JPS59128372A - Pyridine derivative - Google Patents

Abstract

NEW MATERIAL:The pyridine derivative of formula (R<1> is H or lower alkyl; R<2> is R<1> or halogen; R<3> and R<4> are R<1>, cycloalkyl or together form hetero-ring with adjacent N; A is lower alkylene) and its acid addition salt. EXAMPLE:4'-(2-Pyridyl)-4-piperidinobutyrophenone dihydrochloride. USE:A drug such as analgesic and anti-inflammatory agent, etc. Dose: 10-2,000mg daily for adult by oral administration in 1- several divided doses. PROCESS:The compound of formula I can be prepared e.g. by reacting the compound of formula II (X is halogen or residue of reactive derivative derived from alcohol, e.g. p-tolylsulfonyl, methylsulfonyloxy, etc.) with the compound of formula III in a solvent in the presence of an acid acceptor at room temperature- the refluxing temperature of the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutically useful compound of the general formula (wherein R1 represents hydrogen, lower alkyl, R2 represents hydrogen, lower alkyl, or halogen; R3 and R4 are the same or different). , hydrogen, lower alkyl, cycloalkyl, or R and R represent a group forming a heterocycle with the adjacent nitrogen atom; A represents lower alkylene) or its acid. Concerning addition salts.

In the above definition, lower alkyl refers to methyl, ethyl, propyl, p, tyl, etc., halogen refers to chlorine, bromine, fluorine, etc., cycloalkyl refers to cyclohexyl, cyclopentyl, etc., lower alkylene refers to methylene, etc. ,
The heterocycle represented by ethylene and propylene is, for example,
It is a group represented by the formula (in the above formula, R and R represent hydrogen, trifluoromethyl, halogen, or lower alkyl).

In the present invention, the compound of general formula (I) can be produced, for example, by the method shown below.

1) The general formula (in the formula, X is a reactive Ii% conductor (p-) formed from halogen (chlorine, bromine, etc.), alcohol! has the same meaning as above. ) and a compound represented by
A method of reacting with a compound represented by the general formula (in the formula, each symbol has the same meaning as above). This reaction is carried out in a suitable solvent in the presence of a deoxidizing agent at room temperature or under reflux of the solvent used. Solvents include alcohols such as methanol, ethanol, propatool, and impropateur, aromatic hydrocarbons such as benzene, toluene, and xylene, N,N-dimethylformamide, and N-methylpyrrolidone, and deoxidizing agents. Suitable examples include triethylamine, pyridine, potassium chloride, and sodium carbonate.

2) This method is applied when A in the general formula (I) is ethylene, propylene, etc. , ethyl, etc.), formalin or paraformaldehyde and a compound represented by the general formula (ill'),
This method involves the so-called Mannich reaction. Although the well-known Mannich reaction conditions can be applied to this reaction, for example, it proceeds suitably by heating under reflux for several hours to several days in an alcoholic solvent.

The compound of general formula (I) thus obtained can form an acid addition salt by a conventional method.

Acids used to form acid addition salts include hydrochloric acid, sulfuric acid,
You can choose from among bromic acid, citric acid, maleic acid, fumaric acid, etc. as appropriate.

The compounds of general formula (I) and their acid addition salts obtained by the above method have pharmacological effects such as analgesic action, anti-inflammatory action, antipyretic action, platelet aggregation inhibiting action, and antihistamine action, for example, It is useful as a medicine such as analgesic and anti-inflammatory agent.

When the compound of the present invention is used as a medicine, it can be administered by itself or mixed with appropriate pharmacologically acceptable excipients, carriers, diluents, etc. [7. Or it can be administered parenterally. The dosage is
For oral administration, usually 10 mg to 200 mg per day for adults.
The dose is approximately 0 rng, and these doses are administered in one or several divided doses, but this may vary depending on age, body weight, and/or the severity of the condition to be treated and response to treatment.

The invention will be explained more specifically using the following examples.
It is not limited to these.

Example 1 4'-(2-pyridyl)-4-taloloptiroquenone 5
．． 2 g 1 piperidine 5 me to toluene 10 (1 me,
! : Added to a mixed solvent with 50ml of N,N-dimethylformamide and kept under reflux for 10 hours. After cooling, add water, separate the toluene layer, wash with water, and dehydrate and dry with potassium carbonate. Then, the mixture was heated under reduced pressure, and the residue was treated with 30% hydrochloric acid-improper tool to give a hydrochloride. The crystals are separated and recrystallized from impropatul to give 2.8 g of 4'-(2-pyridyl)-4-piperidinobutyrophenone dihydrochloride as pale yellow needle crystals. Melting point 228~
229°C The raw material compound 4°-(2-pyridyl)-4-talobutyrophenone is synthesized by the method shown by the following formula.

Melting point: 133-136°C Melting point: 113-114°C Melting temperature: 110°C Example 2 4°-(4-Methyl-2-pyridyl)-2°-methylacetophenone hydrochloride 1. F3g1 piperidine hydrochloride 40
g, 2.9 g of rose formaldehyde and 20 g of alcohol
0+++e and stirred and refluxed for 3 days.

Concentrate under reduced pressure, add 100% acetone, heat and leave to stand. The resulting crystals were collected and recrystallized from inpropatool to give 4'-(4-methyl-2-
3.2 g of pyridyl)-2°-methyl-3-piperidinopropiophenone sulfate are obtained. Melting point 205~2
06°C Example 3 6.5 g of 4'-(2-pyridyl)-2-glomoacetophenone hydrobromide, 5.8 g of 4-(3-trifluoromethylphenyl)piperazine, 6r of ethylazamine
n! Add it to 200++alcohol, dissolve it by heating, and leave it overnight at room temperature. '-(,2-pyridyl>-2-C4-(3-trifluoromethylphenyl)-1-piperazinyl]acetophenone is obtained. Melting point 163-164°C. This crystal is
Hydrochloride using 0% hydrochloric acid-ituburobanol solution,
When recrystallized from alcohol, the target product 4 is obtained in the form of dihydrochloride.
．． 6g is obtained. Melting point: 241'C (decomposition) Using the same method as described in E, the compound shown below was synthesized.

((-katana 4'-(2-pyridyl)-4-morpholinobutyrophenone-dihydrochloride Melting point 225-227℃ (0)
4'-(2-pyridyl)-4-pyrrolidinobutyrophenone-2 salt e) 4K melting AI 02-104℃ (
o) 4'-(2-pyridyl)-4-(4-(3-
Chlorophenyl)-1-hyperazinyl] phthyrophenone dihydrochloride 1/2 hydrate Melting point 232-234°C @4'-(2-pyridyl)-4-(4-phenyl-1-
Piperazinyl)butyrophenone 2m1la1/2 hydrate Melting point 226-227℃ 04''-(2-pyridyl)-4-(4-(4-methylphenyl)-1-piperazinylbutyrophenone dihydrochloride monohydrate Melting point: 226-227℃ 04°-(2-pyridyl)-4-(4-(3-trifluoromethylphenyl)=■-piperazinyl) butyrophenone 2-metallic acid salt Melting point: 254℃ (decomposition) 04'=(2 -pyridyl)-4-[41<3-ethylphenyl)-1-piperazinyl]phthylophenone dihydrochloride Melting point 235-236℃ (q) 4'-(2-pyridyl)-4-[4-(3-methyl phenyl)-1-piperazinyl]phthylophenone+12 hydrochloride Melting point 240°C
'f Loa enone-2 hydrochloride Melting point 222-225
"Cμ]no 4'-(2-pyridyl)-4-(digtylamino)butyrophenone, 2 salts, 1 dredge, 1/2 hydrate, melting point 86-90°C, 4'-(2-pyridyl)-4- C4-hydroxy-
4-(3-Trifluoromethylphenyl)piperidinocobutyrophenone-dihydrochloride l-hydrate Melting point 230-23
16C (■ 4"-(2-pyridyl)-3-C4'-(3-trifluoromethylphenyl)-1-piperazinyl] propiophenone dihydrochloride Ma2O7℃(9>4'
-(3-pyridyl)-3-piperidinopropiophenone dihydrochloride Melting point 202°C ((Table 4'-(2-pyridyl)-2°-chloro-3-piperidinopropiophenone 2 Hydrochloride Melting Q204205°C (phrase 4°-(3-pyridyl)-3-(dimethylamino)propiophenone dihydrochloride MLa190-191
°C (9) 4°-(2-pyridyl)-3-(N-methyl-N
-cyclohexylamino)propiophenone dihydrochloride Melting point 144-147°C (04°-(2-pyridyl) -'3- (dimethylamino)propiophenone @ di-salt Waa219°C
゛(0)4'-(2-pyridyl)-12-[4-(3-
Dihydrochloric acid scale ・1/2 hydrate Melting point 230℃ (0')
4'-(2-pyridyl)-2-[4-hydroxy-4
-(4-methylphenyl)piperidinocoacetophenone maleate M[199-200℃ (9) 4'-('2-pyridyl)L4-(4-carbamoyl-4-piperidinopiperidino)butyrophenone・Dihydrochloride Melting point: 265-266℃ Agent: Patent attorney Masaru Takamiyagi

Claims (1)

[Claims] 1. General formula (wherein R1 represents hydrogen, lower alkyl, R2 represents hydrogen, lower alkyl, or halogen. R3, R'Ld are the same or different, hydrogen, lower alkyl , cycloalkyl, or R3 and R4 represent a group forming a heterocycle with adjacent nitrogen atoms; A represents lower alkylene) or an acid addition salt thereof.