JPH0421681A - Pyrrolopyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is (substituted)lower alkyl; R<2> is (lower alkyl-substituted)azabicyclo-5-12Calkyl]. EXAMPLE:N-(8-Methyl-8-azabicyclo[3,2,1]octo-3-yl)-1-methyl-1H-pyrrolo- [2,3- b]pyridine-3-carboxylic acid amide dihydrochloride. USE:A 5-hydroxytryptamine(5-HT)-antagonistic agent. Useful for the prevention and therapies of central nervous system diseases such as mental disorder, anxiety and depression, pains such as headache and neuralgia, gastrointestinal injuries such as dyspepsia and peptic ulcer, and nausea and vomiting involved in cancer therapies. PREPARATION:A reaction is made between a compound (reactive derivative) of formula II and a second compound (reactive derivative) of formula H2N-R<2>.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] This invention relates to novel pyrrolopyridine derivatives, and more specifically to 5-hydroxytryptamine (5-HT).
The present invention relates to novel pyrrolopyridine derivatives having pharmacological activities such as antagonistic effects, and pharmaceutically acceptable salts thereof.

[Object of the Invention] An object of the present invention is to provide novel pyrrolopyridine derivatives and pharmaceutically acceptable salts thereof useful as potent selective antagonists of 5-HT receptors.

More specifically, psychosis in humans and animals (e.g., schizophrenia, phthisis, etc.), central nervous system (CNS) disorders such as anxiety and depression, headaches (e.g., migraine, cluster headache, etc.)
Pain such as vascular headaches, etc.) and neuralgia (e.g., trigeminal neuralgia, etc.), gastrointestinal dysfunction symptoms associated with indigestion, peptic ulcers, reflux esophagitis, and flatulence, and gastrointestinal symptoms such as irritable bowel syndrome (IBS). Pyrrolopyridine derivatives and pharmaceutically acceptable pyrrolopyridine derivatives that can be used as active ingredients of 5-HT antagonists that are particularly useful for the treatment or prevention of nausea and vomiting, such as nausea or vomiting associated with cancer treatment, motion sickness, etc. Our goal is to provide that salt.

[Prior Art] In this technical field, for example, the following compounds are known.

[Structure of the Invention] As a result of intensive research aimed at obtaining a new compound having a strong pharmacological activity comparable to that of the above-mentioned compounds and a pharmaceutically acceptable salt thereof, the inventors of the present invention discovered that pyrrolopyridine has a strong pharmacological activity. We succeeded in obtaining a conductor as well as a pharmaceutically acceptable salt thereof.

The pyrrolopyridine conductor of this invention is novel and is as follows:-
The maximum can be represented by (1).

(In the formula, R1 is a lower alkyl group which may have an appropriate substituent; R2 means an azabicyclo(Cs C+□) alkyl group which may be substituted with a lower alkyl group) [Detailed description of the invention] The "azabicyclo(C5Cl2) alkyl group optionally substituted with a lower alkyl group" represented by the symbol R2 in the object substance (I) of this invention takes two configurations, endo configuration and exo configuration, depending on the presence of a bicyclo compound. Is possible. Therefore, although any of these cases falls within the technical scope of the present invention, the endo configuration often exhibits stronger pharmacological activity.

The pharmaceutically acceptable salt of the target product Salts with acids; organic carboxylic acids or sulfonic acids such as malate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, P-toluenesulfonate; Suitable examples include salts with acids such as salts with basic or acidic amino acids such as salts with arginine, salts with aspartic acid, and salts with glutamic acid; and the like.

With regard to each of the above and below definitions in this specification, examples that fall within the technical scope of the present invention are as follows.

The term "lower" means, unless otherwise specified, a carbon number of 1 to 6, preferably a carbon number of 1 to 4.

Suitable "lower alkyl groups" include linear or branched groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, etc. . Among these, methyl is most preferred.

These lower alkyl groups may have appropriate substituents, such as lower alkylidene groups, cycloalkyl groups, aryl groups, halogens, hydroxy groups, protected hydroxy groups, and amino groups. , a mono- or di-lower alkylamino group, a heterocyclic group, and the like.

Among these, examples of lower alkylidene groups include methylene, ethylidene, and impropylidene.

Examples of the cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclohebutyl, and cyclooctyl.

Examples of the aryl group include phenyl, naphthyl, and the like.

Examples of halogen include fluorine, chlorine, bromine, and iodine.

Protecting groups for protected hydroxy groups include, for example, alkyl groups such as di- or triphenyl (lower) alkyl such as benzyl, benzhydryl, trityl, etc., e.g. methoxymethyl, ethoxymethyl, tertiary Alkoxy (lower) such as butoxymethyl, methoxyethoxymethyl, ethoxymethoxyethyl, etc.
Alkyl groups and acyl groups as described below are shown.

Examples of the acyl group include aliphatic acyl group, aromatic acyl group,
Examples include a heterocyclic acyl group, and further an aliphatic acyl group substituted with an aromatic group or a heterocyclic group.

Aliphatic acyl groups include carbamoyl groups, such as lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, etc. Lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl,
For example, lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl, (C3-cy)cycloalkanecarbonyl groups such as cyclohexanecarbonyl,
Amidino groups, such as methoxalyl, ethoxalyl, tertiary
Examples include saturated or unsaturated acyclic or cyclic acyl groups, such as protected carboxycarbonyl groups, such as lower alkanoyl groups such as butoxalyl, and the like.

Examples of the aromatic acyl group include aroyl groups such as benzoyl, toluoyl, and xyloyl, and arenesulfonyl groups such as benzenesulfonyl and tosyl.

Examples of the heterocyclic acyl group include heterocyclic carbonyl groups such as furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, and morpholinocarbonyl.

Aliphatic acyl groups substituted with aromatic groups include alkanoyl groups such as phenyl(lower)alkanoyl groups such as phenylacetyl, phenylpropionyl, phenylhexanoyl, e.g. benzyloxycarbonyl, phenethyloxycarbonyl; Al (lower) such as phenyl (lower) alkoxycarbonyl group such as
Alkoxycarbonyl groups, such as phenoxyacetyl,
Examples include phenoxy (lower) alkanoyl groups such as phenoxypropionyl.

Examples of the aliphatic acyl group substituted with a heterocyclic group include thienyl acetyl, imidazolylacetyl-furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thienylpropionyl, thiadiazolylpropionyl, and the like.

These acyl groups may further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogens such as chlorine, bromine, iodine, fluorine, e.g. methoxy, ethoxy, propoxy, isopropoxy. , lower alkoxy groups such as butoxy, pentyloxy, hexyloxy, e.g. methylthio,
It may be substituted with one or more suitable substituents such as a lower alkylthio group such as ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc., a nitro group, etc. Preferred acyl groups having such substituents include is a mono (or di or tri) eight-mouth alkanoyl group such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, for example chloromethoxycarbonyl, dichloromethoxycarboxyl, 2,2.2-1-dichloroethoxy Mono (or di or tri) haloalkoxycarbonyl groups such as carbonyl, e.g. nitro (or halo or lower alkoxy) such as nitrohensyloxycarbonyl, chlorohensyloxycarbonyl, methoxyhensyloxycarbonyl
Examples include aralkoxycarbonyl groups, such as mono (or di or tri) lower alkyl sulfonyl groups such as fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, and trichloromethylsulfonyl.

The mono- or di-lower alkylamino group refers to an amino group substituted with one or two of the birch lower alkyl groups described above, such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino, etc. can be mentioned.

Further, the term "heterocyclic group" refers to a monocyclic or polycyclic heterocyclic group containing at least one heteroatom, such as an oxygen atom, a sulfur atom, or a nitrogen atom, such as imidazolyl, pyrazolyl, pyridyl, Examples include pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, quinolyl, inquinolyl, imidazolyl, oxasilyl, isoxasilyl, benzoxasilyl, thiazolyl, benzothiazolyl, and the like.

Examples of the azabicyclo(Cs-C+2) alkyl group include azabicyclo[3,2,l]octyl, azabicyclo[2,2,2]octyl, azabicyclo[3,3,1
] Nonyl, etc., and these may be substituted with the above-mentioned lower alkyl group (eg, methyl, ethyl, etc.). Even more preferred is azabicyclo (Cy C+).
alkyl, more preferably azabicyclo (ca -c
o) alkyl, most preferably 8-methyl-8-azabicyclo[3,2,1]octyl, 1-azabicyclo[3,2,1]octyl, 9-methyl-9-azabicyclo[3,3, 1] Nonyl, which may be substituted with the above-mentioned lower alkyl group (eg, methyl, ethyl, etc.). Even more preferred is azabicyclo (c
y -C1°)alkylidene(lower)alkyl, more preferably azabicyclo(Ca-Co)alkylidene(lower)alkyl, most preferably (8-methyl-8-azabicyclo[3,2,1]octylidene)
Methyl, (1-azabicyclo[2,2,2]octylidene)methyl.

Next, a method for producing the target substance of the present invention will be explained.

Process 1 or a reactive derivative thereof at the carboxy group or a salt thereof ■ or a salt thereof Process 2 (I a) or a salt thereof (I b) or a salt thereof (In each of the above formulas, Rl and R2 have the same meaning as before R
1, is a protected hydroxy (lower) alkyl group, RL
Description of Process 1 The object compound (I) or a salt thereof of the present invention is a compound (nr ) or They are obtained by reacting their reactive derivatives or their salts at the amino group.

Examples of reactive derivatives at the carboxy group include acid halides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples thereof include acid chlorides; acid azides: substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, such as methanesulfonic acid; Alkanesulfonic acids such as ethanesulfonic acid, thiosulfuric acid, sulfuric acid, alkyl carbonates such as pivalic acid,
Mixed acid anhydrides with acids such as pentanoic acid, isopentanoic acid, 2-ethy/I/U acids, aliphatic carboxylic acids such as acetic acid or trichloroacetic acid or aromatic carboxylic acids such as benzoic acid: symmetrical acid anhydrides ; activated amides with imidazole, dimethylpyrazole, triazole or tetrazole; or activated esters such as cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [
(CH3)J”-CH-]ester, vinyl ester,
flopargyl ester, p-nitrophenyl ester,
2.4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester,
p-talesyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or N,N
-dimethylhydroxylamine, 1-hydroxy-2-
(IH)-pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide or 1-hydroxy-6
-Chloro-IH-benzotriazole and the like. These reactive derivatives can be arbitrarily selected from them depending on the type of compound (II) to be used.

Suitable reactive derivatives at the amino group of compound (Ill) include conventional reactive derivatives used for amides, such as Schiff's base type imino or its enamine produced by the reaction of compound (HI) with a carbonyl compound. Type tautomer: A silyl tautomer formed by the reaction of the compound (Ill) with a silyl compound such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, etc.; Examples include derivatives generated.

The reaction is usually carried out in conventional solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, but without adversely affecting the reaction. It can be carried out in any other solvent as long as it is not a solvent. In these solvents,
Hydrophilic solvents may be used in combination with water.

When compound (II) is used in the reaction in the form of the free acid or its salt, N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-Nmorpholinoethylcarbodiimide: N-cyclohexyl- N'-(4-diethylaminocyclohexyl)carbodiimide: N,N'-diethylcarbodiimide;N,N"-diisopropylcarbodiimide; N-ethyl-N-(3-dimethylaminopropyl)carbodiimide, N,N- carbonyl bis(
2-methylimidazole); pentamethyleneketene-N
-Cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; ethyl polyphosphate; isopropyl polyphosphate; diethyl phosphorochloridate; phosphorus oxychloride; phosphorus trichloride; phosphorus pentachloride: thionyl chloride: oxalyl chloride: triphenylphosphine ; N-ethyl-7-hydroxybenzisoxazolium fluoroborate: N-ethyl-5-phenylisoxazolium-3'-sulfonate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro- IH-benzotriazole; for example, (chloromethylene)dimethylammonium chloride produced by the reaction of dimethylformamide with thionyl chloride or phosgene, a compound produced by the reaction of dimethylformamide with phosphorus oxychloride, etc., so-called Vilsmeier reagent, etc. Preference is given to carrying out the reaction in the presence of customary condensing agents.

This reaction also applies to alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N-di( The reaction may be carried out in the presence of an inorganic or organic base such as lower) alkylbenzylamine, N,N-di(lower)alkylaniline, and the like. If the base or condensing agent is liquid, they can also be used as solvents. The reaction temperature is not particularly limited, and is usually carried out under cooling or at room temperature.

Description of Process 2 Compound (Ib) or a salt thereof, which is the object of the present invention, can be obtained by subjecting compound (Ia) or a salt thereof to a hydroxy protecting group elimination reaction.

This reaction is carried out according to conventional methods such as hydrolysis and reduction.

(a) Hydrolysis: Hydrolysis is preferably carried out in the presence of a base or 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 (
For example, sodium methoxide, sodium ethoxide,
Potassium tert-butoxide, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal hydrogen carbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.) ) etc. are included.

Suitable acids include organic acids such as saline acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-
toluenesulfonic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). Among these, hydrolysis under acidic conditions using trifluoroacetic acid is generally performed using cation scavengers (e.g. phenol, anisole, etc.).
is promoted by the addition of

This reaction is preferably carried out in a conventional solvent that does not adversely affect the progress of the reaction, such as water, methylene chloride, alcohol (eg, methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, or a mixed solvent thereof. Among bases and acids, liquid ones can be used also as a solvent.

The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling or heating.

(b) Reduction The reduction method applied to this elimination reaction includes, for example, metals (e.g. zinc, zinc amalgam, etc.) and Cr compounds (
Reduction methods using a combination of organic or inorganic acids (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.) and organic or inorganic acids (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); e.g. palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium - carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, palladium hydroxide-carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (
For example, platinum plate, sponge platinum, platinum black, colloidal platinum,
Examples include general catalytic reduction carried out in the presence of a conventional metal catalyst such as platinum oxide, platinum wire, etc.).

When a catalytic reduction method is employed, the reaction is preferably carried out under conditions near neutrality.

This reaction can be carried out using conventional solvents that do not adversely affect the progress of the reaction.
For example, the reaction is preferably carried out in water, alcohol (eg, methanol, ethanol, propatool, etc.), dioxane, tetrahydrofuran, acetic acid, N buffer solution (eg, phosphate buffer, acetate buffer, etc.), or a mixed solvent thereof.

The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling or heating.

If the carboxy protecting group is an allyl group, it can also be protected from hydrolysis using palladium compounds.

Suitable palladium compounds used in this reaction include palladium-carbon, palladium hydroxide-carbon, palladium chloride, such as tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone).
Palladium such as palladium(0), di[1,2-bis(diphenylphosphino)ethanecopalladium(0), tetrakis(triphenylphosphite)palladium(0), tetrakis(triethylphosphite)palladium(0), etc. Examples include ligand complexes.

The reaction can be carried out using, for example, amines (e.g. morpholine, N-methylaniline, etc.), active methylene compounds (e.g. dimedone,
benzoyl acetate, 2-methyl-3-oxovaleric acid, etc.), cyanohydrin compounds (e.g., α-tetrahydropyranyloxybenzyl cyanide, etc.), (lower) alkanoic acids or their salts (e.g., formic acid, acetic acid, ammonium formate, sodium acetate, etc.) ) is preferably carried out in the presence of a scavenger for allyl groups generated during the reaction.

This reaction is effective for lower alkyl amines (e.g. butylamine,
This can be carried out in the presence of a base such as triethylamine, etc.), pyridine, etc.

When a palladium ligand complex is used in this reaction,
For example, triphenylphosphine, triphenyl phosphite,
Preferably, the reaction is carried out in the presence of a corresponding ligand such as triethyl phosphite.

This reaction is usually carried out in a conventional solvent that does not adversely affect the progress of the reaction, such as water, methanol, ethanol, propatool, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, or a mixture thereof. It will be held in

The elimination reaction can be selected depending on the type of hydroxy protecting group to be eliminated.

Compound (I), the object of this invention, is novel and has pharmacological activities such as 5-HT antagonistic activity, especially 5-HT3 antagonistic activity. central nervous system (CNS) disorders, pain such as headaches (e.g. migraines, cluster headaches, vascular headaches, etc.) and neuralgia (e.g. trigeminal neuralgia), indigestion, peptic ulcers, reflux esophagitis and flatulence, etc. It is useful for the treatment or prevention of gastrointestinal dysfunction symptoms and irritable bowel syndrome (IBS) associated with cancer treatment, nausea or vomiting associated with cancer treatment, and motion sickness.

Furthermore, the object compound (1) of the present invention can be used to treat and/or treat obesity, pulmonary embolism, arrhythmia, withdrawal symptoms resulting from addiction to abused drugs or substances, stress-induced mental disorders, rhinitis, and serotonin-induced nasal disorders. or considered to be useful for prevention.

In order to clarify the usefulness of target substance (1), representative compounds of the present invention are selected and their pharmacological activities are as follows.

Bezold-Jaris
ch) Reflex inhibition test method Male Sblague-Dawley rats weighing 260-350 g were intraperitoneally anesthetized with 1.25 g/kg of urethane.

Blood pressure and heart rate were continuously monitored in the left common carotid artery using a pressure transducer. The right major leg vein was intubated and drugs were injected intravenously (iv). The patient's trachea was also intubated to make breathing easier.

2-methyl-5-hydroxytryptamine (3
A control bradycardia response was set up with a bolus injection of 2 μg/kg, fv). - Once the heart rate has returned to basal values, the rat is administered the test compound iv) and again after a 5 minute interval with 2-methyl-5-hydroxytryptamine (32 μg).
/kg, iv) was injected bolus.

Test compound: 1-ethyl-N-(8-methyl-8-azabicyclo[3
,2,1]oct-3-yl)-1H-pyrrolo[2,3
-b] Copyridine 3-carboxylic acid amide dihydrochloride test results: When using the object compound of this invention (■) for therapeutic purposes, it is necessary to use an organic or inorganic solid form suitable for oral, parenteral and external administration. Alternatively, it may be used in the form of a conventional pharmaceutical formulation containing the compound as an active ingredient in admixture with a pharmaceutically acceptable carrier, such as a liquid excipient.

Pharmaceutical formulations may be in solid form such as tablets, granules, powders, capsules, or liquid forms such as solutions, suspensions, syrups, emulsions, lemonades, and the like.

If necessary, auxiliaries, stabilizers, wetting agents, and other substances such as lactose, citric acid, tartaric acid, stearic acid, maglucium stearate, sucrose sugar, corn starch, talc, gelatin, agar, pectin, and peanuts may be added to the above formulations. Commonly used additives such as oil, olive oil, cocoa butter, ethylene glycol, etc. may be included.

The dosage of Compound (I) varies depending on the patient's age, condition, type and condition of disease, type of Compound (1) used, etc. - In terms of numbers, it is 0.01mg per day and about 500m
The subject compound (I) of the present invention may be administered to a patient in an amount between about 0.5 g or more.
05mg, 0.25mg, 0.5mg, 1B, 1
0mg, 20mg, 50mg, and 100mg may be administered.

The present invention will be explained in more detail below according to production examples and examples.

K-Kenriyu IH-Pyrrolo [2,3-b Copyridine (1,77g)
Sodium hydride (60%, in mineral oil, 660 mg) was added to a solution of N,N-dimethylformamide (t5 ml) at 0°C.
It was added in small portions over a period of 5 minutes. After stirring at 5° C. for 20 minutes, a solution of allyl bromide (2.0 g) in N,N-dimethylformamide (5 ml) was added at the same temperature. The resulting mixture was stirred for 1 hour at 0° C. and then for 1 hour at room temperature. The reaction mixture was diluted with cold water and diluted with methylene chloride (30
ml) three times. The organic solvent layers were combined, washed successively with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography packed with silica gel and eluted with methylene chloride to obtain oily 1-(2-propenyl)-1H-pyrrolo[2,3-bl pyridine (2.1 g).

NMR (CDCI, δ): 4.8-5.3 (4)
1. m), 5.9-8.2 (IH, ID).

6.47 (IH, d, J-3, 51Hz), 7.0
-7.1(1)1. m) 7.21 (IH, d, J-
3,518Z), 7.90(IH, d, d, J-1,
55,8,0IH2), 8.33(l)1. d, d,
J''1.55, 4.79 Hz) Production Example 2 N,N-dimethylformamide (10 ml) was treated with m oxychloride (2.36 g) at 5°C for 5 minutes.

The mixture was stirred at 5°C for 5 minutes and then at room temperature for 1°C. Into this, add 2.21 g of 1-(2-propenyl)-1H-pyrrolo[2,3-b]copyridine) in N,N-dimethylformamide (1 o ml) with m:ti of 0 to 5.
The addition was carried out over a period of 10 minutes at <0>C. After stirring at the same temperature for 30 minutes and further at room temperature for 1 hour, the mixture was heated at 50° C. for 30 minutes. The reaction solution was diluted with cold water, made alkaline by adding an aqueous sodium bicarbonate solution, and extracted three times with chloroform. The chloroform layers were combined, washed three times with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure at 50°C to give 1-(2-propenyl)-1H-pyrrolo[
2,3-b]copyridine 3=carbaldehyde crystals (1
, 76 g) was obtained.

mp: 49-53℃ IR (Nujol): 1670.1590.15
65 cm-'NMR (CDCIs, δ): 4.
9-5.4 (48, m), 5.9-6.2 (1)
1. m).

7.27 (IH, d, d, J=4.76.7.04)
1z), 7.89(1)1. s), 8.43 (IH
, d, d, J-1, 62° 4.76 Hz) , 8.56
(IH, d, d, J-1, 62° 7.04Hz),
9.98 (IH, s) Production Example 3 Sodium cyanide (236 mg), manganese dioxide (
1,8g), acetic acid (c+4mg) and methanol (
1-(2-propenyl)-1H-pyrrolo[2,3-b]copyridine 3-carbaldehyde (186.2 mg) was added to the mixture consisting of 5+nl) at room temperature.

After stirring the resulting mixture at room temperature for 6 hours, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water and brine, and then dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, crystalline 1-
Methyl (2-propenyl)-1H-pyrrolo[2,3-b]copyridine 3-carboxylate was obtained, which was used as a raw material for the next step (Production Example 4) without further purification.

mp: 56-59℃ IR (Nujol): 1700.1635.159
5 cm-'NMR (CDC13, δ): 3.92
(3H,s), 4.9-5.4 (4)1. a+)
.

5.9-6.2(1)1. m), 7.2-7.3 (1B
, m).

7.96 (IH, s), 8.3-8.5 (2H,
m)) Mass (m/e): 216 M” Production Example 4 l-(2-propenyl)-1H-pyrrolo[2,3-b]
Methyl copyridine 3-carboxylate (1,568) I
A solution consisting of N aqueous sodium hydroxide solution (17.28 ml) and ethanol (15 ml) was stirred at 60°C for 3 hours. The reaction mixture was neutralized by adding IN hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water to give 1-(2-propenyl)-1H-pyrrolo[2,3-b]copyridine 3.
-carboxylic acid (1.34 g) was obtained.

rnp: 169-171℃ IR (Nujol): 1690.1635.159
5.1570 cl'NMR (DMSO-da): 4
．． 9-5.3 (4)1. m), 6.0-6.2 (
IH, m).

7.2-7.4 (IH, m), 8.23 (IH,
s).

8.3-8.4 (2H, 111), 12.32 (
Oily 1-(2-acetoxy ethyl)-1H-
Pyrrolo[2,3-b]copyridine was obtained.

TR (film): 2900.1735.159
0,1565 cm-'NMR (CDC13, δ):
2. Ol, (3H,s), 4.3-4.6 (4H,
m).

6.46 (1)1. d, J-3, 52) IZ), 7
．． 06 (IH, d, d.

J-4, 72, 7, 83) 1z), 7.23 (IH
,d.

J-3,52Hz), 7.90(IH, d, d, J-
1,557,83Hz), 8.31 (IH, d, d
, J-1,56°4.72Hz) Production Example 6 1-(2-acetoxyethyl)-IH- as a raw material
Oily 1-(2
-acetoxyethyl)IH-pyrrolo[2,3-b]copyridine 3-carbaldehyde was obtained.

IR (Nujol): 1735.16B0.159
5.1575 cm-'NMR (CDCIs, δ)
: 2.04 (38, s), 4.50 (2H, t.

J-4, 62Hz), 4.64 (2)1. t, J-
4,62)IZ).

7.28 (1)1. d, d, J-4, 74, 7, 86
)1z).

7.92 (IH,s), 8.42 (1)1. d,
d, J-1, 56.

4.74Hz), 8.56 (IH, d, d, J-1
,56°7.86Hz) ,10.00 (IH,s)
Production Example 7 Oily 1-ethyl-IH-pyrrolo[2,3-b-copyridine was obtained by performing substantially the same operation as Production Example 1 except that ethyl iodide was used instead of allyl bromide. Ta.

NMR (CDCIs.

δ): 1.4B (38, t, J-7, 26) 1z), 4
．． 35 (2H, q, J-7, 288x), 6.44
(IH, d.

J-3, 52Hz), 7.04 (IH, d, d, J-4
, 71° 7.83) IZ), 7.23 (IH, d, J-
3,49Hz).

7.89 (IH, d, d, J-1, 58, 7, 83H
z), 8.32 (IH, d, d, J=1.56, 4.
71) 1z) k-flit 8 1-ethyl-IH-pyrrolo[2,3-b
1-Ethyl-IH-pyrrolo[2,3
-bcopyridine-3-carbaldehyde was obtained.

mp: 56-58℃ IR (Nujol): l670.1 [i40.159
0.1565 cm-'NMR (CDC13, δ):
1.57 (3o, t, +-7,2aHz), 4.4
2(2H,q,J-7,28)IZ), 7.26
(IH, d, d.

J=4.087.84)1z), 7.90(IH,s
), 8.43 (IH, d, d, J-1, 62, 4, 8
0Hz), 8.55 (IH, d, d, J-1, 62,
7,84Hz), 9.98(IH,S) Production Example 9 1-Ethyl-IH-pyrrolo[2,3-b]copyridine 3
- Carbaldehyde (1.4 g) in acetone (50 ml)
Potassium permanganate (2.52 g) in water (
40ml) solution was added over 1 hour at 25-30°C. After stirring at room temperature for 1 hour, insoluble matter was filtered off. The crystalline residue obtained by concentrating the filtrate under reduced pressure was washed with methylene chloride, suspended in water, and neutralized by adding acetic acid. The precipitate was collected by filtration and washed with water to obtain 1-ethyl-IH-pyrrolo[2,3-b]copyridine 3-carboxylic acid.

mp: 209-210℃ IR (Nujol): 1680.1590.1520
cm-'NMR (DMSO-ds, δ): 1.4
3 (3H, t, J-7, 19) IZ) , 4.37 (
2H, q, J-7, 19) 1z) , 7.28 (1)
1. d, d.

J-4, 78, 7, 79H2), 8.3-8.4 (
3H, m) 12.3 (11 (, bs) Mass (m/e): 190 M” Production Example 10 1-(2-acetoxyethyl)-1H- as a raw material
1-(2-acetoxyethyl)-1H-pyrrolo[2,3 -bcopyridine-3-carboxylic acid was obtained.

mp: 183-185℃ IR (Nujol): 2500.1730.169
0.1590 cm-'NMR (DMSO-da, δ)
: 1.91 (3H, s), 4.44 (2H, t.

J-5,04Hz), 4.59 (2H,t, J-5
,04Hz).

7.29 (11(, d, d, J-4, 61, 7, 78
Hz).

8.3-8.4 (31 (, +++) , 12.3 (
IHlbs) Cause] 1 Tsujiko 1-Methyl-IH-pyrrolo[2,3-b]copyridine 3
- A mixture of carboxylic acid (600 mg), 1-hydroxybenzotriazole (460 mg) and l,3-dicyclohexylcarbodiimide (703 mg) was added to N,N-dimethylformamide (5 ml) at room temperature for 1.5 hours. Stirred.

This mixture was treated with a solution of 3-amino-8-methyl-8-azabicyclo[3,2,1]octane (600 mg) in NN-dimethylformamide (2 ml) for 15 min at room temperature.
Stir for hours. Triethylamine (0,3
ml) was added, and stirring was continued for an additional 5 hours at 50°C.

The generated precipitate was filtered off, and the solvent was distilled off under reduced pressure. The residue was diluted with saturated aqueous sodium chloride solution and extracted five times with chloroform. The organic solvent layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.

The residual oil was developed by column chromatography packed with neutral alumina and eluted with chloroform, resulting in an oil of 1.05%.
g was obtained. When rice is treated with ethanolic hydrochloric acid and further crystallized with an ethanol/ether mixture, N-(8
-Methyl-8-azabicyclo[3,2,1]octo-3
-yl)-1-methyl-IH-pyrrolo[2,3-b]copyridine 3-carboxylic acid amide dihydrochloride (963 mg
)was gotten.

mp: 207-215°C JR (Nujol): 3250.1640. ]55
0.1520 cl'NMR (DMSO-da) δ: 2.0O-2.60 (8H, a+), 2.86 (3
)1. S).

4.00 (3H, s), 3.80-3.33 (3H, m
).

7.60 (IH, t, J-8Hz), 8.13 (I
H,s).

8.43 (IH, d, J-5Hz), 8.7B (
1)1. d.

J=6Hz)
-carboxylic acid (204B), 1-hydroxybenzotriazole (157 mg) and 1-ethyl-3-(3-
Dimethylaminopropylcarbodiimide hydrochloride (338
mg) in N,N-dimethylformamide (3 ml) and the resulting mixture was stirred at room temperature for 1.5 hours.

3-amino-9-methyl-9-azabicyclo[3,3,1 cononane (180 mg) and triethylamine (1t7 mg) were added to this mixture, and the mixture was stirred for an additional 2 hours at the same temperature. After concentrating the reaction mixture under reduced pressure, the residue was developed on column chromatography packed with silica gel (10 g).
Elution was with 10% methanol/chloroform. Fractions containing the target substance were collected and concentrated. The remaining crystalline material was recrystallized from methanol/ethyl acetate to give N-(9-methyl-9-azabicyclo[3,3,1"Jnonan-3-yl)-1-methyl-IH-pyrrolo[2, 3-b]copyridine 3-carboxylic acid amide was obtained.

mp: 280℃ IR (Nujol): 3240.1B40.159
0.1540.1520cl'NMR (DMSO-d6
．． δ): 1.3-1.9 (5H, 誼), 2.0-
2.6 (5H, m), 2.8 (3H, s), 3.
34 (4H, +n).

3.5-3.7 (2H, m), 4.58 (2)1
．． bs) 7.22 (11(, d, d, J-4, 66H
z, 7.88Hz).

8.08 (IH, d, J-7, 3Hz), 8.29
(IH,s).

8.3-8.4 (IH, n), 8.43 (1)1
．． d.

J-7, 88Hz).

Mass (m/e): 312 M”Example 3 l-(2-acetoxyethyl)-1H-pyrrolo[2,3
-bl pyridine-3-carboxylic acid (606 mg), 1-
Hydroxybenzotriazole (405mg) and 1
-ethyl-3-(3-diethylaminopropyl)-3-
Carbodiimide hydrochloride (574 mg) was added to N,N-dimethylformamide (10 ml) and the resulting mixture was stirred at room temperature for 2 hours. The resulting solution contains 3-amino-8
-Methyl-8-azabicyclo[3,2,1]octane (
560 mg) was added thereto, and the mixture was further stirred at room temperature for 3 hours.

After evaporating the solvent, the residue was diluted with 10% methanol/chloroform and washed with aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was developed on column chromatography packed with silica gel and eluted with 15% methanol/chloroform to obtain an oil. This was diluted with ethyl acetate/ether.
When crystallized by washing, 1-(2-acetoxyethyl)-N-(8-methyl-8- azabicyclo
]] Octo-3-yl-1H-pyrrolo[2,:+-b]
Pyridine-3-carboxylic acid amide was obtained (560 m
g).

mp + 145-146°C IR (Nujol): 3220. 1730. 1
625. 1590 cm-'NMR (DMSO-d6
．． δ) :1.5-2.3 (8)1. m), 1
．． 90 (3H, s).

2.13 (31(,s), 3.03 (2H, bs
), 3.7-4.1 (IH, m), 4.2-4.7
(4H, m), 7.19 (IH, d, d, J-4,
95, 8, 91 Hz), 7.41 (lH, d, J-4
,95Hz), 8.27 (18,s).

8.40 (IH, d, J-8, 91Hz) Mass (m
/e): 370 M”lI4 1-ethyl-IH-pyrrolo[2,3-bcopyridine-3
-carboxylic acid (285 mg), 1-hydroxybenzotriazole (202,5 mg) and 1-methyl-3
-(3-diethylaminopropyl)carbodiimide hydrochloride (286B) was dissolved in N,N-dimethylformamide (5m
l) and the resulting mixture was stirred at room temperature for 2 hours.

3-Amino-8-methyl-8-azabicyclo[3,2,1]octane (280 mg) was added to the obtained solution, and after stirring at the same temperature for an additional hour, triethylamine (20
2 mg) was added thereto, and the mixture was further stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was subjected to column chromatography packed with silica gel and developed with 10% methanol/chloroform to obtain an oil. This oil was treated with 12N hydrochloric acid/ethanol (1 ml) and then concentrated under reduced pressure.

The residue was powdered with ether and recrystallized from a mixture of ethanol and ethyl acetate to give 1-ethyl-N-(8-
Methyl-8-azabicyclo[3,2,1]]octo3
-yl-1H-pyrrolo[2,3-bl pyridine-3-carboxylic acid amide dihydrochloride was obtained (260II1g
).

mp: 124-127℃ (decomposition) IR (Nujol): 3200.2500.163
5.1540 cm-'NMR (DMso-aa, δ)
+1.45 (3H, t, J-7,078Z).

2.0-2.8 (8H, m) j, 7-4.1 (3
H, m).

4.37 (2)1. q, J-7,07Hz), 5.
33 (3Lbs), 7.26 (IH, d, d, J-
4,77°7.86)1z) ,8.02 (IH,s
) , 8.34 (IH, d, J-4, 77) 1z) ,
8.52 (IH, d.

J-7,85Hz), 8.60(IH,s), 10
．． 70 (IH, bs) Mass (M/e): 312 M″Tochu Jl
1-(2-propenyl)IH-pyrrolo[
N-(8-
Methyl-8-azabicyclo[3,2,1]]octo3
-yl-1(2-propenyl)-1H-pyrrolo[2,3
-b Copyridine-3-carboxylic acid amide was obtained (1
60m3).

mp: 142-143℃ IR (Nujol): 3350.1615 cm NMR (DMSO-dIl, δ): 1.5-1.2
(8H, m), 2.16 (3H, s).

2.4-2.6 (IH, m), 3.1 (2H, b
s).

4.8-5.3 (4H, m), 5.8-6.4 (
l)I, m).

7.1-7.6 (21 (, m), 8.22 (IH
, s) 8.2-8.5 (2H, +n) Mass (m/e): 324 M" back bottom 916 l-(2-acetoxyethyl)-N-(8-methyl-8
-Azabicyclo[3,2,1]]octo-3-yl-1
H-pyrrolo[2,3-b]copyridine 3-carboxylic acid amide (560a+g) and IN aqueous sodium hydroxide solution (3.5 ml) were added to ethanol (3 ml) and the resulting solution was stirred at room temperature for 2 hours. IN hydrochloric acid (3,5
ml), the solvent was distilled off under reduced pressure, and the residue was extracted three times with 10% methanol/chloroform.

The organic solvent layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was developed by column chromatography packed with silica gel and eluted with 1% methylamine/chloroform to give 1-(2- and droxyethyl)-N
-(8-Methyl-8-azabicyclo[3,2,1cooct-3-yl)-1H-pyrrolo[2,3-b]copyridine 3-carboxylic acid amide was obtained (t67 mg).

mp: 77-79℃ IR (Nujol): 3270.1620 cm-
'NMR(DMSO-(16,δ):1.6-2.2
(8H,+a), 2.17 (3H,s).

Mass (z/e): 3.05 (2H, s), 3.97 (2H, t, J-5,
47Hz), 3.9-4.1 (18,m), 4.33
(2H, t, J-5, 47H2), 5.0 (IH,
bs).

7.20(1)1. d, d, J-4, 66, 7, 89H
1).

7.46 (IH, d, J-4, 54Hz), 8.28 (
IH, s), 8.29 (1)1. d, d, J-1,
55°4.61iHz), 8.40(IH, d, d,
J-1,55゜7.89H2) 328 M''

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 is a lower alkyl group which may have an appropriate substituent, and R^2 is substituted with a lower alkyl group or a pharmaceutically acceptable salt thereof.