JPS5910675B2 - Aralkylamine derivatives - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula R1 R.

□AN<R4 [I] (wherein R1 is hydrogen, lower alkyl or halogen,
R2 represents hydrogen or lower alkyl, R3 and R4 each represent hydrogen, lower alkyl, benzyl, lower alkylcarbonyl, or benzoyl which may have halogen or lower alkoxy as a substituent, or R3
, R4 together with the adjacent nitrogen atom represents a group forming piperidine or piperazine substituted at the N position with hydroxy lower alkyl or halogen-substituted phenyl.

A represents lower alkylene. ) or an acid addition salt thereof. The compound of general formula [I] has pharmacological effects such as anti-inflammatory, analgesic, antipyretic, platelet aggregation inhibition, and anti-allergy, and is useful, for example, as an anti-inflammatory or analgesic or a synthetic intermediate thereof.

In the general formula [I], lower alkyl is methyl, ethyl, etc., halogen is chlorine, bromine, fluorine, etc., lower alkoxy is methoxy, ethoxy, methylenedioxy, etc., lower alkylcarbonyl is acetyl, propionyl, etc.
Examples of lower alkylene include methylene, ethylene, propylene, trimethylene, and methylmethylene.

According to the present invention, the compound of general formula [I] can be synthesized by the following method.

(1) General formula [■] (In the formula, R1 has the same meaning as above.

) and the general formula [where Hal represents halogen (chlorine, bromine, etc.), and the other symbols have the same meanings as above.

] in a suitable solvent in the presence of a deoxidizing agent at room temperature or under reflux of the solvent used.

Alcoholic solvents such as methanol, ethanol, and propanol are suitable as solvents, and as deoxidizing agents, the compound of the general formula [] may be used in excess, or sodium bicarbonate, sodium carbonate, potassium carbonate, etc. Carbonates are suitable.

Moreover, R3. of general formula [1]. A compound in which both R4 are hydrogen can be synthesized by hydrolyzing a compound in which one of R3 and R4 is hydrogen and the other is lower alkylcarbonyl or benzoyl.

This reaction is carried out under basic conditions (sodium hydroxide, potassium hydroxide, etc.) or preferably under acidic conditions (hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

(2) General formula [wherein X is a reactive derivative formed from halogen (chlorine, bromine, etc.) or alcohol (p
-methylbenzenesulfonyloxy, methanesulfonyloxy, etc.), and the other symbols have the same meanings as above.

] and the general formula (In the formula, each symbol has the same meaning as above.

However, lower alkyl carbonyl and benzoyl are excluded. )
It can be obtained by reacting the compound represented by the following in an appropriate solvent in the presence of an acid absorbing agent. Suitable deoxidizers include organic bases such as triethylamine and pyridine, and carbonates such as potassium carbonate and sodium carbonate. Suitable solvents include benzene, toluene, dimethylformamide, ethanol, methanol, and propanol. (3) General formula (in the formula, each symbol has the same meaning as above).

) and the general formula (wherein R5 and R6 each represent hydrogen, lower alkyl, or phenyl which may have halogen or lower alkoxy as a substituent.

), methanol, ethanol,
It can be obtained by reducing a compound obtained by heating under reflux in an alcoholic solvent such as propanol with, for example, sodium borohydride. The compound of general formula [1] thus obtained can be converted into an acid addition salt by a conventional method.

The acid used to form the acid addition salt can be appropriately selected from hydrochloric acid, sulfuric acid, hydrobromic acid, maleic acid, fumaric acid, malic acid, and the like. Next, the general formula [
The pharmacological action of the compound 1] is shown together with the experimental method.

Experimental method 1. Analgesic effect (phenylquinone method) Method of HeIxlerschOt et al. [J. Pharma
cOl. exp. Ther. , volume 125, page 237 (
(1957)].

The test compound was orally administered to female ml mice (6 mice per group) weighing around 20 tons, and 1 hour later, 0.2 ml/20 tons of 0.02% phenylquinone solution was administered intraperitoneally, and then 20
The frequency of minute stretching symptoms was observed, and the ED5O value was determined from the suppression rate relative to the control group by the propit method. Experimental method 2. Anti-inflammatory action (ultraviolet erythema method) Winder et al.'s method [Arch. int. Pharm
acOdyn. , vol. 116, p. 261 (1958)
].

Using a guinea pig weighing 250 to 450 f, a rubber plate with three holes of 7,711 mm in diameter was placed on the side of the guinea pig, which had been dehaired beforehand, and a 600 W mercury lamp was used to heat the guinea pig for 15 mm. 80 from a distance of
Irradiated for seconds. After 2 hours, check the degree of erythema formation.
Scoring was done according to the scoring method of R et al., and the total score was 1.5.
or less was considered effective, and the effectiveness rate was calculated.

The test compound solution was orally administered in half amounts (total amount: 10 ml<9) one hour before and immediately after irradiation. Experimental method 3 Anti-edema effect (carrageenan method) Winter et al.'s method [PrOc. SOc. Exptl
．． BiOl. Med. , vol. 111, p. 544 (197
1)].

The test compound solution was orally administered (25 ml/Kg) to DOnryu rats (5 rats per group) weighing around 150 tons, and 1 hour later, 0.05 ml of 1% carrageenan was injected subcutaneously into the right hind paw, and after a certain period of time, the paw volume was The percentage of increase in the paw volume before carrageenan administration was calculated, and the inhibition rate was determined relative to the control group. This inhibition rate was shown as the average value of 2 to 3 repeated experiments. The results of the above experiments are summarized in Table 1 as follows. A: 1-amino-2-[4-(imidazo[1.21a]pyridin-2-yl)phenyl]ethane hydrochloride/hemihydrate Compound of general formula [1] or its acid addition When salts are used as pharmaceuticals, they can be administered orally by themselves or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents in the form of powders, granules, tablets, capsules, suppositories, injections, etc. Or it can be administered parenterally.

Although the dosage varies depending on the symptoms, it is preferably 50 to 150η. The present invention will be specifically explained below with reference to Examples.

Example 1 24 tons of 4-(2-acetylaminoethyl)-ω-chloroacetophenone and 9.6 tons of 2-aminopyridine were added to 100 ml of ethanol and heated under reflux for 5 hours.

Ethanol was distilled off under reduced pressure, 10 t of sodium hydrogen carbonate and 100 d of water were added to the residue, and the mixture was heated on a water bath at 80°C for 2 hours.
Heat for an hour. After cooling, the resulting crystals are collected and recrystallized from 2-propanol to give 1-acetylamino-2-[4-(
18.77 of imidazo[1.2-a]pyridin-2-yl)phenyl]ethane are obtained. Example 2 1-acetylamino-2-[4-(imidazo[1,2-
a]Pyridin-2-yl)phenyl]ethane 18.7t
was dissolved in 30 ml of concentrated hydrochloric acid and heated under reflux for 6 hours.

After cooling, the mixture is made alkaline with 20% sodium hydroxide, and the precipitated crystals are collected. After washing with water, it is converted into a hydrochloride salt and recrystallized from a mixed solvent of methanol and isopropyl ether to form colorless prismatic crystals of 1-amino-2 with a melting point of 315°C or higher.
-[4-(imidazo[1,2-a]pyridin-2-ino phenyl]ethane dihydrochloride 1/2 hydrate 10.2
t is obtained. Example 3 1-(imidazo[1,2a]pyridin-2-yl)phenethyl obtained by reacting 4-(imidazo[1,2-a]pyridin-2-yl)phenethyl alcohol and tosyl chloride. Ton rate 8.0t and piperazine 5
ml was added to 100 ml of alcohol and heated under reflux for 7 hours.

After the reaction, the alcohol is concentrated under reduced pressure, water is added, and the mixture is left to stand. When the resulting crystals are collected and recrystallized from toluene,
2-[4-
(2-piveridinoethyl)phenyl]imidazo[1・2
-a] 3.4 t of pyridine is obtained. When this is converted into a hydrochloride by a conventional method, the corresponding hydrochloride 3/2 hydrate having a melting point of 278 to 280°C (decomposition) is obtained. Example 4 5.2 t of 1-amino-2-[4-imidazo[1,2-a]pyridin-2-yl)phenyl]ethane was dissolved in 100 ml of ethanol, and then 2.5 t of p-fluorobenzaldehyde was added. The mixture was refluxed on a water bath for 30 minutes, cooled, and reduced with 1.0 t of sodium borohydride at room temperature.
Concentrate under reduced pressure and make 100WLI! Extract with

After drying over potassium carbonate and concentrating under reduced pressure, 30% hydrochloric acid in 1-2-propanol was added to the resulting oil to obtain the hydrochloride salt, which was then recrystallized from cold ethanol to give white crystals of 1-( with a melting point of 235°C). P-fluorobenzylamino)-2
4.0 r of -[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propane dihydrochloride is obtained.
The following compounds are synthesized in the same manner.

Claims (1)

[Claims] 1. An aralkylamine derivative or an acid addition salt thereof represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼. (In the formula, R^1 represents hydrogen, lower alkyl or halogen,
R_2 represents hydrogen or lower alkyl, and R^3 and R^4 each represent hydrogen, lower alkyl, benzyl, lower alkylcarbonyl, or benzoyl which may have halogen or lower alkoxy as a substituent, or R^ 3. R^4 represents a group which, together with the adjacent nitrogen atom, forms piperidine or piperazine substituted at the N-position with hydroxy lower alkyl or halogen-substituted phenyl. A represents lower alkylene. ).