hydrochloride (
0.73 g) is obtained. mp: 127-129℃ IR (Nujol): 3220.1680.1610c
NMR (DMSOd6.δ): 1. O2
(3H, t. J=8Hz), 1.58-1.78 (4H, m),
1°72-1. 82 (2H, m), 2.
65-2. 80 (4H, m), 2.83-3.0
0 (4H, m), 3.02-3.22 (4H,
m), 3.95 (2H, t, J=8Hz), 6.8
2-7.00 (4H, m), 7.28 (LH, s)
, 7.40 (LH, d, J=8Hz). 7.72 (LH, d, J=8Hz), 8.25
(LH.S) [00901 Example 2 Substantially similar to Example 1, 3-[4-(4-(
2=fluorophenyl)piperazin-1-yl)butyl]indole-5-carboxylic acid is obtained. (Yield, 70
．． 5%) mp: 212-214°C IR (Nujol): 3400, 3050, 1590° 1500cm' NMR (DMSO-da, δ): 1. 45
-1. 77 (4H, m), 2.40 (2H, t,
J=5Hz). 2, 50 (4H, t, J=5Hz),
2. 72 (2H. t, J=5Hz), 3.03 (4H, t, J=5H
z), 6. 90-7. 13 (4H, m)
+' 7. 23 (LH,s), 7. 4
0 (LH, d, J=8Hz), 7. 70
(IH, d, J=8Hz), 8.22 (LH, s)
[00911 Example 3 In substantially the same manner as in Example 1, 3-[4-(4-(
2-cyanophenyl)piperazin-1-yl)butyl]
Indole-5-carboxylic acid is obtained. (Yield, 74.
6%) mp: 219-221℃ IR (Nujol): 3400, 2200.1660c
NMR (DMSOd6.δ): 1°48-1.78
(4H, m), 2. 40 (2H,t+'
J=5Hz). 2, 50 (4H, t, J=5Hz),
2. 78 (2H. t, J=5Hz), 3.14 (2H, t, J=5H
z), 7. 01-7. 19 (2H, m)
, 7. 30 (1H, s), 7.40 (L
H, d, J=8Hz), 7.70 (LH, d, J=
8Hz), 7.72 (LH, t, J=8Hz), 8
．． 23 (LH,s) [0092] Example 4 In substantially the same manner as in Example 1, 3-[1-(4-(
2-isopropoxyphenyl)piperazin-1-yl)
Butylcoindole-5-carboxylic hydrochloride is obtained. (
Yield, 85.6%) mp: 103-104°C IR (Nujol): 3350 1680crrr'N
MR (DMSO-ds, δ): 1. 30 (
6HdJ=5Hz), 1. 60-1. 90
(4H, m), 2゜80 (2H, t, J=
8Hz), 3. 10 (2H, t. J=8Hz), 3. 12-3. 40 (8
H, m), 4°52-4. 67 (LH, m)
, 6. 82-7. 00 (4H, m),
7. 31 (LH,s), 7. 42 (L
H. d, J=8Hz), 7.72 (LH, d, J=8H
z), 8.22 (LH,s) [0093] Example 5 In substantially the same manner as in Example 1, 3-[4-(4-(
2nitrophenyl)piperazin-1-yl)butyl]indole-5-carboxylic acid is obtained. (Yield, 81.2
%) mp: 176-182°C IR (Nujol): 2300-2700 1680°1600cm-' NMR (DMSO-d6.
δ): 1, 7 (4H, m), 2. 4-2
．． 8 (8H, m). 3, 00 (4H, m), 7. 12 (LH
, t, J=8Hz), 7. 24 (LH,s
), 7. 32 (LH, d, J=8Hz)
, 7. 35 (LH, d, J=8Hz)
, 7゜60 (LH, t, J=8Hz) ,
7. 69 (LH, d. J=8Hz), 8. 20 (LH,s)[00
94] Example 6 In substantially the same manner as in Example 1, 3-[1-(1-(4
-methoxyphenyl)piperazin-1-yl)butyl 1
Indole-5-carboxylic acid is obtained quantitatively. mp:2
50℃ (decomposition) IR (Nujol): 3450, 3200. 16
901550.1510cm NMR (DMSOd6.δ): L 60
(4H. m), 2. 45 (2) (, m), 2.
58 (2H, m). 2, 75 (2H, m), 3. 00 (4H
, m), 3. 70 (3H, s), 6.80
(2H, d, J=8Hz) 6.87 (2H, d, J=
8Hz), 7.33 (LH. d, J=IHz), 7.39 (LH, d, J=8H
z), 7.70 (LH, dd, J=8Hz, IHz
). 8, 20 (LH,s) [0095] Example 7 In substantially the same manner as in Example 1, 3-[4-(4-(
4chlorophenyl)biperazin-1-yl)butylcoindole-5-carboxylic acid is obtained. (Yield, 98.8%) mp:) 250°C (decomposition) IR (Nujol): 3400, 3200, 2650° 2580.2450, 1700.1610cm 'N
MR (DMSO-dd, δ): 1. 73
(4H.m), 2. 80 (2H, m), 3.
1-3. 5 (10H, m), 7. 00
(2H, d, J=8Hz), 7. 30
(3H, m), 7. 41 (LH, d,
J=8Hz). 7.72 (LH, dd, J=8Hz, IHz), 8.
22 (LH, d, J=IHz) [0096] Example 8 Methyl 3-[4-(4-(2-methoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylate (300 mg) and 0 .6N sodium hydroxide (5m
A solution of 1) in dioxane (15 ml) is refluxed for 5 hours. After cooling, the mixture is concentrated and the resulting residue is acidified with dilute hydrochloric acid. The formed precipitate was collected by filtration and recrystallized with ethanol to give 3-[4-(4-(2-methoxyphenyl)
Piperazin-1-yl)butylcoindole-5-carboxylic acid (180 mg) is obtained. mp: 200℃ (decomposition) IR (nujol): 3600, 3500-2500゜1615.1590, 1580crrr'NMR (DM
SOda, δ): 1.58 (2H. m), 1.73 (2H, m), 2.40 (2H.
, t, J=7.5Hz), 2.79 (2H, t, J
=7.5Hz), 2.97 (4H, m), 3.38
(4H, m). 6.89-6.97 (4H, m), 7.27 (
LH. d, J=2.5Hz), 7.42 (IH, d, J=
10Hz), 7.73 (LH, dd, J=2.5H
z, 10 Hz), 8.24 (LH, s) [0097] The following compound is obtained in substantially the same manner as in Example 8. [0098] Example 9 3-[4-(4-phenylpiperazin-1-yl)butyl 1 indole-5-carboxylic acid mp: 260°C (decomposition) IR (Nushor): 3250, 2650, 2560° 2450.1690 ,1610,1600crrr'N
MR (DMSO-da, δ): 1. 81 (
4H. m), 2. 83 (2H, t, J=5.3
Hz), 3. 17 (IOH, m), 6
．． 92 (LH, t, J=7.0Hz),
7. 05 (2H, d, J=7.0Hz)
, 7. 32 (LH, d, J=2.0H
z), 7. 32 (2H.d, J=7.0Hz), 7. 47 (L
H, d, J=9°0Hz), 7.77 (IH,
dd, J”=2.0Hz. 9.0Hz), 8.29 (LH,s) [0099] Example 10 3-[4-(4-(3-methoxyphenyl)piperazin-1-yl)butyl coin Dole-5-carboxylic acid m
l): 235°C IR (Nujol): 3400.1600cm NMR (
CDCl3, δ): 1. 45-1.
70 (4H, m), 2. 35-2. 55
(2)(,m), 2. 75 (2H, t,
J=6Hz), 3. 05-3. 15 (4
H, m), 3. 20-3. 60 (4H,
m), 3. 70 (3H, S), 6. 3
5-6. 55 (3H, m), 7°10
(LH, dd, J=8Hz, 7.5Hz), 7.25
(IH, br s), 7. 40 (IH
, d, J-7゜5Hz), 7.70 (LH, d
d, J = 7.5Hz. 1.5Hz), 8.20 (LH, brs), 11.
15(LH, br s) [01001 Example 11 3-[4-(4-(2-chlorophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid mp
: 158℃ IR (nujol): 3300, 1580crrr'N
MR (DMSOda, δ): 1. 45-1
．． 75 (4H, m), 2.40 (2H, t, J=
7Hz). 2, 75 (2H, t, J=7Hz), 2
．． 85-3. 00 (4H, m), 3.
10-3. 90 (4H, m). 7.05 (LH, td, J=8Hz, 1.5Hz)
. 7.15 (LH, dd, J=8Hz, 1.5Hz)
. 7, 20-7. 30 (2H, m), 7.
35-7.40 (2H, m), 7. 70 (
LH, dd, J=8Hz. 1, 5Hz), 8. 2C1(IH,br
s) [0101] Example 12 3-[4-(4-(3-chlorophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid mp
: 191-200℃ IR (nujol): 1650, 15゛90cm-'N
MR (DMSOdd, δ): 1. 60-1.
75 (4H, m), 2. 75-3. 50
(12H, m). 6, 80-7. 00 (3H, m), 7.
20 (LH. d, J=8Hz), 7.25 (LH. d, J=1.
5Hz), 7. 40 (LH, d, J=
8Hz), 7. 70 (LH, dd, J=8Hz
, 1.5 Hz), 8.20 (LH, br s) [0102] Example 13 3-[4-(4-(2-ethoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid m
p: 123-126°C IR (Nujol): 3300. 1580,15
40°1230crrr' NMR (DMSO-da, δ): 1. 35
(3H, t. J=7Hz), 1. 50-1. 75 (4H, m
), 2゜75 (2H, t, J=7Hz)
, 2. 95-3. 05 (4H, m), 3
．． 25-3. 50 (6H, m), 4゜0
0 (2H, q, J=7Hz), 6.85-6.90
(4H, m), 7. 25 (LH, d, J
=1. 5Hz), 7.40 (LH, d, J=8.
5Hz), 7.70 (LH, dd, J=8Hz, 1
．． 5 Hz), 8.20 (IHbr s) [0103] The following compound is obtained in substantially the same manner as in Example 1. [0104] Example 14 3-[4-(4-(2-butoxyphenyl)piperazin 1-yl)butylcoindole-5-carboxylic hydrochloride mp: 185-194°C IR (Nujol): 3370, 3170, 2710°2660.2600.1665cm NMR (DMSO-da, δ'): 0.95
(3H, t. J=7Hz), 1.47 (2H, m), 1
．． 75 (6H, m), 2.80 (2H, m
), 3. 10 (6H. m), 3.55 (4H, m), 3.97 (2H.
, t, J=7Hz), 6.95 (4H, m), 7.
28 (LH. d, J=1.5Hz), 7.40 (LH, d, J=
8Hz), 7.70 (LH, dd, J=8Hz,
1.5Hz), 8.20 (LH,s) [0105] Example 15 3,-[4-(4-(2-isobutoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid hydrochloride acid Salt mp: 227-230°C IR (Nujol): 3400, 2660, 2560° 2450.1680 cm NMR (DMSO-da, δ): 1. 03
(6H, d. J=7Hz), 1. 75 (4H, m),
2. 05 (LH, m), 2. 80
(2H, m), 3. 10 (6H, m), 3.55 (4H, m), 3.78 (2H
, d, J=7Hz), 6.95 (4)-I, m),
7.38 (LH. d, J=1.5Hz), 7.42 (LH. d, J=8
Hz), 7. 75 (1 to 1. dd
, J=8Hz, 1. 5Hz), 8.3
3 (LH,s) [0106] Example 16 3- [4-[4-(2-(2-methoxyethoxy)phenyl)piperazin-1-yl 1-butyl 1-indole-
5-carboxylic hydrochloride mp: 203-205°C IR (Nujol): 3250, 2700. 17
00cm-' NMR (DMSOd6.δ): 1. 75
(4H. m), 2. 77 (2H, m), 3. 1
0 (6H, m). 3, 35 (3H,s), 3. 40 (4H
, m), 3. 70 (2H, m), 4.
10 (2H, m), 6. 95 (4H, m)
, 7. 30 (LH, d, J=1.5
Hz). 7, 90 (LH, d, J=8Hz), 7
．． 72 (IH. dd, J=8Hz, 1.5Hz), 8.25 (LH
. S) [0107] The following compound is obtained in substantially the same manner as in Example 8. [0108] Example 17 3-[4-[1-(2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperazin-1-yl 1-butyl 1-indole-5-carboxylic acid mp: 127°C IR (Nujol): 3200, 1680.1610c
NMR (CDC13CD30D, δ): 1.702,
00 (4H, m), 2. 45-2. 60
(4H.m), 2. 80 (2H, t, J=5.
5Hz), 2. 80-3. 00 (2H,
m), 3. 30-3. 45 (4H, m)
, 6. 00 (LH, t t, J=52H
z, 1°5Hz), 7. 05-7. 15
(3H, m), 7. 207, 30 (2
H, m), 7. 35 (LH, d, J=9
Hz), 7. 90 (LH, d, J=9H
z), 8. 35(LH,S) [0109] Example 18 3-[4-(4-(2-trifluoromethoxyphenyl)piperazin-1-yl)butylcoindol-5-
Carboxylic acid NMR (CDCI 3 CD30D δ): 1
．． so (4H, m), 2. 80 (4
H, m), 3. 03 (4H. m), 3. 30 (4H, m), 7. 0
5 (3H, m). 7, 20 (2H, m), 7. 38 (
LH, d, J=8Hz), 7.85 (LH, d
d, J=8Hz, 1.5Hz), 8.35 (LH,s
) [01101 Example 19 3-[4-(4-(2-methylphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid mp
: 120℃ IR (Nujol): 3200.1550cmNMR (
DMSO-d6. (5) :1. 50 1.
75 (4H, m), 2. 20 (3H,s)
, 2. 40 (2H, t, J=7Hz)
, 2. 75-2. 85 (4H, m), 3.20-3.60 (6H, m), 6.90
-7, 05 (2H, m), 7. 10-7.
15 (28m), 7.25 (LH, d, J=
2Hz), 7.40 (LH, d, J=8.5Hz
), 7. 70 (LH, dd, J=8.
5Hz, 1. 5Hz), 8. 20
(LH. br s) [01111 Example 20 3-[4-(4-(2-ethoxyphenyl)piperazin 1-yl)butylcoindole-5-carboxylic acid mp
:150-156℃ IR (Nujol) :3500,3300. 16
70°1610.1180cm NMR (CDCI 3 CD30D, δ): 1.
20 (3H, t, J=7Hz), 1.75-2.0
5 (4H. m), 2.65 (2H, q, J=7Hz), 2.8
5 (2H, t, J=6.5Hz), 3.10 (2H
. m), 3.25-3.40 (6H, m), 7.10
-7.25 (5H, m), 7.40 (LH, d
, J=8°5Hz), 7.90 (LH, dd, J=
8.5Hz. 1.5Hz), 8.35 (LH, d, J=1.5H
z) [0112] Example 21 3-[4-(4-(2,3-dimethylphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid mp: 173-175°C IR (Nujol): 3250 ,2650,2600°1670.1605.1580cm-'NMR(DMS
O-d6. δ): 1.60-1.90 (4H, m
), 2. 15 (3H,S), 2. 22
(3H,S), 2. 78 (2H,t,
J=8Hz), 3. 05-3. 55 (
IOH, m), 6. 90 (2H, t, J
=8Hz), 7.08 (LH,t,J=8Hz),
7゜30 (LH, S), 7.40 (LH, d,
J=8Hz), 7.42 (LH, d, J=8Hz)
, 8.23 (LH,s) [0113] Example 22 3-[4-(4-(2-methylthiophenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid mp: 145-150°C NMR (DMSOda, δ'): 1. 65
(4H. m), 2. 33 (3H,s), 2. 7
0 (4H, m). 2, 90 (4H, m), 3.40 (4H,
m), 7. 10 (4H, m), 7. 2
5 (IH, S), 7. 35 (LH, d, J
=8Hz), 7.70 (LH, d, J=8Hz),
8. 20 (LH,s) [0114] Example 23 3-[4-(4-(2-propoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid mp: 139-141°C IR (Nujol ):3200,1610.1590c
m-' NMR (DMSO-da, δ'): 1.
O2 (3H, t. J=7Hz), 1. 45-1. 9 (6H,
m), 2. 45 (2H, m), 2.
75 (2H, m), 3. 00 (4H, m)
, 3. 35 (,4H,m), 3. 91
(2H.t, J=7Hz), 6. 90 (4H,
m), 7. 25 (LH, S), 7.40 (
LH, d, J = 8H2). 7.72 (LH, d, J-8Hz), 8.23 (L
H. S) [0115] Example 24 3-[4-(4-(2-isopropoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic acid mp: 190-192°C IR (Nujol): 3350, 1620.1580c
m-' NMR (DMSO-d6. δ): 1.25
(6H, d. J=7Hz), 1. 55 (2H, m),
1. 70 (2H, m), 2. 35 (2
H, m), 2. 50 (4H. m), 2.75 (2H, m), 2.97 (4H.
, m). 4.55 (IH, sep, J=7Hz), 6.87
(4H,s), 7. 24 (LH,s),
7. 38 (LH. d, J=8Hz), 7. 70 (LH, d
, J=8Hz), 8.22 (LH,s) [0116] The following compound is obtained in substantially the same manner as in Example 1. [0117] Example 25 3-[4-(4-(2-isopropoxyphenyl)piperazin-1-yl)butylcoindole-5-carboxylic hydrochloride mp: 220-225°C IR (Nujol): 3450, 3250, 2650° 2550.2450, 1700.1600cm 'N
MR (DMSOd6.δ): 1. 25
(6H, d. J=7Hz), 1. 75 (4H, m),
2. 80 (2H, m), 3°O-3,
6, (IOH, m), 4. 62 (LH, sep
, J=7Hz), 6.95 (4H. m), 7. 30 (LH,s), 7.
42 (LH, d, J=8Hz), 7.71
(LH, d, J = 8 Hz), 8°22 (LH, s) [0118] Example 26 3-[4-(4-(2-propoxyphenyl)piperazin-1-yl)butylcoindol-5- Carboxylic hydrochloride salt mp: 239-242°C IR (Nujol): 3400, 2650, 2550° 1690 cm' NMR (DMSOd6.6): 1.03 (3H,
t. J=7Hz), 1.6-1.9 (6H, m), 2.
82 (2H, m), 3. 0-3.3 (6H
, m), 3. 55 (4H, m), 3.95
(2H, t, J=7Hz). 6, 95 (4H, m), 7. 30 (
LH,s), 7. 40 (LH, d, J=8
Hz), 7.70 (LH, d, J=8Hz), 8.
22 (LH,s)

Claims (6)

[Claims] [Claim 1] Formulas: ▲ Numerical formulas, chemical formulas, tables, etc. or a phenyl group substituted with a suitable substituent selected from the group consisting of a polyhalo(lower)alkyl group, a mono- or polyhalo(lower)alkoxy group, and a loweralkoxy(lower)alkoxy group,
each represents a lower alkylene group. ] or its salt. Claim 2: R^1 is unsubstituted or a halogen atom, a nitro group, a C_1-C_4 alkyl group, a cyano group, a C_1-
C_4 alkoxy group, C_1-C_4 alkylthio group,
a phenyl group substituted with a suitable substituent selected from the group consisting of a mono- or polyhalo (C_1-C_4) alkyl group, a mono- or polyhalo (C_1-C_4) alkoxy group and a C_1-C_4 alkoxy (C_1-C_4) alkoxy group; , A each represent a C_1-C_4 alkylene group. 3. R^1 is a phenyl group, a halophenyl group, a nitrophenyl group, a C_1-C_4 alkylphenyl group,
Cyanophenyl group, C_1-C_4 alkoxyphenyl group, C_1-C_4 alkylthiophenyl group, mono, di, tri or tetrahalo (C_1-C_4) alkylphenyl group, mono, di, tri or tetrahalo (C_1-
C_4) alkoxyphenyl group, C_1-C_4 alkoxy (C_1-C_4) alkylphenyl group and C_
3. The compound according to claim 2, which exhibits a 1-C_4 alkoxy (C_1-C_4) alkoxyphenyl group. Claim 4: R^1 is a phenyl group, 2-fluorophenyl group, 2-, 3- or 4-chlorophenyl group, 2-nitrophenyl group, 2-methylphenyl group, 2-ethylphenyl group, 2,3 -dimethylphenyl group, 2-cyanophenyl group, 2-, 3- or 4-methoxyphenyl group,
2-ethoxyphenyl group, 2-propoxyphenyl group,
2-isopropoxyphenyl group, 2-butoxyphenyl group, 2-isobutoxyphenyl group, 2-methylthiophenyl group, 2-trifluoromethoxyphenyl group, 2-(
1,1,2,2-tetrafluoroethoxy)phenyl group or 2-(2-methoxyethoxy)phenyl group, A
4. The compound according to claim 3, wherein each represents a tetramethylene group. [Claim 5] Formula: ▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 is unsubstituted or a halogen atom, nitro group, lower alkyl group, cyano group, lower alkoxy group, lower alkylthio group, mono or a phenyl group substituted with an appropriate substituent selected from the group consisting of a polyhalo(lower) alkyl group, a mono- or polyhalo(lower) alkoxy group, and a lower alkoxy(lower) alkoxy group;
represents a lower alkylene group, and R^2 represents a protected carboxy group. ] Formulas characterized by subjecting a compound represented by or a salt thereof to a carboxy-protecting group elimination reaction of R^2 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and A are each defined above. It is as follows. ] A method for producing a compound represented by or a salt thereof. 6. A dopamine receptor agonist, 5-HT receptor antagonist or α_1 receptor antagonist comprising the compound according to claim 1 or a salt thereof as an active ingredient.