JPS5953278B2 - Aralkylamine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula Υ)-< ■■ [I] good benzyl, lower alkylcarbonyl, or R1,
R2 represents a group that forms morpholine together with the adjacent nitrogen atom.

A represents lower alkylene. ) or an acid addition salt thereof.

The compound of general formula [1] has pharmacological effects such as anti-inflammatory, analgesic, antipyretic, inhibition of blood platelet aggregation, and antiallergy, and is useful, for example, as an anti-inflammatory and analgesic agent or as a synthetic intermediate thereof.

In the general formula [I], lower alkoxy is methoxy, ethoxy, etc., lower alkylcarbonyl is a1 cetyl,
Examples of lower alkylenes such as propionyl 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.

2(1) formula 0゛゛”.

. , 2 and the general formula, Hal-CH2CO□A-N<Nini [■]5 [In the formula, lhl represents halogen (chlorine, bromine, etc.), and the other symbols have the same meanings as above.

] in an appropriate 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 formula [■] may be used in excess, or sodium bicarbonate, sodium carbonate, or potassium carbonate may be used. Carbonates are suitable.

Further, a compound in which Rl and R2 are both hydrogen in general formula [1] can be synthesized by hydrolyzing a compound in which one of Rl and R2 is hydrogen and the other is lower alkylcarbonyl.

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 [In the formula, x represents a reactive derivative formed from halogen (chlorine, bromine, etc.) or alcohol (i≦methylbenzenesulfonyloxy, methanesulfonyloxy, etc.), and other The symbols have the same meanings as above.] Compounds represented by the general formula (wherein, each symbol has the same meanings as above).

However, lower alkyl carbonyl is excluded. ) in a suitable solvent in the presence of a deoxidizing agent.

Obtained by reaction in the presence of a deoxidizing 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 R3 and R4 each represent hydrogen, lower alkyl, or phenyl which may have lower alkoxy as a substituent).

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

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 HenderschOt et al. [J. Pharmac
OLexp. Ther. , Volume 25, Page 237 (19
Female Dd mice weighing around 20 g (1957)]
The test compound was orally administered to 6 animals per group, and 0% after 1 hour.
0.2ml/20g of 02% phenylquinone solution was administered intraperitoneally, and the degree of stretching symptoms was then observed for 20 minutes. ED,
The O value was determined.

Experimental method 2 Anti-inflammatory effect (ultraviolet erythema method) Wiid blindness / et al.'s method [Arch. intPharma
cOdyn, Vol. 6, p. 261 (1958)].

Using a guinea pig weighing between 25.0 and 450 g, a rubber plate with three holes of 7111 in diameter was placed on the side of the guinea pig, which had been pre-dressed, and a 600 W mercury lamp was used to heat the guinea pig from a distance of 15 mm.
Irradiated for 0 seconds. After 2 hours, reduce the degree of erythema formation.
Scoring was performed according to the scoring method of er et al., and the total score was 1.
5 or less was considered effective, and the effectiveness rate was determined.

The test compound solution was orally administered in half doses (10 d/Kg in total) one hour before and immediately after irradiation. Experimental method 3 Anti-edema effect (carrageenin method) Winter et al.'s method [PrOC. SOC. EXPtl
．． BiOl. Med. , vol. 544 pages (197
A test compound solution was orally administered (25d/K) to DOnryu rats (5 animals per group) weighing around 150g during
9) After 1 hour, 0.05 d of 1% carrageenan was subcutaneously injected into the foot pad of the right hind leg, the foot volume was measured after a certain period of time, and the percentage increase relative to the foot volume before carrageenin administration was calculated, and the inhibition rate relative to the control group was determined. I asked for

The results of this experiment are shown as the average value of 2 to 3 repeated actual fittings and are summarized in Table 1 as follows.

When the compound of general formula [1] or its acid addition salt is used as a medicine, it can be used as such or mixed with an appropriate pharmacologically acceptable carrier or diluent, and can be used as a powder, granule, or tablet.
It can be administered orally or parenterally in the form of a 1K capsule, a saline injection, or the like.

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

Example 1 2-[4-(imidazo[2,1-b]thiazole-6-
Add 12.7 g of ino(c)phenyl]propanol to 50 d of pyridine, and add 1 tosyl chloride while stirring.
Add 1.4 g and keep at 60-70°C for 2 hours, pour the reaction solution into water, extract with 200 ml of ethyl acetate, and wash with water.

After drying with magnesium sulfate, the mixture is concentrated under reduced pressure to obtain a tosylated product. Add this to 100% ethanol
d, add 9 g of morpholine, and heat under reflux on a water bath for 5 hours. Concentrate under reduced pressure to give ethyl acetate 20077! l
Extract and wash with water. After drying over magnesium sulfate and concentrating under reduced pressure, the obtained oil is converted into a fumarate salt, which is recrystallized from ethanol to give colorless prismatic crystals with a melting point of 17.
2-[4-(imidazo[2,1-b
7.5 g of [thiazol-6-yl)phenyl]-1-molpolynobu 0-pan fumarate are obtained. Example
2 40 g of 4-(2-acetylaminoethyl)-ω-cucaracetophenone and 20 g of 2-aminothiazole are added to 300 d of alcohol and heated under reflux for 4 hours.

Concentrate under reduced pressure, add 200 d of water and 17 g of sodium hydrogen carbonate, and leave to cool on a water bath for 2 hours. The precipitated crystals are filtered out, washed with water, and crystallized from alcohol to give a melting point of 1.
1-acetylamino-2-[4-(imidazo[2,1-b]thiazole-6), which is a colorless needle crystal with a temperature of 89 to 190°C.
20 g of -yl)phenyl]ethane are obtained. Example
7 g of 34-(imidazo[2,1-b]thiazol-6-yl)phenethylacetamide was placed in 50 ml of concentrated hydrochloric acid and heated under reflux for 7 hours.

After cooling, 10? Make alkaline with sodium hydroxide solution and collect the formed crystals. After washing with water, recrystallization from about 80% isopropanol produces colorless needle-shaped crystals with a melting point of 108.
5.0 g of 4-(imidazo[2,1-b]thiazole-6-inoliphenethylamine of ~109 crystal C) is obtained.
Example 4 5.0 g of 1-methyl-2-[4-(imidazo[2,1-b]thiazol-6-inoliphenyl]ethylamine and 3.0 g of 3,4,5-trimethoxybenzaldehyde
g to alcohol 10077! 1 hour and heated under reflux for 1 hour.

Then, the mixture is cooled on ice, and 0.8 g of sodium borohydride is added for reduction. Concentrate under reduced pressure, add water and dilute with ethyl acetate 2
After extraction with 00d, it is washed with water, dried over potassium carbonate, and concentrated under reduced pressure. 25% hydrochloric acid-isopropanol was added to the remaining oil to form a hydrochloride salt, and after collecting the resulting crystals, recrystallization from alcohol gave a colorless needle crystal with a melting point of 241.
N-[1-methyl-2-(4-(imidazo[2,1
-b]thiazol-6-yl)phenylethyl]-3,
4,5-trimethoxybenzylamine dihydrochloride is obtained. The following compounds are synthesized in the same manner.

Claims (1)

[Claims] 1. An aralkylamine derivative or its acid addition salt represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼. (In the formula, R^1 and R^2 each represent hydrogen, benzyl which may have lower alkoxy on the benzene ring as a substituent, lower alkylcarbonyl, or R^1,
R^2 represents a group that forms morpholine together with the adjacent nitrogen atom. A represents lower alkylene. )