NO137550B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF ANTI-INFLAMMATORY ACTIVITY 2,4,5-TRISUBSTITUTED OXSAZOLE COMPOUNDS - Google Patents

Description

The present invention relates to the production of

new anti-inflammatory active 2, k,5-trisubstituted oxa-

soles with the general formula:

where A is cyclohexyl, thienyl or a radical:

where R is one or more substituents independently selected from the group hydrogen, lower alkyl and halogen, one of the radicals R^

and R? is a lower alkyl group and the other group

, where R^ and R^ are independently selected from hydrogen,

lower alkyl and cycloalkyl,

A preferred group of compounds includes those where A is cyclohexyl, thienyl or a group:

where R is hydrogen or represents from one to three substituents

tuents selected from methyl, chlorine, fluorine,

It is obvious that when only one substituent is present, this can be in the ortho, meta or para positions in the phenyl ring, and further that when more than one substituent is present, all possible mutual positions are relevant,,

Another preferred group of -compounds includes those where is hydrogen, lower alkyl and cyclopentyl or cyclohexyl, while R 1 is hydrogen or lower alkyl

A further preferred group of compounds includes those where R 1 and R 2 are lower alkyl groups containing 1-3 carbon atoms. The compounds of the above formula I exhibit significant anti-inflammatory activity and in some cases also have analgesic properties. They also have a very low toxicity,

The compounds of formula I are produced according to the invention by a compound of the formula:

where A has the meaning given above, and where one of the groups Re- or Rg is lower alkyl and the other a group with the formula: where R^ can be halogen or a lower alkoxy group is reacted with an amine of the formula:

where R^ and R^ had the meaning indicated above.

The presence of a solvent is not necessary in all cases. When an oxazole compound of formula II, where R^ or Rg is the group:

and if a halogen atom is used as starting material, the presence of a tertiary base or an excess of the amine of formula IV is necessary to block the hydrogen halide formed during the reaction. However, it is preferred to carry out the method using solvents. If e.g. the group R^ in the compound of formula III is a lower alkoxy group, thus the preferred solvents are lower alkanols or an excess of the same amine of formula IV. On the other hand, when R 1 is a halogen atom, the solvent is generally selected from inert organic liquids such as e.g. exo benzene, toluene, chlorinated hydrocarbons, dioxane and tetrahydrofuran. The temperature at which the reaction is carried out is not critical and is usually in the range between room temperature and the boiling point of the solvent.

The new compounds of formula I are generally soluble in organic liquids such as acetic acid, dioxane, dimethylformamide and dimethylsulfoxide. The compounds where R 1 and R 2 are hydrogen are fairly soluble in lower alkanols or chloroform and they usually have a very low solubility in water. Suitable solvents for crystallization of these products are mixtures of water and dimethylformamide, water and lower alkanols, lower alkanols and in certain cases water or hexane, depending on the type of substituents found in the k- or 5-position."'

As mentioned above, the new compounds of formula I are particularly active as anti-inflammatory agents. Doses varying from 1/20 to 1/5 of the LD 2 p.o. values were found to be highly effective in carrageenin-induced edema experiments in rats. The compounds were administered orally in doses ranging from 10 to 200 mg/kg and the observed percentage reduction in the induced edema usually ranged from about 30 to about 90. The acute toxicity of the compounds is very low, being in almost all cases higher than 1000 mg/kg.

The new connections have proven to be very

less ulcerogenic than other known and particularly used substances such as e.g. phenylbutazone.

The following examples illustrate the invention.

Example 1 5-carbamyl-4-methyl-2-phenyloxazole

150 ml of concentrated ammonium hydroxide is added dropwise to a solution of 10 g of 5-carbethoxy-2-phenyl-4-methyloxazole in 150 ml of anhydrous ethanol. The mixture is stirred for three days at room temperature, after which it is concentrated to 50 ml by evaporation of the ethanol and cooled. This gives a precipitate which is filtered, washed, dried over sodium sulphate and recrystallized from methanol. Yield 3.7 g of the above compound, melting point 187° - 190°C.

Example 2 4-carbamyl-5-methyl-2-phenyloxazole

9>4 g of 5-niethyl-2~phenyl-^-oxazolecarboxylic acid chloride is added in small portions to 200 ml of concentrated ammonium hydroxide. The mixture is stirred vigorously and the temperature is maintained at approx. 0°C during the addition. After the addition, the temperature is allowed to rise to room temperature and the mixture is left overnight. The solid thus obtained is collected by filtration, washed with water, dried and recrystallized from methanol, which gives 6.35 g of the above compound with melting point 15° - 157°C (from methanol).

Examples 3-5

By using the method described in example 1, the following compounds were prepared: 3) 4-carbamyl-5-methyl-2-(2-thienyl)-oxazole. by reaction of 4-carbethoxy-5-methyl-2~(2-thienyl)»oxazole with ammonium hydroxide. Yield 66%, mp 159° - 161°C (from methanol), k) k - c vcyclohexylcarbamyl-5-methyl-2-(2-thienyl)-oxazole. by reaction of 4-carbethoxy-5-methyl-2-(2-thienyl)-oxazole with cyclohexylamine yield 6l melting point 128°C (from diethyl ether). 5) 4-carbamyl-5-methyl-2-(p-fluorophenyl)-oxazole. by reaction of 4-carbethoxy-5-methyl-2-(p-fluorophenyl)-oxazole with ammonium hydroxide, yield 70 melting point 177° - 180°C (from diethyl ether) <,

Examples 6 - lk

By applying the procedure specified in

Example 2, the following compounds were prepared:

6) 4-carbamyl-2-(p-chlorophenyl)r»5-methyloxazole. by reaction of 2-(p-chlorophenyl)-5-methyl-4-oxazolecarboxylic acid chloride with ammonium hydroxide, yield 82 $>, melting point 199° - 201°C (from methanol). 7) 2-(p-chlorophenyl)-4-ethylcarbamyl-5-methyloxazole. by reaction of 2-(p-chlorophenyl)-5-methyl-4-oxazolecarboxylic acid chloride with ethylamine, yield 77 $>, melting point 98° - 100°C

(from diethyl ether).

8) 2-(p-chlorophenyl)-4-cyclohexylcarbamyl-5-methyloxazole. by reaction of 2-(p-chlorophenyl)-5-methyl-4~oxazolecarboxylic acid chloride with oxyclohexylamine, yield 84 $>, melting point 150° - 152°C (from diethyl ether). 9) 4-carbamyl-5-methyl-2-(p«»tolyl)-oxazole. by reaction of 5-methyl-2-(p-tolyl)-4-oxazolecarboxylic acid chloride with ammonium hydroxide, yield 75%j melting point 169° - 170°C (from methanol). 10) 4-ethylcarbamyl-5-methyl-2-(p-tolyl)-oxazole, by reaction of 5"*methyl-2-(p-tolyl)-4-oxazolecarboxylic acid chloride with ethylamine, yield 80 fo, melting point 99° - 101°C (from diethyl ether). 11) 4-cyclohexylcarbamyl-5-methyl-2-(p-tolyl)-oxazole by reacting 5-methyl-2~(p-tolyl)-4-oxazolecarboxylic acid chloride with cyclohexylamine , yield 75 $» melting point 146° - lk9°C (from diethyl ether). 12) 4- carbamyl- 2- cyclohexyl- 5- methyl- oxazole. by reacting 2- cyclohexyl-5-methyl-4-oxazole carboxylic acid chloride with ammonium hydroxide, yield 72%, melting point'131° - 133°C (from diethyl ether), 13) 2-cyclohexyl-4-ethylcarbamyl-5-methyl-oxazole by reacting 2-cyclohexyl-5-methyl-4-oxazolecarboxylic acid chloride with ethylamine, yield 87 $ >t boiling point 160/0.6 mm Hg. 14) 2- cyclohexyl- 4- cyclohexylcarbamyl- 5- methyl- oxazole, by reacting 2~cyclohexyl-5-methyl-4-oxazolecarboxylic acid chloride with oxyclohexylamine , yield 82%, melting point 52° 54°C (from diethyl ether.

The 4- and 5-carbalkoxyoxazole derivatives used as starting compounds were prepared according to methods described by Chiaki Tanaka and Norio Saito in Yakugaku Zasshi 82, I36,

1962 (Chem. Abs. 58, 3^07 d, 1962 and Chem. Abs. 58, 3407 h,

1962)0 From these carballowoxyoxazole derivatives the corresponding acyl halides were obtained by means of conventional methods,

i.e. So by hydrolysis of the carboxyl group and subsequent reaction with a thionyl or phosphorus halide.

The melting points for the starting oxazole carboxylic acid compounds in examples 1-14 are given below:

Claims (1)

Analogous process for the preparation of anti-inflammatory active compounds with the general formula: where A is cyclohexyl, thienyl or a radical: wherein R is one or more substituents each independently selected from hydrogen, lower alkyl and halogen; one of the radicals R1 and R2 is a lower alkyl group and the other a group: where R^ and R^ are independently selected from hydrogen, lower alkyl and cycloalkyl, characterized in that a compound with the formula: where A has the meaning given above, one of the groups R^ and R^ is lower alkyl and the other is a group of the formula: where R,-, can be a halogen atom or a lower alkoxy group, is reacted with an amine with the formula: where R^ and R^ have the meaning indicated above.