JPH0592980A - Pyrazolo(1,5-a)pyridine-3-carboxylic acid derivative, its production and use - Google Patents

Abstract

(57) [Summary] (Modified) [Structure] General formula (I) [Chemical formula 1] (Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, R ₃ represents an azabicyclo cyclic group containing a tertiary nitrogen atom, and Y represents —O— or —NH—) A pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative or a salt thereof, a method for producing the same, and a serotonin 3 receptor antagonist containing them as an active ingredient. Effect Since the compound (I) of the present invention has an excellent serotonin 3 receptor antagonistic activity, it can be advantageously used as an antiemetic agent, particularly as an antiemetic agent for suppressing nausea and vomiting due to side effects of anticancer agents. It can also be advantageously used as a psychotropic drug such as a gastrointestinal function regulator or anxiolytic.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel pyrazolo [1,5
-A] pyridine-3-carboxylic acid derivative, more specifically, a pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative useful as a medicine such as an antiemetic agent, anxiolytic agent, a method for producing the same, and the like. Regarding its use.

[0002]

2. Description of the Related Art It is known that compounds having serotonin receptor antagonistic activity are useful as neurotrophic agents, antiemetic agents, etc., and many reports have already been made on these compounds (EP 158,265 (JP-A 158,265). Sho 60-231677
No.), USP 4,886,808 (JP-A-61-275).
276), USP 4,882.327 (JP-A-63-
280061) etc.).

[0003]

However, it has been desired to broadly search and find compounds having the above-mentioned pharmacological actions and to provide them.

[0004]

Means for Solving the Problems The present inventors have synthesized various compounds and studied their pharmacological actions. As a result, pyrazolo [1,5-a] represented by the following formula (I)
The pyridine-3-carboxylic acid derivative has not been described in the literature,
Excellent serotonin 3 (5-Hydroxytryptamin 3; 5-H
The present invention was completed by discovering that it has T3) receptor antagonistic activity.

Therefore, the first object of the present invention is to provide the following general formula (I):

[Chemical 14] (Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, R ₃ represents an azabicyclo cyclic group containing a tertiary nitrogen atom, and Y represents —O— or —NH—) To provide a pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative. Further, another object of the present invention is to
It is intended to provide a method for producing a pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative (I). Still another object of the present invention is pyrazolo [1,5-a] pyridine-3-
It is intended to provide a serotonin receptor antagonist containing a carboxylic acid derivative (I) as an active ingredient.

The lower alkyl group in the groups R ₁ and R ₂ of the pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative (I) of the present invention is a straight or branched chain having 1 to 5 carbon atoms. An alkyl group is mentioned. As the lower alkyl group, a methyl group, an ethyl group, a propyl group and the like are particularly preferable. Also, as the replacement position,
In particular, the 7-position-substituted product is preferable, but an unsubstituted product in which both groups R ₁ and R ₂ are hydrogen atoms and a di-substituted product in which both groups R ₁ and R ₂ are lower alkyl groups are also preferred. R ₃ represents an azabicyclo cyclic group containing a tertiary nitrogen atom, and includes a quinuclidyl group, 8-methyl-8-azabicyclo [3.2.1] octyl group, 9-methyl-9-azabicyclo [3 [3.1] Nonyl group and the like are preferable, and quinuclidyl group is particularly preferable. The pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative (I) having a quinuclidyl group may be in a racemic form or an optically active form, but the S form is particularly preferable. 8-methyl-8-azabicyclo [3.2.1] octyl group or 9-
As the pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative (I) having a methyl-9-azabicyclo [3.3.1] nonyl group, its endo form is preferable. Y is-
A compound which shows O- or -NH-, but is generally -O-, has a higher affinity for the serotonin 3 receptor. Further, in the body, the compound which is -NH- is more resistant to hydrolysis and is advantageous.

The pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative (I) of the present invention is represented by the following formula, for example:
It can be obtained by reacting a pyrazolo [1,5-a] pyridine-3-carboxylic acid compound (II) or its reactive derivative with an azabicyclo compound (III).

[0008]

[Chemical 15] (In the formula, R ₁ , R ₂ , R ₃ and Y have the above-mentioned meanings)

The reaction of the pyrazolo [1,5-a] pyridine-3-carboxylic acid compound (II) or its reactive derivative with the azabicyclo compound (III) should be carried out according to a known esterification or amidation reaction. You can

Examples of the reactive derivative of the pyrazolo [1,5-a] pyridine-3-carboxylic acid compound (II) include its acid halide, acid anhydride, acid azide, active ester, active amide and the like. Preferred examples include acid chlorides, acid bromides, acetic acid, pivalic acid, isovaleric acid, trichloroacetic acid, mixed acid anhydrides with carbonic acid monoalkyl ester, p-nitrophenyl ester, and 2,4.
-Active esters such as dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, 1-hydroxy-1H-pyridone, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, active amides such as pyrazole, imidazole, dimethylpyrazole and benzotriazole Is mentioned.

Further, in this reaction, pyrazolo [1,5
When -a] pyridine-3-carboxylic acid (II) is used in the form of a free acid, it is preferable to carry out the reaction in the presence of a binder, and examples of the binder include N, N-dicyclohexyl. Carbodiimide compounds such as carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, diphenylphosphoryl azide , Benzotriazolyl-N-hydroxytris (dimethylamino) phosphonium hexafluorophosphide salt, reagents such as carbonyldiimidazole, amide compounds such as N-methylformamide, N, N-dimethylformamide, and thionyl chloride, phosphorus oxychloride. , Phosgene, etc. Like reagent (the so-called Vilsmeier reagent) produced by reaction with androgenic compound. Other known condensing agents can also be used.

Among the reactive derivatives in this reaction, the reaction using an acid halide and an acid anhydride may be carried out in the presence of a deoxidizing agent. As the deoxidizing agent, for example, organic bases or inorganic bases such as triethylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylaniline, N-methylmorpholine, and pyridine are used.

The ratio of the pyrazolo [1,5-a] pyridine-3-carboxylic acid compound (II) or its reactive derivative and the azabicyclo compound (III) may be theoretically equimolar, but usually it is normal. The azabicyclo compound (III) is used in excess. The amount is at most about 5 times the molar amount.

This reaction is usually carried out in a solvent that does not adversely influence the reaction, and chloroform, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, acetone or a mixed solvent thereof is used as the solvent.

The reaction temperature is not particularly limited, but usually the reaction proceeds at room temperature sufficiently. The reaction time is the reaction temperature, the pyrazolo [1,5-a] pyridine-3-carboxylic acid compound (II)
Alternatively, it depends on the type of the reactive derivative thereof and cannot be generally specified, but it is up to about 24 hours.

Of the starting materials, pyrazolo [1,5-a]
Pyridine-3-carboxylic acid compound (II) is a known compound or a compound which can be easily produced from a known compound. For example, 4- and 6-position lower alkyl substitutions are described in Journal of Chemical Society; Perkin.
According to the method disclosed in Trans Actions Part 1 (JCS PerkinI), pages 406 to 409 (1975), the 5-position lower alkyl substituent is (JCS PerkinI, No. 2).
580-2583 (1973)) in accordance with the method disclosed in the Journal of Organic Chemistry.
Chemistry), Vol. 33, No. 5, 2062-206
According to the method disclosed on page 4 (1968),
The 2,7-position lower alkyl-substituted product can be produced according to the method disclosed in Pharmaceutical Journal, Vol. 91, No. 11, pp. 1154 to 1157 (1971).

On the other hand, as the azabicyclo compound (III) used in the reaction, for example, the following formula (IV)

[Chemical 16] (Wherein Y has the above-mentioned meaning) and a compound of formula (V)

[Chemical 17] (Wherein Y, Z and n have the above-mentioned meanings), and examples of the compound (V) include:
8-Methyl-8-azabicyclo [3.2.1] octane-
3-ol, 8-methyl-8-azabicyclo [3.2.
1] octane-3-amine, 9-methyl-9-azabicyclo [3.3.1] nonan-3-amine and the like.
Of these, those having an end type structure are preferable.
In addition, the azabicyclo compound (III) may be a reactive derivative suitable for this production.

Of these, for example, 3-aminoquinuclidine, 3-quinuclidinol and endo-8-methyl-
8-Azabicyclo [3.2.1] octane-3-ol (tropine) is a compound listed in the reagent manufacturer's catalog and is readily available. In addition, endo-8-methyl-8-azabicyclo [3.2.1] octane-3-amine and endo-9-methyl-9-azabicyclo [3.2.1] nonan-3-amine are also known compounds. , Journal of American Chemical Society (J. Am. Chem.soc), Vol. 79, page 4194 (1957) and European patent (Eur. Pat. Appl.
It can be manufactured by the method of EP13.138,) (1979).
Further, (S) -3-aminoquinuclidine and (R) -3-
Aminoquinuclidine can be obtained by the method of JP-A-63-196583 (EP 280,603), and (S) -3-quinuclidinol and (R) -3-quinuclidinol can be obtained by the European Journal of Medicinal Chemistry ( Eur.J. Med. Chem.), Volume 14, 111-114
It can be produced by the method described on page (1979).

The compound (I) of the present invention produced by the above method can be further purified by known purification methods such as column chromatography and recrystallization.

Further, the obtained compound (I) of the present invention can be converted to a pharmaceutically acceptable non-toxic salt thereof, if necessary. Examples of such salts include hydrochloric acid, sulfuric acid,
Inorganic acid salts such as phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid,
Examples thereof include salts of organic acids such as malic acid, glutamic acid, aspartic acid and methanesulfonic acid.

As is clear from the fact that any compound of the compound (I) of the present invention was not administered to rats (3 animals) by intravenous administration of 30 mg / kg, it was safe to use as a drug. It can be called a compound.

To use the compound of the present invention as a medicine,
This may be formulated and usually administered orally or parenterally, such as injection including infusion.
Although it varies depending on the age, weight, symptoms, etc. of the recipient, it is generally about 0.1 mg to 100 mg / kg per day for an adult.

The dosage form for the above formulation is a tablet,
Pills, powders, granules, capsules, injections and the like can be mentioned. For the production thereof, various carriers corresponding to these preparations, for example, oral preparations such as tablets, granules and capsules are starch. Excipients such as lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, and inorganic salts,
Binders such as starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol, starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose Disintegrators such as hydroxypropyl cellulose, sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, surfactants such as polysorbate 80, talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, etc. Lubricants, fluidity enhancers, flavoring agents, coloring agents, fragrances and the like can be used.

The compound (I) of the present invention or a salt thereof can also be used as a suspension, emulsion, syrup or elixir.

As a diluent for the parenteral agent, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like can be generally used. Furthermore, if necessary, a bactericidal agent, a preservative,
Stabilizers, isotonic agents, soothing agents and the like may be added.

[0026]

[Effects and effects of the invention] As will be apparent from the test examples described below, the compound (I) of the present invention has an excellent serotonin 3 receptor antagonistic activity, so that it suppresses nausea and vomiting due to side effects of an antiemetic drug, especially an anticancer drug. Can be advantageously used as an antiemetic agent. It can also be advantageously used as a psychotropic drug such as a gastrointestinal function regulator or anxiolytic.

[0027]

EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples.

Example 1 N- (1-azabicyclo [2.2.2] oct-3-yl) -3-pyrazolo [1,5-a] pyridinecarboxamide <N- (3-quinuclidinyl) -3- Synthesis of Pyrazolo [1,5-a] pyridinecarboxamide>: 3-
1 g of aminoquinuclidine dihydrochloride (manufactured by Janssen) was neutralized with a 5N NaOH aqueous solution, extracted with chloroform, dried over Na ₂ SO ₄ , and then chloroform was distilled off. Meanwhile, The Journal of Organic Chemistry, Vol. 33,
No. 5, pp. 2062 to 2064 (1968), 3-pyrazolo [1.5-a] pyridinecarboxylic acid (0.27 g, 1.7 mmol) prepared by adding SOCl _{2 (} 3 ml) was refluxed for 30 minutes. After distilling off excess SOCl ₂ , the above-mentioned 3-aminoquinuclidine dissolved in 5 ml of chloroform was added to this residue under ice cooling, and the mixture was stirred at room temperature for 1 hour.
Stir for 2 hours. 2N HCl was added to the reaction solution, the hydrochloric acid layer was made alkaline with Na ₂ CO ₃ , water was distilled off, and the mixture was extracted with chloroform. After drying with Na ₂ SO ₄ , the solvent was evaporated and the residue was subjected to silica gel column chromatography to obtain 0.4 g (yield 88%) of the title compound from a chloroform-methanol (20: 1) eluate.

The compound obtained above was dissolved in anhydrous benzene,
HCl gas was introduced under ice-cooling, and the released crystals were collected by suction filtration and recrystallized from benzene-methanol to obtain N- (3-quinuclidinyl) -3-pyrazolo [1,5-a] pyridinecarboxamide hydrochloride. It was MS (m / z): 270

Reference Example 1 Synthesis of 5-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid: JCS Perkin I, pp. 2580-2583 (1973).
Ethyl 5-methylpyrazolo [1,5-a] pyridine-3-carboxylate prepared by the method described in 1.
5g NaOH aqueous solution 10m to 00g (4.9mmol)
1 and 3 ml of methanol were added, and the mixture was stirred at room temperature for 24 hours. After the reaction, the solvent was distilled off, the residue was dissolved in water,
Washed with benzene. The aqueous layer was acidified with concentrated hydrochloric acid and the precipitated crystals were collected by filtration and washed with water. Yield 0.60g (3.4
mmol) (70% yield)

[0031] Melting point: two hundred thirty-two to two hundred thirty-four ° C. Elemental analysis (as _{C 9 H 8 N 2 0 2} ): Calculated; C 61.36; H 4.58; N 15.90 Found; C 61.11; H 4.57; N 15.78 IRν max cm ^-1 (KBr): 1654 (C = 0)

Example 2 5-Methyl-N- (1-azabicyclo [2.2.2] oct-3-yl) -3-pyrazolo [1,5-a] pyridinecarboxamide <5-methyl-N- Synthesis of (3-quinuclidinyl) -3-pyrazolo [1,5-a] pyridinecarboxamide>: 3-aminoquinuclidine dihydrochloride 1 g
Was neutralized with 5N NaOH aqueous solution, extracted with chloroform, dried over Na ₂ SO ₄ , and then chloroform was distilled off. On the other hand, 5-methyl-3-pyrazolo [1,5 obtained in Reference Example 1
-A] Pyridinecarboxylic acid (0.2 g) was dissolved in thionyl chloride (3 ml) and refluxed for 30 minutes. The above-mentioned 3-aminoquinuclidine was added to the acid chloride obtained after the removal of thionyl chloride by distillation, and the mixture was stirred in 5 ml of chloroform overnight. The reaction mixture was extracted with 2N HCl aqueous solution, and the hydrochloric acid layer was added with Na ₂
It was made alkaline with CO ₃ and the water was distilled off. The residue was extracted with chloroform, the extract was dried over Na ₂ SO _4, the residue was subjected obtained by distilling off the chloroform to a silica gel _{column, CHCl 3 -MeOH (20: 1} ) The title compound from the fraction eluted 0.15 g (yield 47.1%) was obtained. Melting point: 100-102 ° C

Example 3 6-Methyl-N- (1-azabicyclo [2.2.2] oct-3-yl) -3-pyrazolo [1,5-a] pyridinecarboxamide <6-methyl-N- Synthesis of (3-quinuclidinyl) -3-pyrazolo [1,5-a] pyridinecarboxamide>: 3-aminoquinuclidine dihydrochloride.
9 g was neutralized with NaOH solution, extracted with chloroform,
After drying, chloroform was distilled off. On the other hand, JCS, Pe
6-Methyl-3-pyrazolo [1,5-a] pyridinecarboxylic acid prepared according to rkin I, pp. 406-409 (1975).
18 g was dissolved in 2.7 ml thionyl chloride and refluxed for 30 minutes. The above-mentioned 3-aminoquinuclidine was added to the acid chloride obtained after evaporation of thionyl chloride, and chloroform 5 ml was added.
The mixture was stirred overnight. The reaction mixture was extracted with 2N HCl, the hydrochloric acid layer was made alkaline with Na ₂ CO ₃ and the water was distilled off. The residue was extracted with chloroform, and the extract was extracted with Na
_After drying with ₂ SO ₄ , chloroform was distilled off. The residue was applied to a silica gel column, and CHCl ₃ -MeOH (2
0: 1) 0.15 g of the title compound (yield 5
4.4%). Melting point: 142-144 ° C

Example 4 7-Methyl-N- (1-azabicyclo [2.2.2] oct-3-yl) -3-pyrazolo [1,5-a] pyridinecarboxamide <7-methyl-N- Synthesis of (3-quinuclidinyl) -3-pyrazolo [1,5-a] pyridinecarboxamide>: 3-aminoquinuclidine dihydrochloride 1 g
Was neutralized with NaOH solution, extracted with chloroform, dried and then the chloroform was distilled off. On the other hand, J. Org, Chem., 3
7-Methyl-3-pyrazolo [1,5-a] pyridinecarboxylic acid prepared according to Vol. 3, No. 5, 2062-2064 (1968)
0.2 g was dissolved in 3 ml of thionyl chloride and refluxed for 30 minutes. After thionyl chloride was distilled off, the above-mentioned 3-aminoquinuclidine was added to the obtained acid chloride, and chloroform 5 m
The mixture was stirred overnight in 1 liter. The reaction mixture was extracted with 2N HCl, the hydrochloric acid layer was made alkaline with Na ₂ CO ₃ and the water was distilled off. The residue was extracted with chloroform. The extract is Na
After drying over ₂ SO ₄ and distilling off chloroform, the obtained residue was applied to a silica gel column, and CHCl ₃ -MeOH (2
0: 1) 0.26 g of the title compound from the eluate (yield 82
%) Was obtained.

¹ H-NMR (CDCl ₃ , CD ₃ OD)
δ; 8.29 (1H, s, C ² -H), 8.19 (1H, d, J
= 8.4 Hz, C ⁴ -H) 7.31 (1H, dd, J = 8.4 Hz, J = 6.8 Hz, C ⁵
-H) 6.79 (1H, d, J = 6.8Hz, C 6 -H), 4.14-
4.28 (1H, m, quinuclidine 3-H), 1.46-
3.48 (11H, m, quinuclidine H) 2.78 (3H,
_{^{s, C 7 -CH 3) MS}} (m / e): 284 (M +) IRνmax cm -1: 1637 (C = O) Melting point: 198-200 ° C.

Reference Example 2 (1) Synthesis of ethyl 2-methyl-3-pyrazolo [1,5-a] pyridine carboxylate: 1-aminopyridinium prepared according to Org. Syn., Vol. 1, p. 43 (1963). Iodide (2.0 g, 9 mmol) in ethanol (100 m
L) was added K ₂ CO ₃ (3.0 g, 21.4 mmol),
After stirring at room temperature for 30 minutes, ethyl acetoacetate (1.8
g, 13.8 mmol) was added and the mixture was further stirred for 24 hours. After K ₂ CO ₃ was filtered off, ethanol was distilled off, water was added to the resulting residue, and the mixture was extracted with benzene. After distilling off benzene, the resulting residue was applied to a silica gel column,
The crystals obtained from the petroleum benzine-benzene (2: 1) eluate were recrystallized from petroleum benzine to give 0.74 of the title compound.
g (yield 42%) was obtained. Melting point: 93-94 ° C

Reference Example 2 (2) Synthesis of 2-methyl-3-pyrazolo [1,5-a] pyridinecarboxylic acid: ethyl 2-methyl-3-pyrazolo [1,
A small amount of methyl alcohol was added to an aqueous solution of 5-a] pyridinecarboxylate (0.356 g) in 5N NaOH (10 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was washed with benzene, acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by suction filtration. The obtained crystals were dried and then recrystallized from benzene to obtain 0.16 g (52.4%) of the title compound. Melting point: 235-237 ° C (decomposition)

Example 5 2-Methyl-N- (1-azabicyclo [2.2.2] oct-3-yl) -3-pyrazolo [1,5-a] pyridinecarboxamide <2-methyl-N- Synthesis of (3-quinuclidinyl) -3-pyrazolo [1,5-a] pyridinecarboxamide>: 3-aminoquinuclidine dihydrochloride.
7 g was neutralized with NaOH solution and extracted with chloroform,
After drying, chloroform was distilled off. On the other hand, Reference Example 2
2-Methyl-3-pyrazolo [1,5-obtained in (2)
a] Pyridinecarboxylic acid 0.14 g of thionyl chloride 2.
It was dissolved in 1 ml and refluxed for 30 minutes. After the thionyl chloride was distilled off, the above-mentioned 3-aminoquinuclidine was added to the obtained acid chloride, and the mixture was stirred overnight in 5 ml of chloroform.
The reaction mixture was extracted with 2N HCl and the hydrochloric acid layer was extracted with Na ₂
It was made alkaline with CO ₃ and the water was distilled off. The residue was extracted with chloroform, the extract was dried over Na ₂ SO _4, the residue was subjected obtained by distilling off the chloroform to a silica gel _{column, CHCl 3 -MeOH (20: 1} ) The title compound from the fraction eluted Obtained 0.15 g (66.8%).

¹ H-NMR (CDCl ₃ , CD ₃ OD) δ;
8.40 (1H, d, J = 7.0Hz, C 7 -H), 8.01
(1H, d, J = 9.2Hz , C 4 -H), 7.35 (1H, d
d, J = 9.2Hz, J = 6.8Hz, C 5 -H), 6.89
(1H, dd, J = 7.0Hz , J = 6.8, C 6 -H), 4.
16-4.28 (1H, m, quinuclidine 3-H), 1.5
5-3.48 (11H, m, quinuclidine H) 2.68
^{(3H, s, C 2 -CH} 3) MS (m / e): 284 (M +) IRνmax cm -1: 1614 (C = O) Melting point: 124-125 ° C.

Example 6 End-8-methyl-8-azabicyclo [3.2.1] oct-3-yl pyrazolo [1,5-a] pyridin-3
-Carboxylate Synthesis: Journal of Organic Chemistry, Vol. 33, No. 5, 2062-2.
0.2 g of 3-pyrazolo [1,5-a] pyridinecarboxylic acid prepared according to the description of 064 (1968) was dissolved in 2 ml of thionyl chloride and refluxed for 1 hour. After the thionyl chloride was distilled off, 0.2 g of endo-8-methyl-8-azabicyclo [3.2.1] octane-3-ol (tropine; manufactured by Aldrich) was added, and chloroform (3.5 ml) was added.
Refluxed in overnight. Add water with stirring and add Na ₂ CO ₃
The residue obtained by distilling off the chloroform layer was applied to a silica gel column, and 0.09 g (yield 25.
5%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.50
(1H, d, J = 7Hz), 8.25 (1H, s), 8.15
(1H, d, J = 10Hz), 7.42 (1H, dd, J = 1)
0Hz, J = 8Hz), 6.96 (1H, dd, J = 7Hz,
J = 8 Hz), 5.15-5.35 (1H, m), 3.10-
3.40 (2H, m), 2.35 (3H, s), 1.50-2.
30 (8H, m) M S (m / e): 285 (M ⁺ ) IRνmax cm ^-1 (KBr): 1692 (C = O)

Example 7 Synthesis of endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 7-methylpyrazolo [1,5-a] pyridin-3-carboxylate: Journal of・
Organic Chemistry (The Journal of Orga
nicChemistry) Volume 3, Issue 5, 2062-2064
7-methyl-3 prepared according to the description on page (1968).
-Pyrazolo [1,5-a] pyridinecarboxylic acid 0.4 g
Was dissolved in 4 ml of thionyl chloride and refluxed for 30 minutes. Thionyl chloride was distilled off, 0.32 g of endo-8-methyl-8-azabicyclo [3.2.1] octane-3-ol (manufactured by Aldrich) was added, and the mixture was added to 2 ml in 5 ml of chloroform.
Refluxed for 4 hours. 0.19 g of the title compound was obtained as a powder from the eluate of a chloroform-methanol mixed solution (chloroform: methanol = 50: 1). (Yield 28%)
Got

¹ H-NMR (CDCl ₃ ) δ: 8.27
(1H, s), 8.00 (1H, d, J = 8.4Hz), 7.2
6 (1H, dd, J = 8.4Hz, J = 7.8Hz), 6.7
4 (1H, d, J = 7.8Hz), 4.95-5.43 (1
H, m), 2.97-3.50 (2H, m), 2.76 (3H,
s), 2.38 (3H, s), 1.55-2.65 (8H,
m) M S (m / e): 299 (M ⁺ ) IR ν max cm ^-1 (KBr): 1694 (C = O)

Example 8 Synthesis of endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 7-methyl-pyrazolo [1,5-a] pyridine-3-carboxamide: 7- Methyl-3-
0.4 g of pyrazolo [1,5-a] pyridinecarboxylic acid was dissolved in 4 ml of thionyl chloride and refluxed for 30 minutes. After the thionyl chloride was distilled off, endo-8-methyl-8-azabicyclo [3.2.1] octan-3-amine (J. Am.
m. soc. 79, 4194, (1957)) 0.56 g and triethylamine 0.4 g were added, and the mixture was refluxed in 7 ml of chloroform for 24 hours. Water and Na ₂ CO ₃ were added, the chloroform layer was taken, dried over Na ₂ SO ₄ , the solvent was distilled off, and the residue was subjected to silica gel chromatography to obtain a chloroform-methanol mixture (chloroform: methanol = 30:
1) 0.52 g (yield 76.7%) of the title compound was obtained from the eluate as a powder.

¹ H-NMR (CDCl ₃ ) δ: 8.18
(1H, d, J = 8.4Hz), 8.13 (1H, s), 7.2
6 (1H, dd, J = 8.4Hz, J = 7.8Hz), 6.7
7 (1H, d, J = 7.8Hz), 4.21-4.70 (1
H, m), 2.95-3.40 (2H, m), 2.76 (3H,
s), 2.36 (3H, s), 1.52-2.41 (8H,
m) M S (m / e): 298 (M ⁺ ) IRνmax cm ^-1 (KBr): 1637 (C = 0)

Example 9 Synthesis of endo-9-methyl-9-azabicyclo [3.3.1] non-3-yl 7-methyl-pyrazolo [1,5-a] pyridine-3-carboxamide: 7- Methyl-3-pyrazolo [1,5-a] pyridinecarboxylic acid 0.4 g was dissolved in thionyl chloride 4 ml and refluxed for 30 minutes. After the thionyl chloride was distilled off, endo-9-methyl-9-azabicyclo [3.3.1] nonan-3-amine (Eur. Pat. App.
l. EP 13.138, (1979)) 0.62 g and triethylamine
0.4 g was added and the mixture was refluxed in 7 ml of chloroform for 24 hours. Water and Na ₂ CO ₃ were added, the chloroform layer was removed, dried over Na ₂ SO ₄ , the solvent was distilled off, and the residue was subjected to silica gel chromatography to obtain chloroform-
Methanol mixture (chloroform: methanol = 30:
1) 0.47 g (yield 66%) of the title compound from the elution part
Got

¹ H-NMR (CDCl ₃ ) δ: 8.23
(1H, d), 8.16 (1H, s), 7.26 (1H, dd,
J = 8.4Hz, J = 7.8Hz), 6.75 (1H, d, J
= 7.7 Hz), 4.5-4.7 (1 H, m), 3.10 (2
H, d), 2.78 (3H, s), 2.51 (3H, s), 1.
0-2.6 (10H, m) M S (m / e): 212 (M ⁺ ) IRνmax cm ^-1 (KBr): 1636 (C = O)

Example 10 (S)-(-)-N- (1-azabicyclo [2.2.2]]
Oct-3-yl) -7-methylpyrazolo [1,5-
Synthesis of a] pyridine-3-carboxamide: 7-methyl-3-pyrazolo [1,5-a] pyridinecarboxylic acid 88
A solution of 0 mg (5 mmol) of thionyl chloride in 10 ml was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure, and the obtained residue was dissolved in 30 ml of methylene chloride. (S)-(-)-1-azabicyclo [2.2.2] octane-3-amine 644 prepared by the method described in JP-A-63-196583 under ice cooling.
To the solution (mg (5.1 mmol)) in methylene chloride (30 ml) was added dropwise, and the mixture was stirred under ice-cooling for 30 minutes and further at room temperature for 40 minutes. 2N sodium hydroxide was added to the reaction mixture, and 10
After stirring for a minute, the organic layer was separated. Further, the aqueous layer was extracted with methylene chloride and dried over anhydrous potassium carbonate. The residue obtained by distilling off methylene chloride under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 10: 1, 5: 1), and the obtained oil was dissolved in ethyl acetate. The solvent was distilled off under reduced pressure,
The obtained crystals were washed with ether to give the title compound (1.2 g)
(4.2 mmol, 84.5%) was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.25 (1H, s, C 2} -H), 8.20 (1H, d, J =
8.9 Hz, C ⁴ -H) 7.31 (1H, dd, J = 8.9H
z, J = 6.9 Hz, C ⁵ -H), 6.79 (1H, d, J =
6.9 Hz, C ⁶ -H), 6.12 (1H, d, J = 6.9H
z, NH), 4.1-4.3 (1H, m, CH), 1.5-3.
6 (11H, m, quinuclidine-H), 2.78 (3H, s,
_{^{. C 7 -CH 3) MS:}} .. FAB (Pos) 285 (MH +) [α] 20 D = -12.7 (c = 1.0, 1NHCl).

Example 11 (R)-(+)-N- (1-azabicyclo [2.2.2]]
Oct-3-yl) -7-methylpyrazolo [1,5-
Synthesis of a] pyridine-3-carboxamide: 7-methyl-3-pyrazolo [1,5-a] pyridinecarboxylic acid 16
A solution of 6 mg (0.945 mmol) of thionyl chloride in 3 ml was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure, and the resulting residue was dissolved in 5 ml of methylene chloride.
(R)-(+)-1-azabicyclo [2.2.2] octane-3-amine (200 mg) prepared by the method described in JP-A-63-196583 under ice cooling.
(1 mmol) was added dropwise to a solution of methylene chloride in 5 ml,
The mixture was stirred under ice cooling for 30 minutes and at room temperature for 40 minutes. A 2N aqueous sodium hydroxide solution was added to the reaction mixture, the mixture was stirred for 10 minutes, and then the organic layer was separated. Further, methylene chloride was extracted from the aqueous layer, which was dried over anhydrous potassium carbonate.
Methylene chloride was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1, 5: 1), and the obtained oil was dissolved in ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with ether to give the title compound (207 m)
g (0.73 mmol, 77.0%) was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.26 (1H, s, C 2} -H), 8.20 (1H, ds, J =
8.9 Hz, C ⁴ -H), 7.31 (1H, dd, J = 8.9H
z, J = 6.9 Hz, C ⁵ -H), 6.79 (1H, d, J =
6.9 Hz, C ⁶ -H), 6.14 (1H, d, J = 6.3H
z, NH), 4.1-4.3 (1H, m, CH), 1.5-3.
6 (11H, m, quinuclidine-H), 2.78 (3H, s,
^{C 7 -CH) MS:..} . FAB (Pos) 285 (MH +) [α] 20 D = + 13.2 (c = 1.0, 1NHCl).

Example 12 1-Azabicyclo [2.2.2] oct-3-yl 7-
Synthesis of methylpyrazolo [1,5-a] pyridine-3-carboxylate: 3-quinuclidinol 370 mg
(Aldrich Co .; 2.9 mmol) benzene 30
After refluxing the ml suspension for 1.5 hours using a Dean-Stark apparatus, 0.1 g of metallic sodium was added, and 2.5
Refluxed under stirring for a period of time. Unreacted sodium was removed and ethyl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate 200 mg (0.98 mmo)
1) was added, and the mixture was heated under reflux for 24 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 10:
Purified in 1), 240 mg (0.84 mmo) of the title compound.
1, 86%) was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.45 (1H, s, C 2} -H), 8.06 (1H, d, J =
8.9 Hz, C ⁴ -H), 7.38 (1H, dd, J = 8.9H
z, 6.9 Hz, C ⁵ -H), 6.83 (1H, d, J = 6.9
Hz, C ⁶ -H), 5.0-5.1 (1H, m, CH), 1.4
-3.5 (11 H, m, quinuclidine-H), 2.80 (3
H, s, CH ₃ ) MS: FAB (Pos.) 286 (MH ⁺ ).

Example 13 Synthesis of (S)-(−)-1-azabicyclo [2.2.2] oct-3-yl 7-methylpyrazolo [1,5-a] pyridin-3-carboxylate: Eur . J, Med, Che
m., Vol. 14, pages 111-114 (1979), (S)-(+)-3-quinuclidinol 760 mg
1.5 ml of 60 ml suspension of (0.76 mmol) benzene
After refluxing using a Dean-Stark apparatus, 0.2 g of metallic sodium was added, and the mixture was refluxed for 2.5 hours with stirring. Unreacted sodium was removed, 440 mg (2.2 mmol) of ethyl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate was added, and the mixture was heated under reflux for 24 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (500 mg, 1.8 mmol, 81%) as white crystals. .

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.45 (1H, s, C 2} -H), 8.06 (1H, d, J =
8.9 Hz, C ⁴ -H), 7.38 (1H, dd, J = 8.9H
z, 6.9 Hz, C ⁵ -H), 6.83 (1H, d, J = 6.9
Hz, C ⁶ -H), 5.0-5.1 (1H, m, CH), 1.4
-3.5 (11 H, m, quinuclidine-H), 2.81 (3
H, s, CH ₃ ) MS: FAB (Pos.) 286 (MH ⁺ ). [Α] ²⁰ _D = -21.5 (c = 1.0, chloroform).

Example 14 Synthesis of (R)-(+)-1-azabicyclo [2.2.2] oct-3-yl 7-methylpyrazolo [1,5-a] pyridin-3-carboxylate: Eur . J, Med, Che
m., Vol. 14, pp. 111-114 (1979), (R)-(-)-3-quinuclidinol 90 mg (0.1).
A suspension of 71 mmol) in 15 ml of benzene was refluxed for 1.5 hours using a Dean-Stark apparatus, 0.05 g of metallic sodium was added, and the mixture was refluxed for 2.5 hours with stirring. Unreacted sodium was removed, 100 mg (0.49 mmol) of ethyl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate was added, and the mixture was heated under reflux for 24 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (15 mg, 0.05 mmol, 12%) as white crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.45 (1H, s, C 2} -H), 8.06 (1H, d, J =
8.9 Hz, C ⁴ -H) 7.38 (1H, dd, J = 8.9H
z, 6.9 Hz, C ⁵ -H), 6.83 (1H, d, J = 6.9
Hz, C ⁶ -H), 5.0-5.1 (1H, m, CH), 1.4
-3.5 (11 H, m, quinuclidine-H), 2.81 (3
H, s, CH ₃ ). MS: FAB (Pos.) 286 (MH ⁺ ). [Α] ²⁰ _D = + 20.8 (c = 1.0, chloroform).

Example 15 Synthesis of endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 2-methylpyrazolo [1,5-a] pyridin-3-carboxylate: 2-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid 0.5 g
(3 mmol) was dissolved in 5 ml of thionyl chloride and refluxed for 30 minutes. After distilling off the solvent, distilled chloroform 6 ml
Was further added, and 0.4 g (3 mmol) of tropine was further added, followed by stirring for 24 hours. 5N sodium hydroxide aqueous solution 2
After adding ml and stirring for further 30 minutes, water was added and liquid-separated. The chloroform layer was dried over anhydrous sodium sulfate and evaporated, and the remaining oily substance was purified by silica gel column chromatography to obtain chloroform: methanol = 5.
Crystals were obtained from the 0: 1 eluate. It was recrystallized from benzene-methanol to give the title compound 0.27 g (0.90 mm).
ol, 30%) was obtained as crystals.

Melting point: 253-257 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.37 (1 H, d, J =
7.2 Hz, C ⁷ -H), 8.07 (1H, d, J = 8.4H
z, C ⁴ -H), 7.33 (1H, dd, J = 7.8Hz, J =
^{8.4Hz, C 5 -H), 6.83} (1H, dd, J = 7.2H
z, J = 7.8 Hz, C ⁶ -H), 5.0 to 5.5 (1 H, m,
Tropine 3H), 2.9~3.6 (2H, m , tropine 1,5-H), 2.71 (3H , s, C 2 -H3), 2.40
(3H, s, tropine _{N-CH 3), 1.5~2.6 (} 8H,
m, tropine H) MS (m / e): 299 (M) IRν max cm ^-1 (KBr): 1685 (C = 0)

Example 16 Synthesis of endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 4-methylpyrazolo [1,5-a] pyridin-3-carboxylate: Journal of・ Chemical Society, Perkin Trance Actions Part 1 (JCS Parkin I) 406〜
4-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid prepared as described on page 409 (1975).
Dissolve 5 g (3 mmol) in 5 ml of thionyl chloride,
Refluxed for 30 minutes. After distilling off the solvent, distilled chloroform
6 ml was added, and tropine 0.4 g (3 mmol) was added.
Was added and stirred for 24 hours. After adding 2 ml of a 5N sodium hydroxide aqueous solution and further stirring for 30 minutes, water was added to separate the layers. The chloroform layer was dried over anhydrous sodium sulfate and then evaporated, and the remaining oily substance was purified by silica gel column chromatography to obtain crystals from an eluate of chloroform: methanol = 50: 1. It was recrystallized from benzene-methanol to give 0.27 g (0.2%) of the title compound.
90 mmol, 30%) was obtained as crystals.

Melting point: 144 to 146 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.39 (1 H, d, J =
^{6.0Hz, C 7 -H), 8.27} (1H, s, J = C 2 -
H), 7.19 (1H, d , J = 7.2Hz, C 5 -H), 6.
88 (1H, dd, J = 6.0 Hz, J = 7.2 Hz, C ⁶ −
H), 5.1-5.5 (1H, m, tropine 3-H), 3.5
~ 4.1 (2H, m, tropine 1,5-H), 2.87 (3
_{^{H, s, C 4 -CH 3}} ), 2.78 (3H, s, tropine N-
CH ₃ ), 2.1 to 2.8 (8H, m, tropine H) MS (m / e): 299 (M) IRν max cm ^-1 (KBr): 1705 (C = 0)

Example 17 Synthesis of endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 5-methylpyrazolo [1,5-a] pyridin-3-carboxylate: 5-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid 0.5 g
(3 mmol) was dissolved in 5 ml of thionyl chloride and refluxed for 30 minutes. After removing thionyl chloride by distillation, tropine 0.4
g (3 mmol) was added, and the mixture was refluxed in 6.3 ml of chloroform for 24 hours. The oily substance obtained by adding water and a small amount of 5N NaOH aqueous solution to make it alkaline and distilling off the chloroform layer was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 0.11 g (0.10 g) of the title compound. 37 mmol 12.3%) was obtained.

M S (m / e): 299 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 8.39 (1 H, d, J =
^{6.0Hz, C 7 -H), 8.27} (1H, s, C 2 -H), 7.
19 (1H, d, J = 7.2 Hz, C ⁵ -H), 6.88 (1
H, dd, J = 6.0 Hz, J = 7.2 Hz, C ⁶ -H), 5.
1-5.5 (1H, m, Tropin 3-H), 3.5-4.1
(2H, m, tropin 1,5-H), 2.87 (3H, s, C
_{^{5 -CH 3), 2.78 (3H}} , s, tropine N-CH _3),
2.1-2.8 (8H, m, tropin H)

Example 18 Synthesis of endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 6-methylpyrazolo [1,5-a] pyridin-3-carboxylate: 6-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid 0.6 g
(0.003 mol) was dissolved in 6 ml of thionyl chloride,
Refluxed for 30 minutes. After the solvent was distilled off, 7 ml of distilled chloroform was added, and tropine 0.4 g (0.003 m) was added.
was added and the mixture was stirred for 24 hours. 2 ml of 5N sodium hydroxide aqueous solution was added, and the mixture was further stirred for 30 minutes, and then water was added to separate the layers. The chloroform layer was dried over anhydrous sodium sulfate and evaporated, and the remaining oily substance was purified by silica gel column chromatography. The eluent of chloroform: methanol = 50: 1 gave 0.13 g (13
%) Was obtained as crystals. It was recrystallized from benzene-methanol.

¹ H-NMR (CDCl ₃ ) δ: 8.33 (1H, s, C ⁷ —H), 8.26 (1H, s, C ² −)
H), 8.06 (1H, d , J = 7.8Hz, C 4 -H), 7.
21 (1H, d, J = 7.8Hz, C 5 -H) 5.08~5.
50 (1H, m, tropine 3-H), 3.10 to 3.64.
(2H, m, tropin 1,5-H), 2.48 (3H, s, C
_{^{6 -CH 3), 2.36 (3H}} , s, tropine N-CH _3),
1.68 to 2.43 (8H, m, tropine H) MS (m / e): 299 (M)

Reference Example 3 2,7-Dimethylpyrazolo [1,5-a] pyridine-3-
Synthesis of carboxylic acids: Pharmaceutical Journal 91 (11), 1154-1157
5 ml of 3N NaOH aqueous solution and 2 ml of ethanol were added to 1.00 g (4.6 mmol) of ethyl 2,7-dimethylpyrazolo [1,5-a] pyridine-3-carboxylate prepared according to the description on page (1971) to give 100 Stirred at 8 ° C for 8 hours. After the reaction, the solvent was distilled off, the residue was dissolved in water and washed with benzene. The aqueous layer was acidified with concentrated hydrochloric acid and the precipitated crystals were collected by filtration and washed with water. Yield 0.8
5 g (4.5 mmol) (yield 97%)

¹ H-NMR (CDCl ₃ ): 2.76 (s,
3H), 2.78 (s, 3H), 6.78 (d, 1H, J = 6.
9Hz), 7.35 (dd, 1H, J = 8.9Hz, J = 6.9)
Hz), 8.09 (d, 1H, J = 8.9Hz)

Example 19 Synthesis of N- (1-azabicyclo [2.2.2] -oct-3-yl) -2,7-dimethylpyrazolo [1,5-a] pyridine-3-carboxamide: 2, obtained in Reference Example 3,
A solution of 200 mg (1.1 mmol) of 7-dimethyl-3-pyrazolo [1,5-a] pyridinecarboxylic acid in 5 ml of thionyl chloride was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure, and the resulting residue was treated with methylene chloride (5 ml).
Dissolved in. 1-azabicyclo- [2.
2.2] -Oct-3-ylamine 140 ml (1.1
(mmol) in 5 ml of methylene chloride, and the mixture was stirred for 30 minutes at room temperature under ice cooling for 40 minutes. 2 in the reaction mixture
N sodium hydroxide was added and the mixture was stirred for 10 minutes, then, the organic layer was separated. Further, the aqueous layer was extracted with methylene chloride and dried over anhydrous potassium carbonate. Methylene chloride was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 10: 1).
The oily substance thus obtained was dissolved in ethyl acetate. The solvent was distilled off under reduced pressure and the obtained crystals were washed with ether,
170 mg (0.57 mmol, 54%) of the title compound was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm):
7.98 (1H, d, J = 8.9Hz, C 4 -H), 7.26
(1H, dd, J = 8.9Hz , J = 6.6Hz, C 5 -H),
6.71 (1H, d, J = 6.6Hz, C 6 -H), 6.03
(1H, d, J = 6.6Hz, NH), 4.2-4.3 (1H,
m, CH), 1.5-3.6 (11H, m, quinuclidine-
H), 2.74 (3H, s , CH 3), 2.73 (3H, s, C
H ₃ ). M S: FAB (Pos.) 299 (MH ⁺ ).

Example 20 1 1-azabicyclo [2.2.2] oct-3-yl 2,7
Synthesis of dimethylpyrazolo [1,5-a] pyridine-3-carboxylate: 3-quinuclidinol 350 m
A suspension of g (2.76 mmol) in 30 ml of benzene was refluxed for 1.0 hour using a Dean-Stark apparatus, 0.1 g of metallic sodium was added, and the mixture was refluxed for 3 hours with stirring. Unreacted sodium was removed and ethyl 2,7
-Add 200 mg (0.92 mmol) of dimethylpyrazolo [1,5-a] pyridine-3-carboxylate and add 2
The mixture was heated under reflux for 4 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 60 mg (0.20 mmol, 22%) of the title compound as white crystals. .

¹ H-NMR (CDCl ₃ ) δ (ppm):
8.01 (1H, d, J = 8.9Hz, C 4 -H), 7.33
(1H, dd, J = 8.9Hz , 6.9Hz, C 5 -H), 6.
76 (1H, d, J = 6.9Hz, C 6 -H), 5.0-5.1
(1H, m, CH), 1.4-3.5 (11H, m, quinuclidine -H), 2.77 (3H, s , CH 3), 2.73 (3H,
s, CH ₃ ). MS: FAB (Pos.) 300 (MH ⁺ ).

Reference Example 4 (1) Ethyl 7-ethylpyrazolo [1,5-a] pyridine-3
-Synthesis of carboxylate: hydroxylamine-O-
Sulfonic acid 5.0 g (37.6 mmol) water 70 ml
To the solution, 2-ethylpyridine 12.0 g (112.1 m)
mol) was added and the mixture was heated under reflux for 12 hours with stirring. Na ₂
After neutralizing with 4.70 g of CO ₃ , water and 2-ethylpyridine were distilled off. The residue was dissolved in ethanol and the insoluble material was filtered off. The filtrate was concentrated to 20 ml, 57% hydroiodic acid (6.0 ml, 42.9 mmol) was added, and the mixture was left in a freezer. The precipitated crude crystals of 1-amino-2-ethylpyridinium iodide were collected by filtration and washed with ethanol. Yield 4.5 g (18.0 mmol) (48
%).

Next, 4.5 g (18.0 mmol) of DMF containing 1-amino-2-ethylpyridinium iodide was added.
2.2 g of Na ₂ CO ₃ (20.8 mmo) in a 20 ml solution.
1) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl propiolate (3.6 g, 36.7 mmol) was added thereto, and the mixture was further stirred at room temperature for 20 hours. The solvent of the reaction mixture was evaporated, water was added to the residue, and the mixture was extracted with methylene chloride. The methylene chloride layer was dried over Na ₂ SO ₄ , the solvent was distilled off, and the residue was subjected to silica gel column kraft chromatography (CH ₂ C
l ₂ : hexane = 1: 1) and the title compound 0.9
3 g (4.3 mmol) (24%) were obtained as crystals.
(12% at 2-step)

¹ H-NMR (CDCl ₃ ): 1.42 (t,
3H, J = 7.6Hz), 1.44 (t, 3H, J = 7.3H
z), 3.23 (q, 2H, J = 7.6 Hz), 4.39 (q,
2H, J = 7.3Hz), 6.81 (d, 1H, J = 7.3H)
z), 7.39 (dd, 1H, J = 8.9Hz, J = 7.3H
z), 8.08 (d, 1H, J = 8.9 Hz), 8.43 (s,
1H)

Reference Example 4 (2) Synthesis of 7-ethylpyrazolo [1,5-a] pyridine-3-carboxylic acid: ethyl 7-ethylpyrazolo [1,5-
a] Pyridine-3-carboxylate 0.40 g (1.8
(3 mmol), 2.5 ml of 2.5N NaOH aqueous solution and 8 ml of ethanol were added, and the mixture was stirred at 100 ° C. for 8 hours.
After the reaction, the same post-treatment as in synthesizing the 5-methyl, 2,7-dimethyl compound was carried out to obtain crystals. Yield 0.34g
(1.79 mmol) (98%)

¹ H-NMR (CDCl ₃ ): 1.45 (t,
3H, J = 7.6Hz), 3.25 (q, 2H, J = 7.6H
z), 6.87 (d, 1H, J = 6.6 Hz), 7.49 (d
d, 1H, J = 8.9 Hz, J = 6.6 Hz), 8.13 (d,
1H, J = 8.9Hz), 8.52 (s, 1H)

Example 21 N- (1-azabicyclo- [2.2.2] -oct-3-
Yl) -7-ethylpyrazolo [1,5-a] pyridine-
Synthesis of 3-carboxamide: Reference Example 4 (obtained in 2)
A solution of 150 mg (0.79 mmol) of 7-ethylpyrazolo [1,5-a] pyridine-3-carboxylic acid in 4 ml of thionyl chloride was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure, and the resulting residue was added with 5 ml of methylene chloride.
Dissolved in. 1-azabicyclo- [2.
2.2] -Oct-3-ylamine 100 ml (0.7
(9 mmol) was added dropwise to a solution of methylene chloride in 5 ml, and the mixture was stirred under ice cooling for 30 minutes at room temperature for 40 minutes. 2N sodium hydroxide was added to the reaction mixture and the mixture was stirred for 10 minutes, then, the organic layer was separated. Further, the aqueous layer was extracted with methylene chloride and dried over anhydrous potassium carbonate. The residue obtained by distilling off methylene chloride under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and the obtained oil was dissolved in ethyl acetate. The solvent was distilled off under reduced pressure and the obtained crystals were washed with ether,
200 mg (0.67 mmol, 85%) of the title compound was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.38 (1H, s, C 2} -H), 8.19 (1H, d, J =
^{8.9Hz, C 4 -H) 7.33 (} 1H, dd, J = 8.9H
z, J = 6.9 Hz, C ⁵ -H), 6.77 (1H, d, J =
6.9 Hz, C ⁶ -H), 6.25 (1H, d, J = 6.6H
z, NH), 4.2-4.3 (1H, m, CH), 1.5-3.
5 (11H, m, quinuclidine-H), 3.20 (2H, q,
J = 7.6Hz, CH ₂ ), 1.42 (3H, t, J = 7.6H
z, CH ₃ ). MS: FAB (Pos.) 299 (MH ⁺ ).

Reference Example 5 (1) Ethyl 7-propylpyrazolo [1,5-a] pyridine-
Synthesis of 3-carboxylate: hydroxylamine-O
-Sulfonic acid 9.0 g (67.7 mmol) water 100
2-n-propyl pyridine 25.0 g (20 ml)
6.6 mmol) was added and the mixture was heated under reflux for 17 hours with stirring. 8.46 g (79.8 mm) of Na ₂ CO _{3 was} added to the reaction mixture.
water) and water and 2-n-propylpyridine were distilled off. The residue was dissolved in ethanol and the insoluble material was filtered off. 57% hydroiodic acid 11.5 ml (8
2.1 mmol) was added and the solvent was evaporated. Ether was added to the residue and the crude crystals of 1-amino-2-propylpyridinium iodide were deposited by leaving them in a freezer.
Obtained 5.0 g (18.9 mmol) (28%).

Next, 1-amino-2-propylpyridinium iodide (5.0 g, 18.9 mmol) in DM was added.
2.41 g (22.7 mm) of Na ₂ CO _{3 in} F20 ml solution
ol) was added and the mixture was stirred at room temperature for 1 hour. 3.71 g (37.9 mmol) of ethyl propiolate was added to it,
It was stirred at room temperature for another 20 hours. After the reaction, the same post-treatment as for the 7-ethyl compound is performed, and CH ₂ Cl ₂ : hexane = 1: 1.
1.45 g (6.
25 mmol) (33%) was obtained. (9% at 2 steps)

¹ H-NMR (CDCl ₃ ): 1.06 (t,
3H, J = 7.4Hz), 1.42 (t, 3H, J = 7.2H
z), 1.82-1.96 (m, 2H), 3.17 (t, 2H,
J = 7.6 Hz), 4.39 (q, 2H, J = 7.2 Hz),
6.79 (d, 1H, J = 6.9Hz), 7.37 (dd, 1)
H, J = 8.9 Hz, J = 6.9 Hz), 8.07 (d, 1H,
J = 8.9 Hz), 8.42 (s, 1H).

Reference Example 5 (2) Synthesis of 7-propylpyrazolo [1,5-a] pyridine-3-carboxylic acid: ethyl 7-propylpyrazolo [1,5
-A] pyridine-3-carboxylate 0.46 g (1.
To 98 mmol), 2.5 ml of 2.5N NaOH aqueous solution and 5 ml of ethanol were added, and the mixture was stirred at 100 ° C. for 3 hours.
After the reaction, the same post-treatment as that for synthesizing the 5-methyl, 2,7-dimethyl compound was carried out, and the title compound was crystallized to 0.3.
7 g (1.81 mmol) (91%) were obtained.

¹ H-NMR (CDCl ₃ ): 1.07 (t,
3H, J = 7.4 Hz), 1.83-1.97 (m, 2H),
3.19 (t, 2H, J = 7.6Hz), 6.84 (d, 1
H, J = 6.9Hz), 7.42 (dd, 1H, J = 8.9H
z, J = 6.9 Hz), 8.12 (d, 1H, J = 8.9H
z), 8.51 (s, 1H).

Example 22 N- (1-azabicyclo- [2.2.2] -oct-3-
Synthesis of (yl) -7-propylpyrazolo [1,5-a] pyridine-3-carboxamide: 7 obtained in Reference Example 5 (2)
A solution of 150 mg (0.74 mmol) of -propylpyrazolo [1,5-a] pyridine-3-carboxylic acid in 4 ml of thionyl chloride was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure, and the resulting residue was dissolved in 5 ml of methylene chloride. 1-azabicyclo- [2.2.
2] -Oct-3-ylamine 110 ml (0.87 m
(mol) in 5 ml of methylene chloride solution and under ice cooling 3
Stir for 40 minutes at room temperature for 0 minutes. 2N in the reaction mixture
Sodium hydroxide was added and after stirring for 10 minutes, the organic layer was separated. Further, the aqueous layer was extracted with methylene chloride and dried over anhydrous potassium carbonate. Methylene chloride was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 10: 1).
The oily substance thus obtained was dissolved in ethyl acetate.
The solvent was distilled off under reduced pressure, and the obtained crystals were washed with ether to give the title compound (200 mg, 0.64 mmol, 87).
%) As white crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.37 (1H, s, C 2} -H), 8.19 (1H, d, J =
8.3 Hz, C ⁴ -H) 7.32 (1H, dd, J = 8.3H
z, J = 6.6 Hz, C ⁵ -H), 6.77 (1 H, d, J =
6.6 Hz, C ⁶ -H), 6.49 (1H, d, J = 6.9H
z, NH), 4.2-4.3 (1H, m, CH), 1.5-3.
5 (11H, m, quinuclidine-H), 3.15 (2H, t,
_{J = 7.7Hz, CH 2),} 1.81-1.96 (2H, m, C
H ₂ ), 1.05 (3H, t, J = 7.4Hz, CH ₃ ). MS: FAB (Pos.) 299 (MH ⁺ ).

Example 23 1-Azabicyclo [2.2.2] oct-3-yl 7-
Synthesis of ethylpyrazolo [1,5-a] pyridine-3-carboxylate: 3-quinuclidinol 140 mg
A suspension of (1.10 mmol) in 20 ml of benzene was added to 0.1.
After refluxing for 5 hours using a Dean-Stark apparatus, 0.05 g of sodium metal was added, and the mixture was further refluxed for 1.5 hours with stirring. Unreacted sodium was removed, 80 mg (0.37 mmol) of ethyl 7-ethylpyrazolo [1,5-a] pyridine-3-carboxylate was added, and the mixture was heated under reflux for 12 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (100 mg, 0.33 mmol, 91%) as an oil. ..

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.44 (1H, s, C 2} -H), 8.05 (1H, d, J =
8.9 Hz, C ⁴ -H) 7.40 (1H, dd, J = 8.9H
z, 7.3 Hz, C ⁵ -H), 6.83 (1H, d, J = 7.3
Hz, C ⁶ -H), 5.0-5.1 (1H, m, CH), 1.4
-3.5 (11 H, m, quinuclidine-H), 3.23 (2
H, q, J = 7.6 Hz, CH ₂ ), 1.44 (3H, t, J =
7.6 Hz, CH ₃ ). MS: FAB (Pos.) 300 (MH ⁺ )

Example 24 1-Azabicyclo [2.2.2] oct-3-yl 7-
Synthesis of propylpyrazolo [1,5-a] pyridine-3-carboxylate: 3-quinuclidinol 330 mg
A suspension of (2.60 mmol) in 30 ml of benzene was added to 0.10.
After refluxing for 5 hours using a Dean-Stark apparatus, 0.1 g of metallic sodium was added, and the mixture was further refluxed for 2 hours with stirring. Unreacted sodium was removed, 200 mg (0.86 mmol) of ethyl 7-propylpyrazolo [1,5-a] pyridine-3-carboxylate was added, and the mixture was heated under reflux for 20 hours. The solvent of the reaction mixture was distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 230 mg (0.73 mmol, 85%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ (ppm):
^{8.43 (1H, s, C 2} -H), 8.05 (1H, d, J =
8.6Hz, C ⁴ -H) 7.39 (1H, dd, J = 8.6H
z, 6.9 Hz, C ⁵ -H), 6.81 (1H, d, J = 6.9
Hz, C ⁶ -H), 5.0-5.1 (1H, m, CH), 1.4
-3.5 (11 H, m, quinuclidine-H), 3.17 (2
H, t, J = 7.6 Hz, CH ₂ ), 1.82-1.96 (2
H, m, CH ₂ ), 1.06 (3H, t, J = 7.3Hz, C
H ₃ ). M S: FAB (Pos.) 314 (MH ⁺ ).

Test Example 1 5-HT ₃ Receptor Binding Experiment (A) Preparation of rat cerebral cortical membrane fraction: SD male rats (200-300 g) were decapitated, the brain was quickly taken out, and this was cooled on ice. The cerebral cortex was extracted while being immersed in a 0.32 M sucrose solution. To this, 50 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer solution (HEPES, pH 7.4) was added and homogenized. This homogenate was centrifuged (1,000 xg, 1
0 min), and further centrifuge the supernatant (48,000 x
g, 15 min) to obtain a precipitate. This sediment is 0.03
% After resuspending with Triton X-100, centrifugation (48,
The sediment obtained by 000 × g, 15 min) was used as a cerebral cortex membrane fraction.

(B) Measurement of ³ H-quipazine binding ability Method: Rat cerebral cortex membrane fraction (about 200) prepared above
μg protein) and ³ H-quipazine (New England
Nuclea Inc .: NEN) (final concentration: 1 nM) was used as the total binding amount (TB), and ICS 205-930 (Research Biochemicals Incorporated), which is an antagonist of 5-HT ₃ receptor, was added to this. The final concentration of 100 nM) was added and the reaction was made to be the non-specific binding amount (NB). To examine the binding ability of the sample, the sample was added to the membrane fraction, ³ H-quipazine, and reacted (DT).
B). The reaction was carried out at 25 ° C. for 45 minutes using a total of 1 ml. The reaction was stopped by suction filtration of the reaction solution with Whatman GF / C filter. The radioactivity adsorbed on the filter was measured with a liquid scintillation counter. Binding capacity of the sample is calculated by the following formula, ³ H
-Calculated as the inhibition rate of binding of quipazine to the 5-HT ₃ receptor, the results are shown in Table 1.

(Calculation formula)

(Result)

Further, the binding inhibition rate at an appropriate concentration was calculated for each compound, and a concentration-binding inhibition curve was prepared in which the horizontal axis represents the logarithmic value of the concentration and the vertical axis represents the binding inhibition rate. IC ₅₀ value (concentration at which 50% binding inhibition) was determined. The results are shown in Table 2.

[0095]

Comparative Compound ^* 1: Pyrazolo [1,5-a]
Pyridine-3-carboxylic acid Comparative compound ^* 2: 2-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid; obtained in Reference Example 2 Comparative compound ^* 3: 4-methylpyrazolo [1,5-a] Pyridine-3-carboxylic acid Comparative compound ^* 4: 5-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid; obtained in Reference Example 1 Comparative compound ^* 5: 6-Methylpyrazolo [1,5-a] Pyridine-3-carboxylic acid Comparative compound ^* 6: 7-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid Comparative compound ^* 7: 2,7-Dimethylpyrazolo [1,5-
a] pyridine-3-carboxylic acid; obtained in Reference Example 3

Test Example 2 For Antiemetic Treatment: Four female Beagle dogs (manufactured by Toyo Experimental Animal Center) weighing 7.5 to 9.6 kg and 9 to 13 months old were used.
The antiemetic action of the compound of the present invention was investigated. As test compounds, the compounds obtained in Example 8 and Example 9 were weighed, dissolved in 0.01N hydrochloric acid, and then neutralized with 0.01N sodium hydroxide to a pH of about 7, and an aqueous solution for administration was used. . On the other hand, cisplatin (bliplatin injection, manufactured by Bristol-Myers) was used as an emetic.

First, in order to examine the emetic action of cisplatin in each animal, vomiting after cisplatin administration was observed (control group). Then, 7 weeks later, 75 minutes after administration of cisplatin to each of 2 cases, the compound of Example 8 or the compound of Example 9 was 0.1 mg / kg (0.2 m 2).
(l / kg) was administered intravenously and vomiting was observed (administration group of the compound of Example 8 and the compound of Example 9). Cisplatin has a dose of 3 mg / kg and a volume of 6 ml / k
g, administration rate was 10 ml / min, and intravenous administration was performed.

The experimental animals were fasted for about 24 hours before administration of cisplatin and fed 1 hour after administration of cisplatin. Further, vomiting was judged by whether or not the vomited matter was excreted from the mouth, and observations were made regarding the number of times vomiting and the latency thereof until 4 hours after cisplatin administration.

As a result, the latency of initial vomiting and the frequency of vomiting after administration of cisplatin in each experimental animal are shown in Tables 3-A and 3-B.

[0101]

[0102]

Table 3 showing the administration test of the compound of Example 8
In A, the latency of the first vomiting was 126 and 114 minutes and the number of times of vomiting was 13 and 22 times in the control in which the test compound was not administered.
When 0.1 mg / kg of the compound was administered, no vomiting was observed in any of the cases, and an antiemetic effect was observed.

Also in Table 3-B showing the results of the compound administration test of Example 9, the latencies of the first vomiting in the control were 106 and 98 minutes, and the number of vomiting was respectively.
In contrast to 12 and 27 times, when the compound of Example 9 was administered at 0.1 mg / kg, the latency of the first vomiting was extended to 132 and 173 minutes, and the number of vomiting was also 12 and 10, respectively. It decreased in the number of times and 1 case.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/46 ACJ 7252-4C // (C07D 519/00 451: 00 471: 00) (C07D 519 / 00 453: 00 471: 00)

Claims (18)

[Claims] 1. A compound represented by the general formula (I): (Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, R ₃ represents an azabicyclo cyclic group containing a tertiary nitrogen atom, and Y represents —O— or —NH—). A pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative or a salt thereof. 2. An azabicyclo cyclic group R ₃ containing a tertiary nitrogen atom is represented by the following formula: The pyrazolo [1,5-group according to claim 1, which is a group represented by
a] Pyridine-3-carboxylic acid derivative or a salt thereof. 3. An azabicyclo cyclic group R ₃ containing a tertiary nitrogen atom is represented by the following formula: A pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative according to claim 1, which is a group represented by the formula (wherein Z represents a lower alkyl group and n represents a number of 2 or 3). Its salt. 4. Pyrazolo [1,5-a] pyridine-3-
The carboxylic acid derivative has the following general formula (I ′): Wherein R ₁ represents a lower alkyl group and Y and R ₃ have the same meanings as defined above.
The pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative or salt thereof described. 5. Pyrazolo [1,5-a] pyridine-3-
The carboxylic acid derivative is an optically active or racemic N-
(1-Azabicyclo [2.2.2] oct-3-yl)-
Pyrazolo [1,5-a] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-
Yl) -5-methylpyrazolo [1,5-a] pyridine-
3-carboxamide, N- (1-azabicyclo [2.2.
2] Oct-3-yl) -7-methylpyrazolo [1,5
-A] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-yl) -2-methylpyrazolo [1,5-a] pyridine-3-carboxamide, N- (1- Azabicyclo [2.2.2] oct-3-
Yl) -2,7-Dimethylpyrazolo [1,5-a] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-yl) -7-ethylpyrazolo [1,5 -A] pyridine-3-carboxamide, N-
(1-Azabicyclo [2.2.2] oct-3-yl)-
7-Propylpyrazolo [1,5-a] pyridine-3-carboxamide, 1-azabicyclo [2.2.2] oct-
3-yl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate, 1-azabicyclo [2.2.
2] Oct-3-yl 2,7-dimethylpyrazolo [1,
5-a] pyridine-3-carboxylate, 1-azabicyclo [2.2.2] oct-3-yl 7-ethylpyrazolo [1,5-a] pyridine-3-carboxylate,
1-azabicyclo [2.2.2] oct-3-yl 7-
Any one of compounds selected from the group consisting of propylpyrazolo [1,5-a] pyridine-3-carboxylate
The pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative according to claim 2 or a salt thereof. 6. Pyrazolo [1,5-a] pyridine-3-
The carboxylic acid derivative is endo-8-azabicyclo [3.
2.1] Oct-3-ylpyrazolo [1,5-a] pyridine-3-carboxylate, endo-8-methyl-8-
Azabicyclo [3.2.1] oct-3-yl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate, endo-8-methyl-8-azabicyclo [3.2.
1] Oct-3-yl 2-methylpyrazolo [1,5-
a] Pyridine-3-carboxylate, endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 4-methylpyrazolo [1,5-a] pyridin-3-carboxylate, endo-8 -Methyl-8-azabicyclo [3.2.1] oct-3-yl 5-methylpyrazolo [1,5-a] pyridin-3-carboxylate, endo-N- (8-methyl-8-azabicyclo [3. 2.1]
Oct-3-yl-7-methylpyrazolo [1,5-a]
Pyridine-3-carboxysamide, endo-N- (9-
Methyl-9-azabicyclo [3.2.1] non-3-yl) -7-methyl-pyrazolo [1,5-a] pyridine-
The pyrazolo [1,5-] according to claim 3, which is any one of compounds selected from the group consisting of 3-carboxamide.
a] Pyridine-3-carboxylic acid derivative or a salt thereof. 7. A compound represented by the general formula (II): (In the formula, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group), and a pyrazolo [1,5-a] pyridine-3-carboxylic acid compound represented by the formula (III) H —Y—R ₃ (III) (In the formula, Y is —O— or —NH—, and R ₃ is a third group.
A general formula (I), characterized by reacting with an azabicyclo compound represented by an azabicyclo cyclic group containing a primary nitrogen atom) (In the formula, R ₁ , R ₂ , Y and R ₃ represent the same groups as described above) and pyrazolo [1,5-a] pyridine-3-
A method for producing a carboxylic acid derivative or a salt thereof. 8. An azabicyclo cyclic group R ₃ containing a tertiary nitrogen atom is represented by the following formula: The production method according to claim 7, which is a group represented by: 9. An azabicyclo cyclic group R ₃ containing a tertiary nitrogen atom is represented by the following formula: The process according to claim 7, which is a group represented by the formula (wherein Z represents a lower alkyl group and n represents a number of 2 or 3). 10. Pyrazolo [1,5-a] pyridine-3
-The carboxylic acid derivative has the following general formula (I '): 8. A compound represented by the formula: wherein R ₁ is a lower alkyl group and Y and R ₃ are the same groups as described above.
The manufacturing method described. 11. Pyrazolo [1,5-a] pyridine-3
-The carboxylic acid derivative is an optically active or racemic N
-(1-Azabicyclo [2.2.2] oct-3-yl)
-Pyrazolo [1,5-a] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-
Yl) -5-methylpyrazolo [1,5-a] pyridine-
3-carboxamide, N- (1-azabicyclo [2.2.
2] Oct-3-yl) -7-methylpyrazolo [1,5
-A] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-yl) -2-methylpyrazolo [1,5-a] pyridine-3-carboxamide, N- (1- Azabicyclo [2.2.2] oct-3-
Yl) -2,7-Dimethylpyrazolo [1,5-a] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-yl) -7-ethylpyrazolo [1,5 -A] pyridine-3-carboxamide, N-
(1-Azabicyclo [2.2.2] oct-3-yl)-
7-Propylpyrazolo [1,5-a] pyridine-3-carboxamide, 1-azabicyclo [2.2.2] oct-
3-yl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate, 1-azabicyclo [2.2.
2] Oct-3-yl 2,7-dimethylpyrazolo [1,
5-a] pyridine-3-carboxylate, 1-azabicyclo [2.2.2-] oct-3-yl 7-ethylpyrazolo [1,5-a] pyridine-3-carboxylate, 1-azabicyclo [2. 2.2] Oct-3-yl
The production method according to claim 8, which is any one of compounds selected from the group consisting of 7-propylpyrazolo [1,5-a] pyridine-3-carboxylate. 12. Pyrazolo [1,5-a] pyridine-3
The carboxylic acid derivative is endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl pyrazolo [1,5-a] pyridin-3-carboxylate, endo-8-methyl-8- Azabicyclo [3.2.1] oct-3-yl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate, endo-8-methyl-8-
Azabicyclo [3.2.1] oct-3-yl 2-methylpyrazolo [1,5-a] pyridin-3-carboxylate, endo-8-methyl-8-azabicyclo [3.2.
1] Oct-3-yl 4-methylpyrazolo [1,5-
a] pyridine-3-carboxylate, endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 5-methylpyrazolo [1,5-a] pyridine-3-carboxylate, endo-N -(8-Methyl-8-azabicyclo [3.2.1] oct-3-yl) -7-methyl-pyrazolo [1,5-a] pyridine-3-carboxamide, endo-N- (9-methyl- A compound selected from the group consisting of 9-azabicyclo [3.2.1] non-3-yl) -7-methyl-pyrazolo [1,5-a] pyridine-3-carboxamide. Item 9. The production method according to Item 9. 13. A compound represented by the general formula (I): (Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, R ₃ represents an azabicyclo cyclic group containing a tertiary nitrogen atom, and Y represents —O— or —NH—). A serotonin 3 receptor antagonist comprising a pyrazolo [1,5-a] pyridine-3-carboxylic acid compound or a salt thereof as an active ingredient. 14. An azabicyclo cyclic group containing a tertiary nitrogen atom is represented by the following formula: The serotonin 3 receptor antagonist according to claim 13, which is a group represented by: 15. An azabicyclo cyclic group R ₃ containing a tertiary nitrogen atom is represented by the following formula: The serotonin 3 receptor antagonist according to claim 13, which is a group represented by the formula (wherein Z represents a lower alkyl group, and n represents a number of 2 or 3). 16. Pyrazolo [1,5-a] pyridine-3
-The carboxylic acid derivative is represented by the following general formula (I '): A compound represented by the formula: wherein R ₁ is a lower alkyl group, and Y and R ₃ have the above-mentioned meanings.
The serotonin 3 receptor antagonist according to 3. 17. Pyrazolo [1,5-a] pyridine-3
-The carboxylic acid derivative is an optically active or racemic N
-(1-Azabicyclo [2.2.2] oct-3-yl)
-Pyrazolo [1,5-a] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-
Yl) -5-methylpyrazolo [1,5-a] pyridine-
3-carboxamide, N- (1-azabicyclo [2.2.
2] Oct-3-yl) -7-methylpyrazolo [1,5
-A] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-yl) -2-methylpyrazolo [1,5-a] pyridine-3-carboxamide, N- (1- Azabicyclo [2.2.2] oct-3-
Yl) -2,7-Dimethylpyrazolo [1,5-a] pyridine-3-carboxamide, N- (1-azabicyclo [2.2.2] oct-3-yl) -7-ethylpyrazolo [1,5 -A] pyridine-3-carboxamide, N-
(1-Azabicyclo [2.2.2] oct-3-yl)-
7-Propylpyrazolo [1,5-a] pyridine-3-carboxamide, 1-azabicyclo [2.2.2] oct-
3-yl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate, 1-azabicyclo [2.2.
2] Oct-3-yl 2,7-dimethylpyrazolo [1,
5-a] pyridine-3-carboxylate, 1-azabicyclo [2.2.2] oct-3-yl 7-ethylpyrazolo [1,5-a] pyridine-3-carboxylate,
1-azabicyclo [2.2.2] oct-3-yl 7-
Any one of compounds selected from the group consisting of propylpyrazolo [1,5-a] pyridine-3-carboxylate
The serotonin 3 receptor antagonist according to claim 14, which is 18. Pyrazolo [1,5-a] pyridine-3
The carboxylic acid derivative is endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl pyrazolo [1,5-a] pyridin-3-carboxylate, endo-8-methyl-8- Azabicyclo [3.2.1] oct-3-yl 7-methylpyrazolo [1,5-a] pyridine-3-carboxylate, endo-8-methyl-8-
Azabicyclo [3.2.1] oct-3-yl 2-methylpyrazolo [1,5-a] pyridin-3-carboxylate, endo-8-methyl-8-azabicyclo [3.2.
1] Oct-3-yl 4-methylpyrazolo [1,5-
a] pyridine-3-carboxylate, endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 5-methylpyrazolo [1,5-a] pyridine-3-carboxylate, endo-N -(8-Methyl-8-azabicyclo [3.2.1] oct-3-yl) -7-methylpyrazolo [1,5-a] pyridine-3-carboxamide, endo-N- (9-methyl-9- 16. A compound selected from the group consisting of azabicyclo [3.2.1] non-3-yl) -7-methylpyrazolo [1,5-a] pyridine-3-carboxamide.
The described serotonin 3 receptor antagonist.