JPH05271230A - Diazabicyclo derivative - Google Patents

Abstract

PURPOSE:To obtain a new diazabicyclo derivative useful as a selective antagonistic agent for 5-hydroxytryptamine (5-HT) in a 5-HT3 receptor. CONSTITUTION:The objective compound of formula I [R1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl, acyl, aryl, heteroarylalkyl, arylalkyl, etc.; R<2> is H or alkyl; R<3> and R<4> are H, alkyl, alkenyl, acyl, alkoxyalkyl or arylalkyl, except that R1 is H, alkyl, unsubstituted benzyl or dimethylaminoethyl; R<2> is H and R<3> and R<4> are methyl] or its acid addition salt or quaternary ammonium salt, e.g. endo-3,9-dimethyl-3,9-diazabicyclo[3.3.1]non-7-yl-1-allylindazole-3- carboxamide. This compound is obtained by reacting an indazole-3-carboxylic acid of formula II with a 3,9-diazabicyclo[3.3.1] non-7-amine derivative of formula III.

Description

Detailed Description of the Invention

The present invention relates to a novel diazabicyclo derivative and its pharmacologically acceptable acid addition salts and quaternary ammonium salts.

Furthermore, the present invention relates to a novel diazabicyclo derivative which is a selectively effective antagonist of 5-HT (serotonin) at the 5-HT ₃ receptor, a pharmacologically acceptable acid addition salt thereof and a fourth diazabicyclo derivative. With respect to primary ammonium salts. The compounds of this invention are the compounds of central nervous system 5-H
It acts on the T ₃ receptor and is effective in the treatment of psychiatric disorders such as schizophrenia, mania, depression, anxiety, dementia, cognitive disorders or drug dependence, and also in diseases of the nervous system such as migraine. Used for treatment. In addition, 5-of the peripheral nervous system
Acts on HT receptors, for example, gastrointestinal dysfunction symptoms such as delayed gastric emptying, dyspepsia, flatulence, esophageal reflux, and gastrointestinal disorders such as gastritis, peptic ulcer, Crohn's disease, ulcerative colitis, and diarrhea caused by various causes. Used in the treatment of. It is also effective in treating vomiting and nausea, especially vomiting and nausea induced during cancer chemotherapy and radiation therapy.

[0003]

2. Description of the Related Art Vomiting is a serious problem frequently observed in patients who have been treated with cancer chemotherapeutic agents, and vomiting management is a sufficient anti-cancer treatment. Is an extremely important adjunctive therapy.

Since it was reported that high dose intravenous administration of metoclopramide was effective in suppressing this vomiting (Grall
a, RJ. et al., N. Engl. J. Med., 305, 905-909 (198
1)), but now it is possible to manage vomiting well, if not completely. However, it has been revealed that existing antiemetics, especially compounds having a benzamide structure, have unfavorable side effects such as sedation, ataxia, diarrhea, and akathisia because they have a dopamine blocking effect and a central nervous system depressant effect.

Recently, a specific antagonist of the 5-HT ₃ receptor has been reported to suppress vomiting induced by cancer chemotherapy (Cunningham, D. et al., The Lancet, 1, 1461).
-1463 (1987)), a 5-HT ₃ antagonist is considered to be a drug that suppresses vomiting at a lower dose than existing antiemetics and has no undesirable side effects.

As conventional 5-HT ₃ antagonists, there are JP-A-59-67284, JP-A-60-226858, JP-A-62-270583 and JP-A-64-.
It has an azabicyclo ring partial structure as disclosed in Japanese Patent No. 71874, or JP-A-60-21.
Those having an imidazole ring partial structure as disclosed in Japanese Patent No. 4784 have been known, but it is desired to develop a substance that selectively antagonizes 5-HT in the 5-HT ₃ receptor. Was there.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have synthesized novel diazabicyclo derivatives and their salts, and these compounds have been investigated for 5-HT at the 5-HT ₃ receptor. The present invention has been completed by finding that they selectively antagonize.

That is, the present invention has the following general formula (I)

[Chemical 2] [Wherein R ¹ is a hydrogen atom, a (C ₁ -C ₁₀ ) alkyl group, or (C
₃ -C ₁₀₎ alkenyl, (C _{3 ~C 6)} alkynyl group,
Cyclo (C ₃ -C ₇₎ alkyl group, a cycloalkyl (C ₃ -C ₆₎ alkyl (C ₁ -C ₄₎ alkyl group, (C ₁ -C ₆₎ alkoxy (C ₂ -C ₆₎ alkyl group, oxo ( C ₃ -C ₆₎ alkyl group, (C ₁ ~C ₆₎ alkoxycarbonyl (C ₁ ~C ₄₎
Alkyl group, (C ₁ -C ₆₎ alkoxycarbonyl group, acyl group, di (C ₁ -C ₆₎ alkylamino (C ₂ -C ₆₎ alkyl group, hydroxy (C ₂ -C ₆₎ alkyl group, halo ( C ₂ -C ₆₎ alkyl group, cyano (C ₁ -C ₄₎ alkyl group, heterocyclo (C ₁ -C ₄₎ alkyl group, an aryl group, heteroaryl (C ₁ -C ₄₎ alkyl group, an aryl (C ₁ To C ₄ ) alkyl group, and heteroaryl (C ₁
To C ₄ ) alkyl group and aryl (C _{1 to} C ₄ ) alkyl group have any one of (C ₁ to
It may be substituted with any one of C ₄ ) alkoxy group, nitro group, (C ₁ -C ₆ ) alkyl group, amino group and halogen atom, and R ² is a hydrogen atom or a (C ₁ -C ₁₀ ) alkyl group. And R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a (C ₁ -C ₁₀ ) alkyl group, a (C ₃ -C ₁₀ ) alkenyl group, an acyl group, a (C ₁ -C ₆ ) alkoxy (C ₂ ~ C ₆ )
An alkyl group, an aryl (C ₁ -C ₄ ) alkyl group,
An ortho-position, a meta-position of an aryl (C ₁ -C ₄ ) alkyl group,
Any of the para positions may be substituted with any of a (C ₁ -C ₄ ) alkoxy group, a nitro group, a (C ₁ -C ₄ ) alkyl group, an amino group and a halogen atom. However,
R ¹ is a hydrogen atom, an alkyl group, an unsubstituted benzyl group or a dimethylaminoethyl group, R ² is a hydrogen atom,
R ³ and R ⁴ are each a methyl group] or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof.

The alkyl group represented by R ¹ in the general formula (I) of the above-mentioned diazabicyclo derivative of the present invention includes methyl, ethyl, n-propyl, iso-propyl and n-propyl.
Butyl, iso-butyl, n-pentyl, neo-pentyl, n-hexyl, octyl, decyl group and the like can be mentioned, and as the alkenyl group, allyl, isopropenyl,
Decenyl, pentenyl, hexenyl, octenyl, butenyl groups and the like, alkynyl groups include butynyl, hexynyl, propynyl groups and the like, cycloalkyl groups, cyclopropyl, cyclopentyl,
Examples thereof include cyclohexyl and cycloheptyl groups, examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclohexylethyl groups, and examples of alkoxyalkyl groups include 2-methoxyethyl and 2-ethoxy. Examples thereof include an ethyl group, examples of an oxoalkyl group include a 2-oxopropyl group, examples of an alkoxycarbonylalkyl group include methoxycarbonylmethyl, butoxycarbonylmethyl group, etc., examples of an acyl group include acetyl, Examples thereof include propionyl, butyryl, hexanoyl and benzoyl groups. Examples of the dialkylaminoalkyl group include 2- (diethylamino) ethyl and 2-
(Dimethylamino) ethyl group and the like, and as the alkoxycarbonyl group, iso-butoxycarbonyl,
Examples thereof include a methoxycarbonyl group, examples of the hydroxyalkyl group include 2-hydroxypropyl and 2-hydroxyethyl group, and examples of the haloalkyl group include 2
-Chloropropyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl group and the like, the cyanoalkyl group and the like, cyanomethyl group and the like, the heteroarylalkyl group, 2-pyridylmethyl, 4,
6-diamino-2-triazinylmethyl group and the like, the aryl group includes phenyl, naphthyl group and the like, the heterocycloalkyl group includes piperidinyl, pyrrolidinyl group and the like, arylalkyl group or As the substituted arylalkyl group, benzyl, phenethyl, paramethoxybenzyl, metachlorobenzyl, orthonitrobenzyl, paraaminobenzyl,
Paranitrobenzyl, para-tert-butylbenzyl, parafluorobenzyl group and the like can be mentioned.

The alkyl group represented by R ² in the general formula (I) includes methyl, ethyl, n-propyl and iso.
-Propyl, n-butyl, iso-butyl, n-pentyl, neo-pentyl, n-hexyl groups and the like can be mentioned.

The alkyl groups represented by R ³ and R ⁴ in the general formula (I) include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
Examples thereof include n-pentyl, neo-pentyl and n-hexyl groups, examples of the alkenyl group include allyl, isopropenyl, pentenyl, hexenyl, octenyl and butenyl groups, and examples of the acyl group include acetyl, propionyl and butyryl. , Hexanoyl, benzoyl groups and the like, alkoxyalkyl groups such as 2-methoxyethyl, 2-ethoxyethyl groups and the like, and arylalkyl groups or substituted arylalkyl groups such as benzyl, phenethyl, para. Methoxybenzyl, metachlorobenzyl, orthonitrobenzyl, paraaminobenzyl, paranitrobenzyl, para-tert.
-Butylbenzyl, parafluorobenzyl group and the like can be mentioned.

The compound represented by the general formula (I) of the present invention is
It can be produced by various methods based on known synthetic reactions.

That is, the compound represented by the general formula (I) is basically represented by the following general formula (II)

[Chemical 3] (Wherein R ¹ has the above meaning) and an indazole-3-carboxylic acid or acid amide-forming reactive derivative thereof and the following general formula (III)

[Chemical 4] It can be obtained by reaction with a 3,9-diazabicyclo [3.3.1] nonane-7-amine derivative represented by

The amidation reaction in this case is represented by the following general formula (I
V)

[Chemical 5] Diindazolo [2,3-a, 2 ', 3'-d]
Pyrazine-7,14-dione (1H-indazole-3
-Carboxylic acid dimer) and a compound of the general formula (III) described above.

Furthermore, the compound of the present invention is the amidation of the compound of the general formula (II), the mixed acid anhydride or acid halide thereof or the compound of the general formula (IV) with the compound of the general formula (III). 1H-indazole-3-carboxylic acid and 3,9-diazabicyclo [3.
3.1] Regarding the acid amide with nonane-7-amine, the substituent R ¹ on the indazole ring, the substituent R ² bonded to the amide nitrogen atom, or the substituents R ³ and R ⁴ on the diazabicyclononane ring. In order to obtain the desired one of the above-mentioned general formula (I), they can be obtained by means of newly introducing these or modifying or changing existing groups.

The diazabicyclononane amine derivative represented by the general formula (III) described above is, for example, J. Org. Che.
m., 26 , 395 (1961), and N-N-bis (2,2-dimethoxyethyl) methylamine can be condensed to give 7-oxo-3,9-dimethyl-3,
9-diazabicyclo [3.3.1] nonane was converted to oxime with hydroxylamine and amination was conducted by catalytic reduction to give 3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane-7. -It can be prepared by a reaction such as an amine. The diazabicyclononanamine thus obtained is reacted with an amide-forming reactive derivative of indazolecarboxylic acid. Taking the case of using an indazolecarboxylic acid dimer as the amide-forming reactive derivative as an example, the series of reaction steps described above is shown in the following reaction scheme 1.

The desired product of interest thus produced is obtained by washing, extracting and purifying the reaction mixture.

Reaction scheme 1

[Chemical 6]

When an acid halide such as indazole-3-carboxylic acid chloride is used as the acid amide-forming reactive derivative of indazolecarboxylic acid represented by the general formula (II), diethyl ether or diisopropyl ether is used. , Tetrahydrofuran, dimethoxyethane, 1,4-dioxane, methylene chloride, chloroform or dimethylformamide, dimethylsulfoxide and the like in a non-aqueous organic solvent at a temperature range of −80 ° C. to the boiling point of the solvent, if necessary triethylamine, tri-n- In the presence of an inorganic or organic acid binder such as butylamine, pyridine, dimethylaniline, tetramethylurea, magnesium metal, n-butyllithium, lithium diisopropylamine, sodium amide, sodium hydride, sodium metal, etc. It is reacted with diazabicyclononane amine of formula (III). Then, the reaction mixture is washed, and the desired diazabicyclo derivative of the general formula (I) can be obtained through extraction and purification steps.

However, the diazabicyclo derivative obtained by the above-mentioned amidation reaction is introduced into the substituents R ^{1 to} R ⁴ and modified or changed to give a desired diazabicyclo derivative of the general formula (I). This can often be done from the viewpoint of the reactivity of these substituents, the ease of reaction operation, and the like.

For example, an amidation reaction product in which R ¹ and R ² are hydrogen is treated with an alkyl halide (eg methyl iodide or methoxybenzyl chloride) in the presence of a base such as sodium hydride or n-butyllithium. By doing so, the desired diazabicyclo derivative of the general formula (I) can be obtained by the reaction of converting R ¹ or R ¹ and R ² into an alkyl group. Also, R ²
The amidation reaction product in which R is hydrogen is treated with an alkyl halide such as methyl iodide in the presence of a base such as n-butyllithium to convert R ² into an alkyl group, and the desired general formula ( The diazabicyclo derivative of I) is obtained.

Further, a reaction for converting R ¹ into an acyl group by treating an amidation reaction product in which R ¹ is hydrogen with an acyl halide (eg, acetyl chloride) in the presence of a base such as sodium hydride. The desired diazabicyclo derivative of the general formula (I) is obtained. These reactions can be illustrated in Reaction Scheme 2.

Reaction scheme 2

[Chemical 7]

For compounds in which R ³ and / or R ⁴ are benzyl groups and the other substituents are lower alkyl groups, R ³ and / or R ³ are hydrogenated in the presence of a hydrogenation catalyst such as palladium. The benzyl group of ⁴ can be converted to hydrogen. This reaction is Reaction Scheme 3
Can be illustrated by.

Reaction scheme 3

[Chemical 8]

Similarly, the reduction reaction product in which R ³ and / or R ⁴ is hydrogen is treated with an alkyl halide, an acyl halide, or an acid anhydride in the presence of a base to give R ³ and / or R ^3. A desired diazabicyclo derivative of the general formula (I) is obtained by a reaction of converting R ⁴ into an alkyl group or an acyl group. This reaction can be illustrated in Reaction Scheme 4.

Reaction scheme 4

[Chemical 9]

When R ¹ is a hydroxyalkyl group, the corresponding carbonyl group-containing alkyl group is reduced, and when R ¹ is an amino-substituted phenyl group, the corresponding nitro-substituted phenyl group is reduced to give a compound of the desired general formula (I). It can be induced to an azabicyclo derivative.

Furthermore, when R ¹ is a 4,6-diamino-2-triazinylmethyl group, the desired azabicyclo derivative of the general formula (I) is obtained by reacting a compound in which R ¹ is a cyanomethyl group with dicyandiamide. Can be guided to.

The acid addition salt of the compound represented by the general formula (I) of the present invention means a compound in which an acid is added to the nitrogen atom at the 3-position and / or the 9-position of the azabicyclo ring in the general formula (I). To do. These acid addition salts are pharmacologically acceptable salts, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and oxalic acid. Organic salts such as salts, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates and methanesulfonates can be mentioned.

The quaternary ammonium salt of the compound represented by the general formula (I) is, for example, methyl iodide,
A lower alkyl halogenide such as methyl bromide, ethyl iodide and ethyl bromide, a lower alkyl sulfonate such as methyl methane sulfonate and ethyl methane sulfonate, a lower alkyl aryl sulfonate such as methyl p-toluene sulfonate and the like can be represented by the general formula (I).
And the quaternary ammonium salt added to the nitrogen atom at the 3-position and / or the 9-position of the diazabicyclo ring therein.

This quaternary ammonium chloride reaction can be carried out under various reaction conditions. For example, in an organic solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, benzene, toluene, xylene or dimethylformamide, dimethylsulfoxide, at -20 ° C.
A lower alkyl halide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, a lower alkyl sulfonate such as methyl methanesulfonate, ethyl methane sulfonate, methyl p- The desired quaternary ammonium salt can be formed by reacting a lower alkylaryl sulfonate such as toluene sulfonate and the like. Further, when a low boiling point solvent such as diethyl ether is used, or when a low boiling point reactant such as methyl chloride is used, it is preferable to carry out under pressure in a stainless steel sealed tube. Further, the above reaction can be carried out without solvent.

The compound represented by the general formula (I) and its acid addition salt and quaternary ammonium salt may exist in the form of a hydrate or a solvate, so that the hydrate and the solvate thereof may be present. Those are also included in the compound of the present invention.

Further, the compounds represented by the general formula (I) include stereoisomers and their compounds, as is clear from their chemical structures.

Specific examples of the diazabicyclo derivative represented by the general formula (I) of the present invention include the following compounds.

Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-allylindazole-3-carboxamide Endo-3,9-dimethyl-3,9-diazabicyclo [3. 3.3.1] Non-7-yl 1-cyclohexylmethylindazole-3-carboxamide endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-cyclopropylmethyl Indazole-3-carboxamide endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-methoxybenzyl) indazole-3-carboxamide endo-3,9-dimethyl -3,9-diazabicyclo [3.3.1] non-7-yl 1- (7-octenyl)
Indazole-3-carboxamide endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-propynyl)
Indazole-3-carboxamide

Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (3-methyl-2-butenyl) indazole-3-carboxamide Endo-3,9- Dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-nitrobenzyl) indazole-3-carboxamide Endo-3,9-dimethyl-3,9-diazabicyclo [3.3. 1] Non-7-yl 1-cyanomethylindazole-3-carboxamide endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-tert-butylbenzyl ) Indazole-3-carboxamide endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-oxopropyl) indazole-3-carboxamide Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (3-chlorobenzyl) indazole-3-carboxamide Endo-3,9-dimethyl-3,9- Diazabicyclo [3.3.1] non-7-yl 1- (2-nitrobenzyl) indazole-3-carboxamide

Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-pyridylmethyl) indazole-3-carboxamide Endo-3,9-dimethyl-3 , 9-Diazabicyclo [3.3.1] non-7-yl 1-methoxycarbonylmethylindazole-3-carboxamide endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7- Il 1- (2-ethoxyethyl) indazole-3-carboxamide endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-isobutoxycarbonylindazole-3-carboxamide endo -3,9-Dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-hydroxypropyl) indazole-3-carboxami Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-aminobenzyl) indazole-3-carboxamide Endo-3,9-dimethyl-3,9- Diazabicyclo [3.3.1] non-7-yl 1- (4,6-diamino-
2-triazinylmethyl) indazole-3-carboxamide

Endo-9-benzyl-3-methyl-3,
9-diazabicyclo [3.3.1] non-7-yl 1H
-Indazole-3-carboxamide endo-3-methyl-3,9-diazabicyclo [3.3.
1] Non-7-yl 1H-indazole-3-carboxamide endo-3-benzyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide endo- 9-Methyl-3,9-diazabicyclo [3.3.
1] Non-7-yl 1H-indazole-3-carboxamide endo-3-allyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide endo- 3- (4-fluorobenzyl) -9-methyl-
3,9-diazabicyclo [3.3.1] non-7-yl 1
H-indazole-3-carboxamide

Endo-3-acetyl-9-methyl-3,
9-diazabicyclo [3.3.1] non-7-yl 1H
-Indazole-3-carboxamide endo-3-isobutyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide endo-3- (2-ethoxyethyl) -9-methyl-
3,9-diazabicyclo [3.3.1] non-7-yl 1
H-indazole-3-carboxamide N- (endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) N-methyl 1-methylindazole-3-carboxamide

The compounds of the present invention can be administered orally or parenterally, usually in the form of pharmaceutical preparations. The form of the pharmaceutical preparation includes tablets, capsules, troches, syrups, granules, powders, injections, suspensions and the like. Further, it can be made into a double-layer tablet or a multi-layer tablet together with other drugs.
Furthermore, tablets are tablets that have been given a normal coating as necessary,
For example, sugar-coated tablets, enteric-coated tablets, and film-coated tablets can also be used.

In the case of preparing a solid preparation, solid additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, gum arabic, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol, stearic acid. , Magnesium stearate, talc and the like are used.

In the case of a semisolid preparation, vegetable or synthetic wax or fat is used.

In the case of liquid preparations, liquid additives such as sodium chloride aqueous solution, sorbitol, glycerin,
Olive oil, almond oil, propylene glycol, ethyl alcohol and the like are used.

The amount of active ingredient in these preparations is 0.
001 to 100% by weight, suitably 0.01 to 50% by weight in the case of preparations for oral administration, and 0.001 to 10% by weight in the case of injectable preparations.

The administration method and dose of the compound of the present invention are not particularly limited and may be appropriately selected depending on various dosage forms, degree of disease, age of patient, sex and the like.
The daily dose is 0.01 mg to 1000 mg.

Specific synthetic methods of the compounds of the present invention will be shown below as Examples.

Example 1 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-allylindazole-
3-carboxamide

[Chemical 10] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3
-Carboxamide (1.00 g, 3.19 mmol) in DMF
It was dissolved in (30 ml), 60% sodium hydride (0.153 g, 3.83 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes. Then, at room temperature, allyl bromide (0.463 g, 3.83 g)
mmol) was added and the mixture was stirred for 10 hours. The reaction solution is water (300 m
l) and extracted with ethyl acetate (100 ml x 3).
The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a crude product (1.03 g). This was recrystallized from ethanol to obtain the title compound (0.52 g).

Mp 163-164 ° C. ¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15Hz, 2H), 2.45 (s, 3)
H), 2.53 (s, 3H), 2.47-2.51 (m, 2H), 2.56-2.60 (m,
2H), 2.72 (d, J = 11Hz, 2H), 2.87 (bs, 2H), 4.62 (td,
J = 7, 10Hz, 1H), 4.99 (td, J = 2, 5Hz, 2H), 5.16 (d
d, J = 2, 17Hz, 1H), 5.24 (dd, J = 1, 10Hz, 1H), 6.03
(ddd, J = 5, 10, 17Hz, 1H), 7.20-7.29 (m, 1H), 7.36-
7.40 (m, 2H), 8.42 (d, J = 8Hz, 1H), 11.22 (d, J = 10H
z, 1H) IR (KBr) 2826, 2798, 1650, 1519, 1489, 1373, 1263,
1189, 788, 742cm ^-1

Example 2 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-allylindazole-
3-carboxamide hydrochloride Compound obtained in Example 1 (0.50 g, 1.41 mmol)
Was dissolved in a mixture of ethyl acetate (10 ml) and chloroform (3 ml), and 4N hydrochloric acid-ethyl acetate solution (1 ml) was added at room temperature.
Was added. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (0.60 g, 1.40 mmol). mp 129-130 ℃

Example 3 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-cyclohexylmethylindazole-3-carboxamide

[Chemical 11] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with cyclohexylmethyl bromide according to Example 1 and extracted from hexane-ethyl acetate. Recrystallisation gave the title compound.

Mp 155-156 ° C. ¹ H NMR (CDCl ₃ ) δ 0.98-1.07 (m, 2H), 1.16-1.21 (m,
3H), 1.50 (d, J = 15Hz, 2H), 1.60-1.73 (m, 5H), 1.9
4-2.04 (m, 1H), 2.48 (s, 3H), 2.54 (s, 3H), 2.45-
2.51 (m, 2H), 2.59 (dd, J = 3, 11Hz, 2H), 2.74 (d, J
= 11Hz, 2H), 2.88 (bs, 2H), 4.18 (d, J = 7Hz, 2H), 4.
64 (td, J = 7, 10Hz, 1H), 7.20-7.25 (m, 1H), 7.35-7.3
9 (m, 2H), 8.41 (d, J = 8Hz, 1H), 11.09 (d, J = 10Hz,
1H) IR (KBr) 2924, 2844, 2802, 1650, 1525, 1489, 145
1, 1335, 1274, 1217, 1177, 794, 751cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 152-154 ° C

Example 4 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-cyclopropylmethylindazole-3-carboxamide

[Chemical 12] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with cyclopropylmethyl bromide according to Example 1 to give hexane-ethyl acetate. Recrystallization was performed to obtain the title compound.

Mp 136-137 ° C. ¹ H NMR (CDCl ₃ ) δ 0.40 (m, 2H), 0.59 (m, 2H), 1.36
(m, 1H), 1.50 (d, J = 15Hz, 2H), 2.44-2.51 (m, 2H),
2.48 (s, 3H), 2.53 (s, 3H), 2.59 (dd, J = 3,11Hz, 2
H), 2.73 (d, J = 11Hz, 2H), 2.87 (bs, 2H), 4.26 (d,
J = 7Hz, 2H), 4.64 (td, J = 7, 11Hz, 1H), 7.20-7.25
(m, 1H), 7.35-7.39 (m, 2H), 8.42 (d, J = 8Hz, 1H), 1
1.13 (d, J = 11Hz, 1H) IR (KBr) 2926, 2798, 1642, 1516, 1491, 1372, 133
5, 1266, 1205, 1165, 1132, 794, 782, 760cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 235-237 ℃ (decomposition)

Example 5 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-methoxybenzyl) indazole-3-carboxamide

[Chemical 13] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with 4-methoxybenzyl chloride according to Example 1 and subjected to silica gel column chromatography. Graphography (chloroform-methanol-ammonia water =
20: 1: 0.05) to give the title compound.

Bubble solid ¹ H NMR (CDCl ₃ ) δ 1.46 (d, J = 15Hz, 2H), 2.35 (s, 3
H), 2.41-2.48 (m, 2H), 2.48 (s, 3H), 2.54 (d, J = 11
Hz, 2H), 2.67 (d, J = 11Hz, 2H), 2.81 (bs, 2H), 3.71
(s, 3H), 4.59-4.65 (m, 1H), 5.48 (s, 2H), 6.79-6.
80 (m, 2H), 7.10-7.12 (m, 2H), 7.18-7.24 (m, 1H),
7.27-7.33 (m, 2H), 8.43-8.45 (m, 1H), 11.23 (d, J =
11Hz, 1H) IR (KBr) 2930, 2836, 2802, 1650, 1614, 1515, 148
9, 1247, 1175, 1030, 789, 705cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 152-154 ° C

Example 6 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (7-octenyl) indazole-3-carboxamide

[Chemical 14] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with 8-bromo-1-octene according to Example 1 to give silica gel. Column chromatography (chloroform-methanol-ammonia water = 20:
Purification by 1: 0.05) to give the title compound.

Pale yellow oil ¹ H NMR (CDCl ₃ ) δ 1.26-1.35 (m, 6H), 1.49 (d, J = 15)
Hz, 2H), 1.91-2.02 (m, 4H), 2.44-2.50 (m, 2H), 2.4
8 (s, 3H), 2.53 (s, 3H), 2.56-2.60 (m, 2H), 2.72
(d, J = 11Hz, 2H), 2.86 (bs, 2H), 4.33-4.36 (m, 2H),
4.64 (td, J = 7,10Hz, 1H), 4.92 (dd, J = 2, 10Hz, 1
H), 4.97 (dd, J = 1, 17Hz, 1H), 5.77 (ddd, J = 7, 10,
17Hz, 1H), 7.21-7.25 (m, 1H), 7.34-7.39 (m, 2H),
8.42 (d, J = 8Hz, 1H), 11.11 (d, J = 10Hz, 1H) IR (neat) 2932, 2853, 2802, 1648, 1528, 1493, 146
4, 1376, 1271, 1218, 1178, 796, 753cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 114-116 ° C

Example 7 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-propynyl) indazole-3-carboxamide

[Chemical 15] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with propargyl chloride according to Example 1 to obtain the title compound.

¹ H NMR (CDCl ₃ ) δ 1.47 (d, J = 15Hz, 2
H), 1.92 (bs, 1H), 2.49 (s, 3H), 2.53 (s, 3H), 2.4
5-2.51 (m, 2H), 2.56-2.60 (m, 2H), 2.72 (d, J = 11H
z, 2H), 2.87 (bs, 2H), 4.59-4.65 (m, 1H), 5.73 (d,
J = 6Hz, 2H), 7.28-7.32 (m, 1H), 7.39-7.44 (m, 1H),
7.77 (d, J = 8Hz, 1H), 8.45 (d, J = 8Hz, 1H), 11.28
(d, J = 10Hz, 1H) IR (KBr) 2934, 2810, 1658, 1535, 1497, 1340, 1273,
1184, 799, 758cm ^-1

Further, a hydrochloride was prepared according to Example 2. m.
p.216-220 ℃

Example 8 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (3-methyl-2-butenyl) indazole-3-carboxamide

[Chemical 16] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with isoprenyl bromide according to Example 1 to obtain the title compound. ..

¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15Hz, 2
H), 1.75 (s, 3H), 1.78 (s, 3H), 2.43-2.52 (m, 2H),
2.47 (s, 3H), 2.53 (s, 3H), 2.57 (dd, J = 3, 11Hz,
2H), 2.73 (d, J = 11Hz, 2H), 2.86 (bs, 2H), 4.61-4.6
5 (m, 1H), 4.99 (d, J = 7Hz, 2H), 5.41 (m, 1H), 7.21
-7.25 (m, 1H), 7.37 (d, J = 4HZ, 2H), 8.42 (d, J = 8H
z, 1H), 11.16 (d, J = 11Hz, 1H) IR (KBr) 2930, 2805, 1652, 1530, 1522, 1493, 126
5, 1178, 753cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 133-135 ° C / 180 ° C / 210 ° C (decomposition)

Example 9 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-nitrobenzyl) indazole-3-carboxamide

[Chemical 17] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with 4-nitrobenzyl chloride according to Example 1 and subjected to silica gel column chromatography. Graphography (chloroform-methanol-aqueous ammonia = 3
0: 1: 0.05) to give the title compound.

Yellow oil ¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15Hz, 2H), 2.27 (s, 3
H), 2.43-2.56 (m, 4H), 2.53 (s, 3H), 2.66 (d, J = 11
Hz, 2H), 2.86 (bs, 2H), 4.63 (td, J = 7, 10Hz, 1H),
5.68 (s, 2H), 7.26-7.29 (m, 4H), 7.37 (d, J = 8Hz, 2
H), 8.15 (d, J = 9Hz, 2H), 8.46 (d, J = 8Hz, 1H), 11.1
1 (d, J = 11Hz, 1H) IR (neat) 2939, 2812, 1649, 1532, 1497, 1351, 126
3, 1221, 1180, 864, 794, 760cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 166-168 ℃ (decomposition)

Example 10 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-cyanomethylindazole-3-carboxamide

[Chemical 18] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with bromoacetonitrile according to Example 1 and subjected to silica gel column chromatography (chloroform). -Methanol-ammonia water = 10:
Purification by 1: 0.05) to give the title compound.

Mp 201-202 ° C. (recrystallized from hexane-ethyl acetate) ¹ H NMR (CDCl ₃ ) δ 1.47 (d, J = 15 Hz, 2H), 2.45-2.54
(m, 2H), 2.51 (s, 3H), 2.54 (s, 3H), 2.59-2.62 (m,
2H), 2.72 (d, J = 11Hz, 2H), 2.88 (bs, 2H), 4.61 (t
d, J = 7, 10Hz, 2H), 5.27 (s, 2H), 7.33-7.37 (m, 1
H), 7.44 (d, J = 8Hz, 1H), 7.50-7.54 (m, 1H), 8.47
(d, J = 8Hz, 1H), 11.37 (d, J = 10Hz, 1H) IR (KBr) 2938, 2840, 2798, 1640, 1525, 1491, 146
7, 1413, 1372, 1261, 1184, 1132, 785, 757cm ^-1

Further, a hydrochloride was prepared according to Example 2. m.
p. 157-159 ℃ (decomposition)

Example 11 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-tert-butylbenzyl) indazole-3-carboxamide

[Chemical 19] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with 4-tert-butylbenzyl bromide according to Example 1 and silica gel Purification by column chromatography (chloroform-methanol-aqueous ammonia = 20: 1: 0.05) gave the title compound.

Light yellow oil ¹ H NMR (CDCl ₃ ) δ 1.28 (s, 9H), 1.48 (d, J = 15Hz, 2
H), 2.30 (s, 3H), 2.43-2.50 (m, 2H), 2.52 (s, 3H),
2.54-2.69 (m, 2H), 2.86 (d, J = 7Hz, 2H), 2.92 (bs,
2H), 4.63 (td, J = 7, 10Hz, 1H), 5.54 (s, 2H), 7.12
(d, J = 8Hz, 2H), 7.21-7.25 (m, 1H), 7.31 (d, J = 8H
z, 2H), 7.33-7.34 (m, 2H), 8.43 (d, J = 8Hz, 1H), 1
1.20 (d, J = 11Hz, 1H) IR (neat) 2970, 2932, 2810, 1648, 1529, 1494, 127
6, 1263, 1180, 914, 795, 755, 738cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 171-173 ° C

Example 12 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-oxopropyl) indazole-3-carboxamide

[Chemical 20] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with chloroacetone according to Example 1 and reconstituted from hexane-ethyl acetate. Crystallization gave the title compound.

Mp 230-232 ° C. ¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15 Hz, 2H), 2.05 (s, 3
H), 2.39 (s, 3H), 2.42-2.51 (m, 2H), 2.53 (s, 3H),
2.57 (dd, J = 3, 11Hz, 2H), 2.69 (d, J = 11Hz, 2H),
2.87 (bs, 2H), 4.62 (td, J = 7, 10Hz, 1H), 5.08 (s,
2H), 7.26-7.32 (m, 2H), 7.42-7.46 (m, 1H), 8.47 (d,
J = 8Hz, 1H), 11.26 (d, J = 10Hz, 1H) IR (KBr) 2920, 2832, 1737, 1649, 1644, 1525, 149
2, 1373, 1314, 1268, 1173, 791, 743cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 169-171 ℃

Example 13 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (3-chlorobenzyl) indazole-3-carboxamide

[Chemical 21] According to Example 1, endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with chlorobenzyl chloride, and silica gel column chromatography ( Chloroform-methanol-aqueous ammonia = 10:
Purification by 1: 0.05) to give the title compound.

Mp 159-161 ° C. (recrystallized from hexane-ethyl acetate) ¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15 Hz, 2H), 2.29 (s, 3)
H), 2.53 (s, 3H), 2.44-2.56 (m, 4H), 2.68 (d, J = 11
Hz, 2H), 2.86 (bs, 2H), 4.63 (td, J = 7, 10Hz, 1H),
5.54 (s, 2H), 7.03 (d, J = 7Hz, 1H), 7.18 (s, 1H),
7.19-7.40 (m, 5H), 8.45 (d, J = 8Hz, 1H), 11.19 (d,
J = 11Hz, 1H) IR (KBr) 2924, 2802, 1646, 1617, 1521, 1475, 125
2, 1215, 1174, 1085, 783, 753cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p.141-143 ℃

Example 14 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-nitrobenzyl) indazole-3-carboxamide

[Chemical formula 22] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with 2-nitrobenzyl chloride according to Example 1 and subjected to silica gel column chromatography. Graphography (chloroform-methanol-aqueous ammonia = 2
0: 1: 0.05) to give the title compound.

Mp 174 to 175 ° C. (recrystallized from hexane-ethyl acetate) ¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15Hz, 2H), 2.17 (s, 3)
H), 2.51 (s, 3H), 2.43-2.53 (m, 4H), 2.63 (d, J = 11
Hz, 2H), 2.84 (bs, 2H), 4.62 (td, J = 7, 10Hz, 1H),
6.01 (s, 2H), 6.52 (m, 1H), 7.29-7.32 (m, 2H), 7.3
8-7.47 (m, 3H), 8.17-8.19 (m, 1H), 8.49 (d, J = 8Hz,
1H), 11.26 (d, J = 10Hz, 1H) IR (KBr) 2916, 2802, 1645, 1608, 1533, 1489, 133
7, 1269, 1186, 1177, 1134, 862, 787, 749, 727cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 154-156 ℃

Example 15 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-pyridylmethyl) indazole-3-carboxamide

[Chemical formula 23] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with 2-chloromethylpyridine according to Example 1 and subjected to silica gel column chromatography. Graphography (chloroform-methanol-aqueous ammonia = 20:
Purification by 1: 0.05) to give the title compound.

Mp 106-108 ° C. (recrystallized from hexane-ethyl acetate) ¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15 Hz, 2H), 2.29 (s, 3)
H), 2.44-2.55 (m, 4H), 2.52 (s, 3H), 2.67 (d, J = 11
Hz, 2H), 2.85 (bs, 2H), 4.62 (td, J = 7, 10Hz, 1H),
5.72 (s, 2H), 6.60 (d, J = 8Hz, 1H), 7.18-7.22 (m, 1
H), 7.24-7.29 (m, 1H), 7.35-7.39 (m, 2H), 7.54-7.58
(m, 1H), 8.45 (d, J = 8Hz, 1H), 8.60 (d, J = 4Hz, 1H),
11.28 (d, J = 10Hz, 1H) IR (KBr) 3042, 2908, 2824, 1645, 1635, 1599, 153
9, 1516, 1507, 1477, 1436, 1312, 1262, 1183, 958, 9
05, 788, 736cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 152-154 ° C

Example 16 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1-methoxycarbonylmethylindazole-3-carboxamide

[Chemical formula 24] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with methoxyacetyl chloride according to Example 1 and extracted from hexane-ethyl acetate. Recrystallisation gave the title compound.

Mp 149-151 ° C. ¹ H NMR (CDCl ₃ ) δ 1.46 (d, J = 15Hz, 2H), 2.41 (s, 3)
H), 2.40-2.53 (m, 2H), 2.53 (s, 3H), 2.57 (dd, J =
3, 11Hz, 2H), 2.71 (d, J = 11Hz, 2H), 2.86 (bs, 2H),
3.76 (s, 3H), 4.61 (td, J = 3, 10Hz, 1H), 5.13 (s,
2H), 7.27-7.33 (m, 2H), 7.41-7.45 (m, 1H), 8.44
(d, J = 8Hz, 1H), 11.27 (d, J = 11Hz, 1H) IR (KBr) 2916, 2802, 1708, 1651, 1510, 1489, 126
6, 1208, 1182, 905, 788, 746cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 154-156 ℃

Example 17 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-ethoxyethyl) indazole-3-carboxamide

[Chemical 25] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide was reacted with ethoxyethyl bromide according to Example 1 and silica gel column chromatography ( Chloroform-methanol-ammonia water = 15:
Purification by 1: 0.05) to give the title compound.

Light yellow oil ¹ H NMR (CDCl ₃ ) δ 1.10 (t, J = 7Hz, 3H), 1.48 (d, J =
15Hz, 2H), 2.48 (s, 3H), 2.44-2.50 (m, 2H), 2.53
(s, 3H), 2.57-2.61 (m, 2H), 2.72 (d, J = 11Hz, 2H),
2.87 (bs, 2H), 3.42 (q, J = 7Hz, 2H), 3.85 (t, J = 6H
z, 2H), 4.53 (t, J = 6Hz, 2H), 4.63 (td, J = 7, 10Hz, 1
H), 7.22-7.26 (m, 1H), 7.36-7.40 (m, 1H), 7.48 (d,
J = 8Hz, 1H), 8.40 (d, J = 8Hz, 1H), 11.16 (d, J = 11Hz,
1H) IR (neat) 2974, 2928, 2800, 1676, 1651, 1526, 149
2, 1373, 1268, 1189, 1128, 795, 753cm ^-1

Further, according to Example 2, a hydrochloride was prepared. m.
p. 190-193 ℃

Example 18 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl-1-isobutoxycarbonylindazole-3-carboxamide

[Chemical formula 26] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3
-Carboxamide (1.00 g, 3.19 mmol) in DMF
It was dissolved in (30 ml) and triethylamine (0.3 g, 3.
75 mmol) and 4-dimethylaminopyridine (0.1
5 g, 1.23 mmol) was added, and the mixture was stirred under ice cooling for 30 minutes. Then isobutyl chloroformate (0.51 g,
(3.75 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water (300 ml) and ethyl acetate (150 ml x 3) was added.
It was extracted with. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give crude product (0.8
7 g) was obtained. This product was subjected to silica gel column chromatography (chloroform-methanol-ammonia water =
15: 1: 0.05) to give the title compound (0.4
8 g) was obtained.

Pale yellow oil ¹ H NMR (CDCl ₃ ) δ 1.07 (d, J = 7Hz, 6H), 1.48 (d, J = 1
5Hz, 2H), 2.19 (sep, J = 7Hz, 1H), 2.44-2.50 (m, 2H),
2.52 (s, 3H), 2.53 (s, 3H), 2.59 (dd, J = 3Hz, 2H),
2.73 (d, J = 11Hz, 2H), 2.88 (bs, 2H), 4.30 (d, J = 7
Hz, 2H), 4.63 (td, J = 7, 10Hz, 1H), 7.39-7.43 (m, 1
H), 7.53-7.58 (m, 1H), 8.19 (d, J = 9Hz, 1H), 8.59
(d, J = 8Hz, 1H), 11.60 (d, J = 10Hz, 1H) IR (neat) 2937, 2815, 2250, 1772, 1750, 1662, 153
3, 1364, 1341, 1218, 1077, 760, 739cm ^-1

Further, according to Example 2, hydrochloric acid was salified. m.
p. 235-237 ° C

Example 19 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (2-hydroxypropyl) indazole-3-carboxamide

[Chemical 27] The product of Example 12 (2.00 g, 5.41 mmol) was dissolved in a mixture of methanol (40 ml) and chloroform (10 ml) and sodium borohydride (0.215) was added under ice cooling.
g, 5.68 mmol) was added. After stirring under ice cooling for 30 minutes and at room temperature for 14 hours, the solvent was evaporated, the residue was dissolved in chloroform (50 ml), and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a crude product (2.72 g). This product was subjected to silica gel column chromatography (chloroform-methanol-aqueous ammonia = 10:
1: 0.05) and the title compound (1.52 g)
Got

Mp 179 to 180 ° C. ¹ H NMR (CDCl ₃ ) δ 1.27 (d, J = 5Hz, 3H), 1.44 (d, J =
15Hz, 2H), 2.40-2.49 (m, 2H), 2.44 (s, 3H), 2.49
(s, 3H), 2.54 (dd, J = 3, 11Hz, 2H), 2.67 (d, J = 11Hz,
2H), 2.82 (bs, 2H), 3.22 (bs, 1H), 4.27-4.40 (m,
3H), 4.57-4.63 (m, 1H), 7.23-7.26 (m, 1H), 7.37-7.4
1 (m, 1H), 7.44 (d, J = 8Hz, 1H), 8.40 (d, J = 8Hz, 1
H), 11.09 (d, J = 10Hz, 1H) IR (neat) 3336, 2932, 2800, 1629, 1527, 1488, 137
2, 1265, 1194, 1128, 958, 787, 742cm ^-1

Further, according to Example 2, hydrochloric acid was added. m.
p. 157-159 ℃

Example 20 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4-aminobenzyl) indazole-3-carboxamide

[Chemical 28] The product of Example 9 (0.50 g, 0.96 mmol) was dissolved in a mixture of ethanol (4 ml) and concentrated hydrochloric acid (6 ml) and stannous chloride dihydrate (2.16 g) under ice cooling. , 9.60mmo
l) in ethanol solution (5 ml) was added. 30 under ice cooling
After stirring for 2 minutes at room temperature for 2 hours, the mixture was left overnight. The precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure. This was dissolved in water (30 ml), made alkaline with sodium hydroxide, and the aqueous layer was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure to give a brown oil (0.39 g). This was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia = 10: 1: 0.05) to obtain the title compound (0.14 g).

Mp 186-187 ° C. (recrystallized from ethyl acetate) ¹ H NMR (CDCl ₃ ) δ 1.48 (d, J = 15 Hz, 2H), 2.37 (s, 3
H), 2.43-2.58 (m, 4H), 2.53 (s, 3H), 2.70 (d, J = 11
Hz, 2H), 2.86 (bs, 2H), 3.66 (bs, 2H), 4.60-4.66
(m, 1H), 5.46 (s, 2H), 6.60 (d, J = 8Hz, 2H), 7.00
(d, J = 8Hz, 2H), 7.20-7.24 (m, 1H), 7.30-7.40 (m, 2
H), 8.41 (d, J = 8Hz, 1H), 11.19 (d, J = 10Hz, 1H) IR (neat) 3410, 3156, 2932, 2804, 1649, 1638, 161
9, 1525, 1510, 1485, 1312, 1176, 797, 749cm ^-1

Further, according to Example 2, hydrochloric acid was added. m.
p. 180-183 ℃ (decomposition)

Example 21 Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1- (4,6-diamino-
2-triazinylmethyl) indazole-3-carboxamide

[Chemical 29] The product of Example 10 (0.58 g, 1.64 mmol) and dicyandiamide (0.18 g, 2.14 mmol) were dissolved in ethylene glycol monomethyl ether (15 ml),
At room temperature, 0.2N potassium hydroxide ethylene glycol monomethyl ether solution (1 ml) was added. 90 ° C thereafter
After stirring for 5 hours, the precipitated crystals were collected by filtration and washed with warm water to obtain the title compound (0.38 g).

Mp> 300 ° C. ¹ H NMR (d-DMSO) δ 1.27 (d, J = 15Hz, 2H), 2.21 (s,
3H), 2.30-2.56 (m, 6H), 2.38 (s, 3H), 2.74 (bs, 2
H), 4.33-4.38 (m, 1H), 5.35 (s, 2H), 6.60 (bs, 4
H), 7.23 (t, J = 7Hz, 1H), 7.38-7.42 (m, 1H), 7.67
(d, J = 8Hz, 1H), 8.18 (d, J = 8Hz, 1H), 11.19 (d, J = 1
0Hz, 1H) IR (KBr) 3312, 3118, 2934, 2900, 2798, 1647, 161
0, 1538, 1532, 1463, 1318, 1227, 1181, 797, 749cm ^-1

Further, according to Example 2, hydrochloric acid was added. m.
p. 211-215 ° C

Example 22 Endo-3-benzyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide

[Chemical 30]

I) Synthesis of N, N-bis (2,2-dimethoxyethyl) benzylamine Bromoacetaldehyde dimethyl acetal (200 m
A mixture of l), benzylamine (69.2 ml) and potassium hydroxide (74.6 g) was heated at 100 ° C. for 6 hours.
The reaction solution was returned to room temperature, extracted with chloroform, the organic layer was dried over potassium carbonate, and the solvent was evaporated. The obtained black oily substance was purified by silica gel chromatography to obtain 161.13 g (yield 71.4%) of a reddish brown oily substance.

¹ H NMR (CDCl ₃ ) δ 1.18 (t, J = 7Hz, 12
H), 2.74 (d, J = 5Hz, 4H), 3.48 (dq, J = 10Hz, 4H), 3.6
3 (dq, J = 10Hz, 4H), 3.79 (s, 2H), 4.56 (t, J = 5Hz,
2H), 7.19-7.36 (m, 5H)

Ii) Synthesis of 3-benzyl-9-methyl-7-oxo-3,9-diazabicyclo [3.3.1] nonane N, N-bis (2,2-dimethoxyethyl) benzylamine (80. Hydrochloric acid (128 ml) and water (1400 m)
l) was added and the mixture was refluxed for 1.5 hours. This solution was added with citric acid (4
3.46 g), disodium hydrogen phosphate (92.84 g)
Then, the mixture was poured into a solution of water and water (1400 ml), methylamine hydrochloride (19.09 g) and acetonedicarboxylic acid (48.20 g) were added, and then 40% aqueous sodium hydroxide solution was added to adjust the pH to 5.5, and the mixture was allowed to stand at room temperature for 5 minutes. It was stirred for a day.

The reaction mixture was adjusted to pH 13 with sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained black oil was purified by silica gel chromatography to give the title compound (9.33 g).

Iii) 3-benzyl-7-hydroxyimino-9-methyl-3,9-diazabicyclo [3.3.1]
Synthesis of Nonane 3-Benzyl-9-methyl-7-oxo-3,9-diazabicyclo [3.3.1] nonane (9.33 g), hydroxylamine hydrochloride (3.98 g), pyridine (12.5 m)
The mixture of l) and ethanol was heated to reflux for 2 hours. After returning the reaction solution to room temperature, potassium carbonate (15 g) and water (8 ml) were added and stirring was continued for a while. The obtained suspension was filtered through Celite, and the solvent was evaporated under reduced pressure. 200 ml of chloroform was added to the obtained residue, this was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography and crystallized to give the title compound (3.87 g).

¹ H NMR (CDCl ₃ ) δ 2.26 (d, J = 16Hz, 1
H), 2.38 (dd, J = 6, 16Hz, 1H), 2.44-2.52 (m, 2H),
2.56 (s, 3H), 2.60-2.73 (m, 3H), 3.00-3.07 (m, 3
H), 3.40 (s, 2H), 7.20-7.31 (m, 5H)

Iv) Synthesis of endo-7-amino-3-benzyl-9-methyl-3,9-diazabicyclo [3.3.1] nonane 3-benzyl-7-hydroxyimino-9-methyl-3 was added to the autoclave. , 9-diazabicyclo [3.3.1] nonane (3.50 g), ammonium acetate (12.48 g)
And Raney Ni (W4) (50ml) were added, hydrogen pressure 120kg
Shake at 90 ° C./cm ² for 9 hours. The reaction solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. A 20% aqueous sodium hydroxide solution (100 ml) was added to the residue and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and the solvent was evaporated to give an oily substance (1.54 g). This product was used in the next experiment without purification.

V) endo-3-benzyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1
Synthesis of H-indazole-3-carboxamide Crude endo-7-amino-3-benzyl-9-methyl-
3,9-diazabicyclo [3.3.1] nonane (1.54
g) was dissolved in DMF (25 ml), and then diindazolo [2,3-a, 2 ', 3'-d] pyrazine-7,14-dione (0.90 g) and DMAP (about 0.06 g) were added. Stir overnight at room temperature. The insoluble material was removed by filtration through Celite, and the filtrate was concentrated. The obtained yellow oily matter was purified by silica gel chromatography to obtain the title compound (2.36 g).

¹ H NMR (CDCl ₃ ) δ 1.46 (d, J = 15Hz, 2
H), 2.46 (s, 3H), 2.50-2.43 (m, 2H), 2.58 (dd, J =
3, 11Hz, 2H), 2.70 (d, J = 11Hz, 2H), 2.82 (br, 2H),
3.82 (s, 2H), 4.69 (dt, J = 7, 7Hz, 1H), 7.11-7.48
(m, 8H), 8.43 (d, J = 8Hz, 1H), 10.72 (s, 1H), 10.82
(d, J = 10Hz, 1H) mp 183-185 ° C (hydrochloride)

Example 23 Endo-9-methyl-3,9-diazabicyclo [3.3.
1] Non-7-yl 1H-indazole-3-carboxamide

[Chemical 31] Endo-3-benzyl-9-methyl-3.9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide (1.56 g) was added to acetic acid (30 m).
After dissolving in 1), 6% of 10% Pd-C was added, and the mixture was shaken at room temperature for 4 hours in the presence of hydrogen gas (normal pressure). The reaction mixture was filtered through Celite and concentrated, and the obtained residue was purified by silica gel chromatography. The obtained solid was triturated in ethyl acetate and then collected by filtration to give the title compound (0.27).
g) was obtained.

¹ H NMR (CDCl ₃ -CD ₃ OD) δ 1.53 (d, J = 15H
z, 2H), 2.52-2.59 (m, 2H), 2.59 (s, 3H), 2.93 (d, J
= 10Hz, 4H), 3.33 (dd, J = 3, 12Hz, 2H), 4.63 (t, 7H)
z, 1H), 7.26 (t, J = 8Hz, 1H), 7.40 (t, J = 8Hz, 1H),
7.52 (d, J = 8Hz, 1H), 8.31 (d, J = 8Hz, 1H) mp 198-203 ° C (hydrochloride)

Example 24 Endo-9-benzyl-3-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide

[Chemical 32] i) 9-benzyl-3-methyl-7-oxo-3,9
-Synthesis of diazabicyclo [3.3.1] nonane N-N-bis (2,2-dimethoxyethyl) methylamine, benzylamine, and acetonedicarboxylic acid were synthesized in the same manner as in Example 22.

¹ H NMR (CDCl ₃ ) δ 2.20 (s, 3H), 2.27
(d, J = 16Hz, 2H), 2.44 (dd, J = 2, 10Hz, 2H), 2.55
(d, J = 10Hz, 2H), 2.62 (dd, J = 6, 16Hz, 2H), 3.20-3.
22 (m, 2H), 3.88 (s, 2H), 7.25-7.41 (m, 5H)

Ii) 9-Benzyl-7-hydroxyimino-3-methyl-3,9-diazabicyclo [3.3.1]
Nonane ¹ H NMR (CDCl ₃ ) δ 2.17 (s, 3H), 2.26-2.42 (m, 4
H), 2.55-2.69 (m, 3H), 3.00-3.04 (m, 3H), 3.84
(s, 2H), 7.23-7.39 (m, 5H)

Iii) Endo-7-amino-9-benzyl-3-methyl-3,9-diazabicyclo [3.3.1] nonane ¹ H NMR (CDCl ₃ ) δ 1.34 (d, J = 16Hz, 2H) , 2.25 (s,
3H), 2.36 (dd, J = 7,16Hz, 2H), 2.42 (dd, J = 3, 10H
z, 2H), 2.55 (d, J = 10Hz, 2H), 2.78-2.80 (m, 2H),
3.14 (t, J = 7Hz, 1H), 3.78 (s, 2H), 7.20-7.37 (m, 5
H)

Iv) endo-9-benzyl-3-methyl-3,9-diazabicyclo [3.3.1] non-7-yl
1H-indazole-3-carboxamide endo-7-amino-3-methyl-9-benzyl-3,
A solution of 9-diazabicyclo [3.3.1] nonane (3.6 g) in DMF (40 ml) was charged with diindazolo [2,3-a,
2 ', 3'-d] pyrazine-7,14-dione (2.5
g) and DMAP (0.1 g) were added, and the mixture was stirred at room temperature for 1 day. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. The obtained yellow oily substance was subjected to silica gel chromatography (mobile phase: methanol-chloroform) and then crystallized from isopropyl ether to obtain 4.7 g of the title compound as a pale yellow powder (yield 81%).

¹ H NMR (CDCl ₃ ) δ 1.49 (d, J = 15Hz, 2
H), 2.42 (s, 3H), 2.45 (dd, J = 6, 15Hz, 2H), 2.55
(dd, J = 3, 11Hz, 2H), 2.68 (d, J = 11Hz, 2H), 2.88 (b
road s, 2H), 3.85 (s, 2H), 4.69 (ddd, J = 3, 6, 10H
z, 1H), 7.22-7.28 (m, 5H), 7.32 (t, J = 7Hz, 1H), 7.
36-7.41 (m, 1H), 7.48 (d, J = 8Hz, 1H), 8.45 (d, J = 8
Hz, 1H), 10.60 (broad s, 1H), 11.41 (d, J = 10Hz, 1
H) IR (KBr): 3410, 1642, 1542, 1534, 1470, 1158, 91
8,758,702cm ^-1 (hydrochloride) mp 175-185 ° C (decomposition: hydrochloride)

Example 25 Endo-3-methyl-3,9-diazabicyclo [3.3.
1] Non-7-yl 1H-indazole-3-carboxamide

[Chemical 33] Endo-9-benzyl-3-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide (4.0 g) in acetic acid (80 ml)
10% Palladium on carbon (16 g) was added to the solution and shaken at room temperature for 30 minutes in the presence of hydrogen gas (normal pressure). After the catalyst was filtered off, the solvent was removed under reduced pressure. The obtained yellow oily substance was subjected to silica gel chromatography (mobile phase: methanol-methylene chloride-ammonia water) to obtain 2.2 g of the title compound as a white powder (yield 74%).

¹ H NMR (CD ₃ OD) δ 1.72 (d, J = 14 Hz, 2
H), 2.34 (dd, J = 7, 14Hz, 2H), 2.41 (dd, J = 3, 11Hz,
2H), 2.44 (s, 3H), 2.88 (d, J = 11Hz, 2H), 3.14 (bro
ad s, 2H), 4.52 (t, J = 7Hz, 1H), 7.23 (t, J = 10Hz, 1
H), 7.39 (t, J = 10Hz, 1H), 8.20 (d, J = 10Hz, 1H), 8.
22 (d, J = 10Hz, 1H) IR (KBr): 3425, 1665, 1542, 1162, 755cm ^-1 (hydrochloride) mp 215-220 ° C (decomposition: hydrochloride)

Example 26 End-3-allyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide

[Chemical 34] Endo-9-methyl-3,9-diazabicyclo [3.3.
1] Nona-7-yl 1H-indazole-3-carboxamide (0.20 g) was added to ethylene glycol (5 ml).
Then, 1 ml of allyl bromide was added and the mixture was heated under reflux for 3 hours. The reaction solution was diluted with chloroform, washed with an aqueous sodium hydroxide solution and water, dried over potassium carbonate, and evaporated under reduced pressure. The obtained oily matter was purified by silica gel chromatography to obtain the title compound (0.14 g).

¹ H NMR (CDCl ₃ ) δ 1.42 (d, J = 15Hz, 2
H), 2.39-2.51 (m, 4H), 2.46 (s, 3H), 2.71 (d, J = 11
Hz, 2H), 2.81-2.84 (m, 2H), 3.07 (d, J = 7Hz, 2H),
4.58-4.65 (m, 1H), 5.00 (d, J = 10Hz, 1H), 5.10 (d,
J = 17Hz, 1H), 6.10-6.21 (m, 1H), 7.30 (t, J = 8Hz, 1
H), 7.17 (t, J = 8Hz, 1H), 7.40 (d, J = 9Hz, 1H), 8.36
(d, J = 8Hz, 1H), 10.86 (d, J = 10Hz, 1H), 11.40 (s,
1H) mp 169-171 ° C (hydrochloride)

Example 27 End-3- (4-fluorobenzyl) -9-methyl-
3,9-diazabicyclo [3.3.1] non-7-yl 1
H-indazole-3-carboxamide

[Chemical 35] Synthesized according to the method of Example 26.

¹ H NMR (CDCl ₃ ) δ 1.49 (d, J = 15Hz, 2
H), 2.51 (s, 3H), 2.53-2.57 (m, 2H), 2.58-2.64 (m,
2H), 2.73 (d, J = 11Hz, 2H), 3.83 (s, 2H), 2.88 (s,
2H), 4.71 (dd, J = 7, 10Hz, 1H), 6.83-6.90 (m, 2H),
7.38-7.30 (m, 3H), 7.54-7.42 (m, 2H), 8.47 (d, J = 8
Hz, 1H), 10.16 (s, 1H), 10.75 (d, J = 10Hz, 1H) mp 173 to 175 ° C (hydrochloride)

Example 28 Endo-3-acetyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide

[Chemical 36] Endo-9-methyl-3,9-diazabicyclo [3.3.
1] Nona-7-yl 1H-indazole-3-carboxamide (0.20 g) was suspended in chloroform (10 ml), triethylamine (0.10 ml) and acetic anhydride (0.07 ml) were added, and the mixture was allowed to stand at room temperature for 5 minutes. After stirring, the solvent was distilled off under reduced pressure. Purification by silica gel chromatography gave the title compound (0.15 g).

¹ H NMR (CDCl ₃ ) δ 1.56 (d, J = 15Hz, 1
H), 1.69 (d, J = 15Hz, 1H), 2.13 (s, 3H), 2.51 (d, J =
8Hz, 1H), 2.55 (d, J = 7Hz, 1H), 2.58 (s, 3H), 3.11-
3.04 (m, 2H), 3.33 (dd, J = 3, 13Hz, 1H), 3.49 (d, J =
12Hz, 1H), 3.65 (dd, J = 4,12Hz, 1H), 4.18 (d, J = 14H
z, 1H), 4.58-4.55 (m, 1H), 7.20 (t, J = 8Hz, 1H), 7.3
3 (t, J = 8Hz, 1H), 7.48 (d, J = 8Hz, 1H), 7.67 (d, J =
9Hz, 1H), 8.29 (d, J = 8Hz, 1H), 12.54 (br, 1H) mp 268-269 ° C (hydrochloride)

Example 29 End-3-isobutyl-9-methyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3-carboxamide

[Chemical 37] Endo-9-methyl-3,9-diazabicyclo [3.3.
1] Nona-7-yl 1H-indazole-3-carboxamide (0.30 g) was dissolved in DMF (7.5 ml), and isobutyl bromide (2.75 g) and triethylamine (0.11 g) were added to the mixture to give about 80 The mixture was heated and stirred at 13 ° C for 13 hours. The reaction solution was diluted with chloroform, washed with an aqueous sodium hydroxide solution and water, dried over potassium carbonate, and the solvent was evaporated under reduced pressure. The obtained oily substance was purified by silica gel chromatography to give the title compound (0.25
g) was obtained.

¹ H NMR (CDCl ₃ ) δ 0.78 (d, J = 6Hz, 6H),
1.52 (d, J = 15Hz, 2H), 1.9-2.0 (m, 1H), 2.32 (d, J
= 7Hz, 2H), 2.4-2.6 (m, 4H), 2.53 (s, 3H), 2.78 (d,
J = 11Hz, 2H), 2.89 (s, 2H), 4.7-4.8 (m, 1H), 7.2-
7.5 (m, 3H), 8.34 (d, J = 8Hz, 1H), 10.49 (d, J = 10H
z, 1H), 11.2-11.3 (bs, 1H)

Example 30 End-3- (2-ethoxyethyl) -9-methyl-
3,9-diazabicyclo [3.3.1] non-7-yl 1
H-indazole-3-carboxamide

[Chemical 38] Synthesized according to the method of Example 27.

¹ H NMR (CDCl ₃ ) δ 1.16 (t, J = 7Hz, 3H),
1.47 (d, J = 15Hz, 2H), 2.4-3.0 (m, 10H), 2.53 (s,
3H), 3.44 (q, J = 7Hz, 2H), 3.79 (d, J = 6Hz, 2H), 4.6
-4.7 (m, 1H), 7.2-7.5 (m, 3H), 8.42 (d, J = 8Hz, 1H),
10.91 (d, J = 10Hz, 1H), 11.0-11.1 (bs, 1H)

Example 31 N- (endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) N-methyl 1-methylindazole-3-carboxamide

[Chemical Formula 39] Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl 1H-indazole-3
-Carboxamide (1.00 g, 3.19 mmol) with dry T
Dissolve in HF (30 ml) and under argon flow 1.6 M n
-Butyl lithium hexane solution (10.2 ml) was added. Iodomethane (1 ml) was added dropwise, and the mixture was allowed to stand at room temperature for 2
Reacted for hours. After extraction with chloroform, the organic layer is dried,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

¹ H NMR (CDCl ₃ ) δ 1.20-1.36 (m, 2H),
2.22 (s, 2H), 1.80-3.10 (m, 8H), 3.13 (s, 3H), 4.05
(s, 3H), 5.26-5.40 (m, 1H), 6.88-7.56 (m, 4H)

Pharmacological test for 5-HT ₃ antagonism The compounds prepared according to Examples 1 to 31 above were tested for antagonism to 5-HT at the 5-HT ₃ receptor.

Administration of 5-HT (serotonin) to the jugular vein of anesthetized rats produces transient bradycardia (von Bezo
ld Jarisch Reflex) (Paintal, AS., Physiol. Rev, 5
3, 159-210 (1973)). And, it is suggested that the 5-HT main reflex occurs via the 5-HT ₃ receptor by Richardson.
(Nature, 316, 126-131 (19
85)). Therefore, the effective and selective antagonism of 5-HT at the 5-HT ₃ receptor by the compounds of the present invention is
This can be verified by the inhibitory effect on this reflex. That is, rats were anesthetized with urethane (1 g / kg, ip), and blood pressure and heart rate were recorded from the left femoral artery. 5-HT (30
(μg / kg) was administered to the jugular vein, and the inhibitory rate was calculated from the bradycardia caused by 5-HT administration 5 minutes after the jugular administration of the compound of the present invention. In this test, all tests were conducted in the form of hydrochloride.

The test results of the compounds used in the test are shown in Table 1 below.
Shown in.

[0143]

[Table 1]

Finally, the specific forms of pharmaceutical preparations containing the compound of the present invention (all of which is a hydrochloric acid addition salt) as an active ingredient are shown below.

[Formulation Example 1] The components are uniformly mixed to obtain a powder for direct compression. This is molded into a tablet having a diameter of 6 mm and a weight of 100 mg with a rotary tableting machine.

Formulation Example 2 Granules (1 package) A: Compound of Example 10 1 mg Lactose 99 mg Corn starch 50 mg Crystalline cellulose 50 mg B: Hydroxypropyl cellulose 10 mg Ethanol 9 mg After uniformly mixing the components, The solution of B is added and kneaded, sized by extrusion granulation, and then dried by a dryer at 50 ° C. The dried granules have a particle size of 297 μm to 1460 μm
Granulate the sieved product. 200 mg per package
And

[Formulation Example 3] Sucrose, D-sorbitol, ethyl paraoxybenzoate,
Propyl paraoxybenzoate and the above active ingredients are dissolved in 60 g of warm water. After cooling, a solution of flavoring agent dissolved in glycerin and ethanol is added. Next, water is added to this mixture to make 100 ml.

[Formulation Example 4] Sodium chloride and the active ingredient are dissolved by adding distilled water to make the total volume 1.0 ml.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masashi Suzuki 2-23-16 Midorigaoka, Oi-cho, Iruma-gun, Saitama (72) Inventor Koichiro Hagiwara 247, Fujikubo, Miyoshi-cho, Iruma-gun, Saitama Castle Castle No. 8 2 Miyoshi 408 (72) Inventor Toru Hayakawa 3-4, Suehiro-cho, Kawagoe City, Saitama Prefecture (72) Inventor Takeo Arai 3-4-8, Suehiro-cho, Kawagoe City, Saitama Prefecture (72) Inventor Setsuko Mino Fujimi City, Saitama Prefecture Tsuruse Nishi 2-7-2-8

Claims (1)

[Claims] 1. A compound represented by the general formula (I): [Wherein R ¹ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkoxyalkyl group, an oxoalkyl group, an alkoxycarbonylalkyl group, an alkoxycarbonyl group, an acyl group, a dialkylaminoalkyl. A group, a hydroxyalkyl group, a haloalkyl group, a cyanoalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylalkyl group, an arylalkyl group, and an ortho position, a meta position, a para position of a heteroarylalkyl group and an arylalkyl group. Any of them may be substituted with any of an alkoxy group, a nitro group, an alkyl group, an amino group and a halogen atom, R ² is a hydrogen atom or an alkyl group, R ³ and R ⁴ are the same or different, and are hydrogen. Atom, alkyl group, alkenyl group An acyl group, an alkoxyalkyl group, an arylalkyl group, the ortho position of the aryl alkyl group, meta, or an alkoxy group of the para position,
Nitro group, lower alkyl group having 1 to 4 carbon atoms, amino group,
It may be substituted with any of halogen atoms. Provided that R ¹ is a hydrogen atom, an alkyl group, an unsubstituted benzyl group or a dimethylaminoethyl group, and R ²
Is a hydrogen atom, and R ³ and R ⁴ are methyl groups], or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof.