JPS59112991A - Alcoholic derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (A is lower alkylene; X is H or lower alkylcarbonyl) or an acid addition salt thereof. EXAMPLE:2-{4-[Imidazo(2,1-b)thiazol-6-yl]phenyl}-1-propanol. USE:An analgesic, antipyretic and anti-inflammatory agent or a synthetic intermediate therefor. PROCESS:A compound of formula II (Hal is a halogen, e.g. chlorine or bromine), e.g. 2-(4-chloroacetylphenyl)propyl acetate, is reacted with a 2-aminothiazole of formula III preferably at 1:2 molar ratio in an alcoholic solvent, e.g. methanol, under refluxing.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an alcohol derivative represented by the general formula (wherein A is lower alkylene, X is hydrogen, and lower alkylcarbonyl t indicates t-0) or an acid addition salt thereof.

In the above definition, lower alkyl refers to methyl, ethyl, etc., and lower alkylene refers to methylene, ethylene, trimethylene, propylene, etc.

According to the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (wherein A and X have the same meanings as above, and Hal represents a halogen (chlorine, bromine, etc.). ] is produced by reacting the compound represented by the formula with the compound represented by the formula.

The reaction is preferably carried out in an alcoholic solvent such as methanol or ethanol under reflux. At that time, the compound of formula ([1) is used as a deoxidizer in an amount twice the molar amount of the compound of general formula (11), but sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide is used. May be added.

Further, a compound in general formula (I) in which X is hydrogen can be produced by hydrolyzing a compound in which X is lower alkylcarbonyl.

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

Furthermore, the compound of general formula (I) can be obtained by subjecting a compound represented by the general formula (wherein R represents hydrogen, lower alkyl, or lower alkoxy, and 2 represents a single bond or represents lower alkylene to a reduction reaction. It can also be obtained by

The reaction is carried out by using sodium borohydride in a solvent such as methanol or ethanol when R is hydrogen or lower alkyl, or by using lithium aluminum hydride in tetrahydrofuran when R is lower alkoxy. or using sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as benzene or toluene.

Compounds of general formula (I) having an asymmetric carbon can usually be separated into optically active enantiomers by well-known methods.

The compound of general formula (I) can be converted into an acid addition salt by a conventional method.

As is clear from the following experiments, the compound of general formula (I) has analgesic, antipyretic, and antiinflammatory effects, and is useful, for example, as an analgesic and antiinflammatory agent, and as a synthetic intermediate thereof.

Next, the pharmacological action of the compound of general formula (I) will be shown along with experimental methods.

Experimental method l Analgesic effect (phenylquinone method) Hende
The method of rgchot et al. [J, 'Pharmaco 1. e
xp.

Ther, Volume 125, Page 237 (1957)
] According to Female DD mice weighing around 20g (6 per group)
The test compound was orally administered to 0.02%
A phenylquinone solution was administered intraperitoneally at 0.2 m/20 g, and the frequency of stretch symptoms was then observed for 20 minutes, and the ED5o value was determined from the inhibition rate relative to the control group using the probit method.

Experimental method 2 Anti-inflammatory action (ultraviolet erythema method) Winder et al.'s method (Arch, lnt, Pharmacodyn.

Volume 116, page 261 (1958)].

Using a guinea pig weighing 250 to 450 g, a rubber plate with three 7M diameter holes was placed on the flank, which had been previously depilated, and irradiated with a 600 W mercury lamp from a distance of 151 for 80 seconds. After 2 hours, the degree of erythema formation was scored according to the scoring method of Wlnder et al., and a total score of 1.5 or less was considered effective, and the effectiveness rate was determined. In addition, the test compound solution was applied in half volume 1 hour before and immediately after irradiation (100% in total volume).
tr, l/Kg) was administered orally.

Experimental method 3 Anti-edema effect (carrageenan method) Winter
(Proe, Soc, Exptl, Biol.

Med, volume iti, page 544 (1971)]. A test compound solution was orally administered (25 ml!/Kg) to Donryu rats (5 rats per group) weighing around 150 g,
After 1 hour, 0.05% of 1% carrageenan was subcutaneously injected into the right hind foot pad, and after a certain period of time, the paw volume was measured, and the percentage increase with respect to the paw volume before carrageenan administration was calculated to determine the inhibition rate 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.

Table 1 Test compound A in the table is as follows.

A: 2-(4-(imidazo[:2.1-b)thiazol-6-yl)phenyl)-1-7' lovanol When the compound of general formula (I) or its acid addition salt is used as a medicine, it By itself or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, powders, granules, tablets,
It can be administered orally or parenterally in the form of capsules, tablets, injections, etc. The dosage varies depending on the symptoms, etc., but is preferably 50 to 150 μm.

one or less margin one The present invention will be specifically explained below with reference to Examples.

Example I 127 g of 2-4-thalolacetylphenyl)propyl acetate and 10 g of 2-aminothiazole are added to 1 oatnl of alcohol and heated under reflux on a water bath for 4 hours. Concentrate the alcohol under reduced pressure and add 200ml of ethyl acetate.
After extraction with water and drying with magnesium sulfate. When the crystals obtained by concentrating under reduced pressure are recrystallized from isopropanol, 2.
-1:4-(imidazo(2,1-b)thiazole-6-
Fumecil] propyl acetate 8.0 g Ka(
W Rahru.

Example 2 8.0 g of 2-(4-(imidazo(2,'I-b,:Ithiazol-6-yl)fumesyl)propyl acetate was added to 50% alcohol and hydroxylated to 20%)
Add IJ Kum solution Ionl and leave at room temperature for about 1 hour. Concentrate under reduced pressure, separate the resulting crystals, wash with water, and recrystallize from alcohol to obtain 2-[4-(imidazo(2,1-b:)thiazole), which is a colorless needle crystal with a melting point of 176-178°C. -6-yl)phenyl)-1-7' lobanol 4.5 g was obtained.

Example 3 4-(imidazo[2,1-b)thiazol-6-yl)
A solution of 8.6 g of ethyl phenylacetate dissolved in 200 ml of tetrahydride 7 ml was added dropwise to a solution in which 2.3 g of aluminum hydride was suspended in 50 ml of tetrahydro 7 ml under water cooling. After being kept at room temperature for about 1 hour, it is heated under reflux on a water bath for 1 hour. The reaction solution is cooled with water, and a saturated aqueous solution of Lotusel's salt is added dropwise to decompose excess lyticum aluminum hydride. After separating the tetrahydrofuran layer and concentrating it under reduced pressure, the resulting crystals were recrystallized from Improper Tool to give 4-(imidazo[2,1-b
) thiazol-6-yl) phenethyl alcohol 4.5
g is obtained.

Thereafter, the following compounds are synthesized in the same manner.

Claims (1)

[Scope of Claims] An alcohol derivative or an acid addition salt thereof represented by the general formula (wherein, human represents lower alkylene, and X represents hydrogen or lower alkylcarbonyl)0