JPH04257591A - Pyrazolo(1,5-a)pyridine derivative - Google Patents

Abstract

PURPOSE:To obtain a new pyrazolopyridine derivative useful as an antiemetric, peptic, or antimigrane agent, etc., having excellent antagonismic action on serotonin 3(5-HT3) acceptor. CONSTITUTION:A pyrazolo[1,5-A]pyridine derivative shown by formula I (R<1> is H or lower alkyl; R<2> is H, lower alkyl or benzyl; X is NH or O; (n) is 2 or 3) and a salt thereof such as exo-N-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl) pyrazolo[1,5-a]pyridine-3-carboxamide. A compound shown by formula I wherein R2 is lower alkyl or benzyl and X is NH is obtained by converting an carboxylic acid shown by formula II into an acid chloride according to a conventional procedure and reacting the acid chloride with an amino compound shown by formula III in an organic solvent such as THF, in the presence of a base such as pyridine as a dehydrohalogenating agent, at a temperature from under cooling with ice to the reflux temperature of the solvent.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention provides excellent serotonin 3 (5)
-HT3) A novel pyrazolo [1,5
-a] Pyridine derivatives and pharmacologically acceptable salts thereof.

0002

[Prior art] JP-A-59-36675 and JP-A-Sho. 5
No. 9-67284 discloses an indole derivative having an azabicyclo side chain, and JP-A-61-275276 discloses an indazole derivative, which is said to have serotonin 3 (5-HT3) receptor antagonistic activity. However, the pyrazolo[1,5-a]pyridine derivatives according to the present invention have not been known at all so far.

0003

[Problems to be Solved by the Invention] When using these compounds as medicines, there is a strong desire in clinical practice to develop new drugs that are more effective and have fewer side effects.

0004

[Means for Solving the Problems] As a result of intensive research in view of the above-mentioned circumstances, the present inventors have found that the novel pyrazolo[1,5-a]pyridine derivative according to the present invention has excellent serotonin antagonistic activity. They discovered this and completed the present invention. That is, the present invention provides the following general formula (I)

[Formula 2] (wherein, R1 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom or a lower alkyl group,
represents a hydrogen atom, a lower alkyl group or a benzyl group, X represents -NH- or -O-, and n represents an integer of 2 or 3. )
The present invention relates to a pyrazolo[1,5-a]pyridine derivative represented by the following formula and a pharmacologically acceptable salt thereof.

In the general formula (I) of the present invention, the lower alkyl groups represented by R1 and R2 include, for example,
Methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, s
Examples include ec-butyl group and tert-butyl group.

Examples of the pharmacologically acceptable salts of the compound represented by the general formula (I) of the present invention include mineral salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Acid salts, or organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, mandelic acid, etc. etc.

The compound represented by the general formula (I) of the present invention has different conformations. For example, the piperidine ring to which the amide moiety is attached may have a chair, boat, or intermediate configuration. There are also two different steric configurations in the amide moiety. That is, if the carbon part of the piperidine ring is drawn as a plane, the nitrogen atom at position 1 of the piperidine ring can be drawn above the plane, and the alkylene bridge can be drawn below the plane, but on the other hand, the amide part can be drawn like the alkylene bridge. It is located below the plane and has an α-configuration. This configuration is an endo configuration and corresponds to the configuration of tropin and the like. The other case is when the amide moiety is located above the plane like the nitrogen atom of the piperidine ring, and has a β-configuration. This configuration is an exo configuration and corresponds to the configuration of pseudotropin and the like. Hereinafter, exo/endo nomenclature will be used.

Particularly preferred compounds of the present invention include the following compounds. exo-N-(8-methyl-8-azabicyclo[3.2
．． 1] Oct-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamidoendo-N-(8-methyl-8-azabicyclo[3.2
．． 1] Oct-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide exo-N-(9-methyl-9-azabicyclo[3.3
．． 1]Non-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamidoendo-N-(9-methyl-9-azabicyclo[3.3
．． 1] Non-3-yl) pyrazolo[1,5-a]pyridine-3-carboxamidoendo-5-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) Pyrazolo [1,
5-a] Pyridine-3-carboxamide endo-5-methyl-N-(9-methyl-9-azabicyclo[3.3.
1]Non-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamidoendo-N-(9-ethyl-9-azabicyclo[3.3
．． 1]Non-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamidoendo-N-(9-benzyl-9-azabicyclo[3.
3.1] non-3-yl) pyrazolo [1,5-a] pyridine-3-carboxamide endo-N-(9-azabicyclo [3.3.1] non-
3-yl) pyrazolo[1,5-a]pyridine-3-carboxamide endo-8-methyl-8-azabicyclo[3.2.1]
Oct-3-yl pyrazolo[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

The novel pyrazolo[1,5-a]pyridine derivative of the present invention represented by the general formula (I) can be produced by various methods.

According to the first mode of the method for producing a compound according to the present invention, the compound in which R2 in the general formula (I) is a lower alkyl group or a benzyl group and X is -NH-,
The following general formula (II)

After converting the carboxylic acid represented by the formula (wherein R1 has the same meaning as above) into an acid chloride according to a conventional method, the following general formula (III) is obtained.

Presence of an amino compound represented by [Formula 4] (wherein R3 represents a lower alkyl group or a benzyl group, and n represents the same meaning as above) and a base as a dehydrohalogenation agent in an organic solvent. It can be produced by condensation below.

Examples of the organic solvent used in this production method include dichloromethane, chloroform, carbon tetrachloride, halogenated hydrocarbon solvents such as 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N , N-dimethylformamide, etc., and examples of the base used include triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.
4.0] undec-7-ene, pyridine, etc.,
Further, the reaction is carried out at a temperature ranging from ice cooling to the reflux temperature of the solvent.

[0012] The compound represented by the general formula (II), which is the starting material in this production method, is a known compound and has been published in The Journal of Organic Chemistry (The Journal of Organic Chemistry).
Chemistry), Volume 33, Page 2062, 1
It can be produced by the method described in 1968.

According to the second mode of the method for producing compounds according to the present invention, the compound in which R2 in the general formula (I) is a lower alkyl group or a benzyl group and X is -O- Using the carboxylic acid represented by (II) according to a conventional method,
After converting into acid chloride, the following general formula (IV)

It can be produced by condensing an alcohol compound represented by the following formula with an alkali metal salt such as a lithium salt or a sodium salt in an organic solvent. can.

[0014] Examples of the organic solvent used in this production method include aprotic polar solvents such as tetrahydrofuran and 1,4-dioxane, and the reaction is carried out in a temperature range from -100°C to room temperature. It will be done.

[0015] The alkali metal salt of the compound represented by the general formula (IV) used in this production method can be prepared by, for example, reacting the compound represented by the general formula (IV) with n-butyllithium in tetrahydrofuran. It can be manufactured by a conventional method as described above.

According to the third mode of the method for producing a compound according to the present invention, the compound in which R2 in the general formula (I) is a hydrogen atom is a compound in which R2 in the general formula (I) is a benzyl group. can be produced by hydrogenolyzing it in an organic solvent under a transition metal catalyst.

Examples of organic solvents used in this production method include methanol, ethanol, and acetic acid, and examples of transition metal catalysts used include palladium-carbon, palladium hydroxide-carbon, and platinum oxide. , Raney nickel, etc., and the reaction is carried out in a temperature range from room temperature to 100°C and a pressure range from normal pressure to 150 atmospheres.

According to the fourth mode of the method for producing a compound according to the present invention, the compound in which R2 in the general formula (I) is a lower alkyl group or a benzyl group is a compound in which R2 in the general formula (I) is hydrogen. In the compound which is an atom, the following general formula (V)R
A halogenated compound represented by 3 -Y (V) (in the formula, Y represents a halogen atom and R3 represents the same meaning as above) in an organic solvent in the presence of a base as a dehydrohalogenation agent. It can be produced by reaction.

Examples of the organic solvent used in this production method include alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, tetrahydrofuran, acetonitrile,
Examples include aprotic polar solvents such as N,N-dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide, and examples of bases used include:
Examples include metallic sodium, sodium hydride, sodium amide, sodium carbonate, potassium carbonate, etc., and the reaction is carried out at a temperature ranging from ice cooling to the reflux temperature of the solvent.

The above general formula (I) produced in this way
The novel pyrazolo[1,5-a]pyridine derivative and its pharmacologically acceptable salts can be prepared into tablets, powders, capsules, injections, eye drops, nasal drops, inhalers or It can be made into preparations such as external preparations, and is clinically administered by oral or parenteral administration. The dosage depends on the symptoms to be treated and the administration method, but is usually 1 to 1000 mg per day when administered orally to adults.

[0021]

[Examples] The present invention will be explained below with reference to Examples.
The invention is not limited to the specific details of these examples.

Example 1 Exo-N-(8-methyl-8-azabicyclo[3.2
．． 1] Oct-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide pyrazolo[1,5-a]pyridine-3-carboxylic acid 1.
00 g in 5 ml of dichloromethane under stirring at room temperature.
Add 0.81 ml of oxalyl chloride, then N
, N-dimethylformamide was added. After stirring at room temperature for 2 hours, the reaction solution was dried under reduced pressure to give pyrazolo[1,
5-a] Pyridine-3-carbonyl chloride was obtained. Exo-8-methyl-8-azabicyclo [3.3.1]
Octane-3-amine 0.95g, triethylamine 1
．． The above-obtained pyrazolo[1,5-a]pyridine-
3-carbonyl chloride (total amount) in dichloromethane 7
ml solution was added dropwise. After stirring at room temperature for 1.5 hours, the reaction solution was washed with water and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate to give a melting point of 197.
0.88 g of pale brown plate crystals with a temperature of 5 to 199°C were obtained. Elemental analysis value C16H20N4 O Theoretical value C, 67.58; H, 7.09;
N, 19.70 experimental value C, 67.41; H,
7.08; N, 19.69

Compounds of Examples 2 to 8 were obtained according to the method of Example 1.

Example 2 Endo-N-(8-methyl-8-azabicyclo[3.2
．． 1] Oct-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Properties Pale yellow needles (EtOH) Melting point 140
〜142℃ 208〜209℃ Elemental analysis value C16H20N4 O・H2O theoretical value C, 63.56; H, 7.33; N, 1
8.53 Experimental value C, 63.82; H, 7.
15; N, 18.45

Example 3 Exo-N-(9-methyl-9-azabicyclo[3.3
．． 1]Non-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Properties Colorless feathery crystals (AcOEt) Melting point 1
68-169.5°C Elemental analysis value C17H22N4O Theoretical value C, 68.43; H, 7.43;
N, 18.78 experimental value C, 68.39; H,
7.68; N, 18.70

Example 4 Endo-N-(9-methyl-9-azabicyclo[3.3
．． 1] Non-3-yl) pyrazolo[1,5-a]pyridine-3-carboxamide Properties Pale brown needle crystals (AcOEt) Melting point 1
76-177°C Elemental analysis value C17H22N4O Theoretical value C, 68.43; H, 7.43;
N, 18.78 experimental value C, 68.41; H,
7.44; N, 18.81

Example 5 Endo-5-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)pyrazolo[1,
5-a] Pyridine-3-carboxamide Properties Slight yellow prismatic crystals (EtOH) Melting point 198-199°C Elemental analysis value C17H22N4 O・1/2H2O theoretical value C, 66.42; H, 7.54; N
, 18.23 experimental value C, 66.51; H,
7.48; N, 18.18

Example 6 Endo-5-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)pyrazolo[1,5
-a]Pyridine-3-carboxamide Properties Slight yellow needle crystals (EtOH) Melting point 199
~201°C Elemental analysis value C18H24N4O Theoretical value C, 69.20; H, 7.74;
N, 17.93 experimental value C, 69.13; H,
7.93; N, 17.74

Example 7 Endo-N-(9-ethyl-9-azabicyclo[3.3
．． 1] Non-3-yl) pyrazolo[1,5-a]pyridine-3-carboxamide Properties Colorless needle crystals (AcOEt-n-Hexan
e) Melting point 152-155°C Elemental analysis value C18H24N4O Theoretical value C, 69.20; H, 7.74;
N, 17.93 experimental value C, 69.15; H,
7.91; N, 17.85

Example 8 Endo-N-(9-benzyl-9-azabicyclo [3.
3.1]Non-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Properties Colorless needle crystals (DMF) Melting point 210-213°C 219-220°C Elemental analysis value C23H26N4O Theoretical value C, 73 .77; H, 7.00;
N, 14.96 experimental value C, 73.53; H,
7.10; N, 14.87

Example 9 Endo-N-(9-azabicyclo[3.3.1]Non-
3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide-N-(9-phenylmethyl-9-azabicyclo[3.3.1]non-3-yl)pyrazolo[1,5-a]
]Pyridine-3-carboxamide 1.47g, acetic acid 4m
Pearlman's catalyst (
0.22 g of 20% palladium hydroxide on carbon was added, and hydrogenolysis was performed at room temperature and pressure for 3 hours. The catalyst was removed and the filtrate was concentrated under reduced pressure. Add water and 10% hydrochloric acid to the residue to adjust the pH.
After the solution was reduced to about 200 ml, the solution was washed with ethyl ether. Potassium carbonate was added to the aqueous layer to adjust the pH to approximately 9, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from methanol,
0.56 g of colorless needle crystals with melting points of 100-103°C and 161-162°C were obtained. Elemental analysis value C16H20N4 O・7/4H2O theoretical value C, 60.84; H, 7.50; N
, 17.74 experimental value C, 60.72; H,
7.38; N, 17.73

Example 10 Endo-8-methyl-8-azabicyclo [3.2.1]
Oct-3-yl pyrazolo[1,5-a]pyridine-3-carboxylatepyrazolo[1,5-a]pyridine-3-carboxylic acid 1.
To a suspension of 0 g in 8 ml of dichloromethane, 0.81 ml of oxalyl chloride was added under stirring at room temperature, and then N,N
- 1 drop of dimethylformamide was added. After stirring at room temperature for 2 hours, the reaction solution was dried under reduced pressure, and 10 ml of toluene was added to the residue and dried under reduced pressure to obtain pyrazolo[1,5-a].
Pyridine-3-carbonyl chloride was obtained. In a nitrogen atmosphere, 1.39 g of tropine in anhydrous tetrahydrofuran 6
．． Add n-butyllithium/n- to 60ml solution under ice-cooling and stirring.
6.20 ml of hexane solution (1.58M) was added dropwise, and the mixture was stirred for 15 minutes. Next, the pyrazolo obtained above [1
, 5-a] A solution of pyridine-3-carbonyl chloride (total amount) in 4.40 ml of anhydrous tetrahydrofuran was added dropwise. After stirring for 2 hours under ice cooling, the reaction solution was adjusted to pH approximately 10 with a 10% aqueous hydrochloric acid solution, tetrahydrofuran was distilled off under reduced pressure, and then extracted with dichloromethane. After drying the extract over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain yellow needle-shaped crystals.
74g was obtained. This was recrystallized from ethyl acetate, with a melting point of 120-121°C.
1.01 g of pale yellow needle crystals were obtained. Elemental analysis value C16H19N3 O2 Theoretical value C
, 67.35; H, 6.71; N, 14.7
3 Experimental value C, 67.33; H, 6.57;
N, 14.64

According to the method of Example 10, the compound of Example 11 was obtained.

Example 11 Endo-8-methyl-8-azabicyclo [3.2.1]
Oct-3-yl 5-methylpyrazolo[1,5-a
]Pyridine-3-carboxylate properties Slight yellow prismatic crystals (AcOEt) Melting point
141.5-143℃ Elemental analysis value C17H22N3 O2 Theoretical value C
, 67.98; H, 7.38; N, 13.9
9 Experimental value C, 68.13; H, 7.13;
N, 13.91

[0035]

Effect of the invention: The above general formula (I) produced in this way
) The novel pyrazolo[1,5-a]pyridine derivatives and their pharmacologically acceptable salts are excellent 5-H
It has T3 receptor antagonistic action and is extremely useful as an antiemetic, stomachic, antimigraine, etc.

Claims (1)

[Claims] Claim 1: The following general formula [Formula 1] (wherein, R1 is a hydrogen atom or a lower alkyl group, R2
represents a hydrogen atom, a lower alkyl group or a benzyl group, X represents -NH- or -O-, and n represents an integer of 2 or 3. )
Pyrazolo[1,5-a]pyridine derivatives and pharmacologically acceptable salts thereof.