AU477231B2 - New 2, 4, 5-trisubstituted oxazoles - Google Patents

Description

6,9 8 2 n3

The present invention relates new pharmacologically active compounds. More particularly, this invention re- fers to 2 ,4,5-trisubstituted oxazoles of the general formula

A 2

wherein A is cyclohexyl, thienyl or a radical

in which R represents one or more substituents each of them independently selected from hydrogen, lower alkyl, halogen, halogen-alkyl, lower alkoxy, nitro, cyano, amino, sulfamoyl, carbamoul, acetamido or carboxy; one of the radicals R1 and R2 represents a lower alkyl group and the other a group CON wherein R3 is independently selec- ted from hydrogen, lowe4 alkyl, lower alkenyl, cycloalkyl, aryl, aryl-lower alkyl, hydroxy-lower alkyl, carboxylic- acyloxy-lower alkyl, hydroxy, amino, lower alkylideneamino, cycloalkylideneamino, aralkylideneamino, R4 is independently selected from hydrogen, lower alkyl, lower alkenyl, cyclo- alkyl, aryl, aryl-lower alkyl, hydroxy-lower alkyl, carboxy- lic-acyloxy-lower alkyl, or R3 and R4 taken together may also form with the nitrogen atom a 5 to 7 membered saturated heterocyclic ring which may contain one other hetero-

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.982 r

atom selected from N, 0 and S. The heterocyclic ring may

be substituted by an alkyl radical, for example a 4-methyl-

1-piperazinyl ring may be formed.

Ordinarily, the lower alkyl and lower alkenyl groups

may be straight or branched and may contain from one to

six carbon atoms. The cycloalkyl moieties generally are

to 8 membered rings.

Ary. and aralkylidene groups are essentially represent-

ed by phenyl or halogen, lower alkyl, lower alkoxy, sub-

stituted phenyl radicals and their benzylidene homologs. A preferred group of compounds comprises the one in which

A is cyclohexyl, thienyl or a group

wherein R is hydrogen or represents from one to three

substituents selected from methyl, chloro, fluoro, methoxy

or trifluoromethyl. It is obvious that when only one sub-

stituent is present, it can be in the positions ortho, meta

or para of the phenyl ring, and that when more than one sub- stituent is present all the possible mutual positions are

taken into account. Another preferred group of compounds comprises the

ones wherein R3 represent hydrogen, lower alkyl, hydroxy,

cyclopentyl, cyclohexyl, amino, isopropylideneamino and

p-methylbenzylideneamino, while R 4 represents hydrogen or

lower alkyl. comprises the A further preferred group of compounds groups containing one in which R1 or R2 are lower alkyl

from 1 to 3 carbon atoms. The compounds of the present activity, invention exhibit a remarkable antiinflammatory

and in some cases 3 477.231

56.9 82 n3

they are endowed also withI&a--,ete properties. More-

over they have very low toxicity.

The general method for preparing these new compounds comprises reactlngcompound of the formula

N S

A 0 wherein A has the above meaning, and one of the groups

is lower alkyl and the other a group of the formula R7 -C

0 in which R17 may be a halogen atom or a lower alkoxy group, with an amine of the formula

~iv

wherein R 3 and R 4 have the meanings given before.

The presence of a solvent may be not necessary. When an oxazole of the formula II wherein R5 or R6

represent the group

0

and R7 is a halogen atom is employed as the starting

substance, the presence of a tertiary organic base

or an excess of the same smine IV is required to block

the hydrogen halide whiah formed during the reaction. in- However, the preferred mode of carrying out the instance, vention involves the use of solvents.. Thus, for

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56.982 nm if in the compound of the formula III R7 is a lower alkoxy group, the preferred solvents are selcted from lower alkanols or an excess of the same smine of

the formula IV, On the other hand, when R7 represents

a halogen atom, the solvent is generally selected from

inert organic liquids, such as for instance benzene,

toluene, chlorinated hydrocarbons, dioxane, and tet-

rahydrofuran. The temperature at which the reaction

is carried out is not critical and is generally selected

in the range between the room temperature and the boiling

temperature of the solvent. The compounds of the invent-

ion wherein R3 represents a lower alkylideneamino, a

cycloalkylidene or an aralkylideneamino group are more

conveniently prepared from the corresponding derivatives

when the foregoing radical is an amino group through

a condensation with a predeterminated aldehyde or

ketone by conventional methods; the compounds wherein R3 or R4 are sayoi-l ower alkyl groups are prepared

from the corresponding hydroxy compounds by the usual acylation precedures. The compounds of the invention are generally sol- uble in organic media like acetic acid, dioxene, dim-

ethylformamide and dimethylsulfoxide. The ones in whi-

ch R and R4 are hydrogen are fairly soluble in lower

alkanols or chloroform and generally they have a very low solubility in water. Sutiable solvents for the crystallization of these products are mixtures of water and dimethylformemide, water and lower alkanols, lower alkanols and in some cases water or hexane, depending

on the nature of the substituents of the position 4 or

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As previously stated, the compounds of the invention

proved particularly active as anti-inflammatory substances.

Doses varying from one twentieth to one fifth of the

values p.o. were found to be highly effective in the carrageenin induced edema test in rats. The com-

pounds were orally administered at dosages varying from

to 200 mg/kg. and the observed percent decreases of the induced edema were in general varying from about

to 90. The acute toxicity of these compounds is ordin-

arily very low, as being almost always higher than 1000 mg/kg. Moreover the compounds of this invention proved to be much less ulcerogenic than other known and widely used substances, such as, for instance, phenylbutazone.

The following non limitative examples describe

in detail the compounds of the invention and the methods

fr their manufacture.

EXAMPLE 1 t -4-methyl-2-phenyloxazole

150 Ml. of concentrated ammonium hydroxide are added

dropwise to a solution of 10 g. of 5-eeb44 ho. 4 -2- phenyl-4-methybxazolein 150 ml. of anhydrous ethanol.

The mixture is stirred three days at room temperature, then it is concentrated to 50 ml. by evaporating the

ethanol and chilled. A product precipitates which is

filtered washed, dried over sodium sulfate and recry-

stallized from methanol. Yield 3.7 g. of the title

compound. M.p. 187-90°C.

EXAMPLE 2

4-bcrby-5-methyl-2-phenyloxazole

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9.4 Grams of 5-methyl-2-phenyl-4-oxazolecarboxylic acid

chloride are added in small portions to 200 ml. of concentra- ted ammonium hydroxide. The mixture is vigorously stirred and the temperature is maintained at about 0°C during the addi- tion step. After the addition, the temperature is allowed

to raise to room temperature and the mixture is left stand-

ing overnight. The solid which forms in collected by filtra- tion, washed with water, dried and recrystallized from me- thanol. 6.35 Grams of the title product are obtained. M.p.

154-157°C (from methanol). EXAMPLES 3

According to the procedure described in Example 1 the following compounds are prepared: 3) 4--Carbamoyil-5-methyl-2-(2-thienyl)-oxazole, by reacting ethyl 4 5-methyl-2-(2-thienyl)- -oxazole carboxylate with ammonium hydroxide. Yield 66% M.p. 159-61 0 C (from methanol). 4) 4-Cyclohexylcarbamoyl-5-methyl-2-(2-thienyl)-oxazole, by reacting ethyl-5-methyl-2-(2-thienyl)-4-oxazole carboxy-

late with cyclohexylamine. Yield 61%. A.P. 128-29 0 C (from diethyl ether)

4-Carbamoyl-5-methyl-2-(p-fluorophenyl)-oxazole, by

reacting ethyl-5-methyl-2(p-fluorophenyl)-4-oxazole carboxy- 0 late with ammonium hydroxide. Yield 70% M.p. 177- 180 C (from diethyl ether). EXAMPLES 6 18 According to the procedure described in Example 2 the following compounds were prepared:

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6) 4I-Carbamoyl-2.(p-.chlorophenyl).5-.methyloxazole, by reacting 2-(p-chlorophenyl )-5-methyl-4-oxazolecarboxy lic acid chloride with amnmonium hydroxide. Yield 83%. M.P. 199-201 0 C (from methanol). 2 7) by reacting 2-(p-chlorophenyl)-5-methyl-4-oxazolecarboxylic acid chloride with ethylamine. Yield 77% M.p. 98-1l000C (from diethyl ether). 2 8) zole, by reacting 2-(p-chlorophenyl)-5-methyl-4-oxazole. carboxylic acid chloride with cyclohexylamine. Yield 84% 0 M.P. 150-152 C (from diethyl ether). 9) 4-abmy--ehl2(-oy)oaoe by reacting 1 1-2- (p-toly 1) -oxazolecarboxylic acid chloride with amnmonium hydroxide. Yield 75% M.p. 169-170 0 C (from methanol). 4-Ethylcarbamoyl-5-methyl-2-(p-tolyl)oxazole, by reacting 5-methyl-2- (p-toly -4-oxazolecarboxy3-c acid chloride with ethylaniine. Yield 80% M.p. 99-101 0 C (from diethyl ether). 11) 1'4-Cyclohexylcarbazoyl-5-methyl-2-(p-tolyl)-oxazole by reacting 5-methy 1-2- (p-toly -4-oxazolecarboxylic acid chloride with cyclohexylamine. Yield 75% M.P. 1146-1490 (from diethyl ether). 12) 4-abmy--ylhxy--ehloaoe by reacting 1 4-oxazolecarboxylic acid chloride with amimonium hydroxide. Yield 72% M.p. 131-133 0 C (from diethyl ether).

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13) 2-Cyclohexyl-4-ethylcarbamoyl-5-methyl-oxazole, by reacting 2-cyclohexyl-5-methy l--oxazolecarboxylic acid chloride with ethylamine. Yield 87%. B.p. 160/0.6 mmHg. 14) by reacting 2-cyclohexy l-5-methyl-4-oxazolecarboxylic acid 0 chloride with cyclohexylamine. Yield 82%. M.p. 52-54 C (from diethyl ether). -Carbamoyl-2-(o-flutorophenyl)-5-methyloxazole, by reacting 2-(o-fluorophenyl)-5-methyl-4-oxazolecarboxylic acidchloride with ammonium hydroxide. Yield 78% M.p. 162- 164 0 C (from methanol). 16) 4-Ethylcarb by reacting 2-(o-fluorophenyl)-5-methyl-4-oxazolecarboxylic acid chloride with ethylamine. Yield 86%. M.p. 53-55 0 C (from diethyl ether). 17) 4-Cyclohexlcarbamoyl-2-(o-fluorophenyl)-5-methyl oxazole, by reacting 2-(o-fluorophenyl)-5-methyl-4-oxazo- lecarboxylic acid chloride with cyclohexylamine, Yield 78%. M.p. 69-720C (from diethyl ether). 18) 5-Cyclohexylcarbamoyl-h -mothyl-2-phenyloxaz ole by reacting 4-methyl-2-phenyl-5-oxazolecarboxylic acid chlo- ride with cyclohexylamine. Yield 81%. M.p. 144-460 C (from diethyl ether). Typical compounds which can be prepared according to the procedure hereinbefore described in the Examples are listed below, without any intention of establishing the limits of the invention:

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1-2 -pheny 1- 1 -oxazole carb oxy lie acid hy drazide 1-2-phony 1-I-penty lcarbanioyl-oxazole 1-2-phony 1-4-n-propy icarbamoy 1-oxazole 11-CBenzylcarbamoy 1-5-methy 1-2-phenyl-oxazole 11..Allylcarb amoy 1-5-methy 1-2-phony 1-oxazole 1-C 2-Hydroxyethylcarbamoyl)-5-methy-2-phny-oxazole 3Hydroxypropylcarbamoy1)-5-methy1-2-pheny1-oxazole 1-Isopropylcarbamoyl-5-methyl-2-( p-toly1) -oxazole si-Ia obutylcarb amoy 2-5-mothy 1-2-phony 1-oxazole 4-Cyolohexy lcarbamoyl-5-methyl-2-phony 1-oxazole 1- 1 -morpholinocarb ony 1-2-phenyl-oxazole 1-Carbazoyl-5-mthyl-2-( 3,1, il-Carbamoy 1-5-methy 1-2-C m-tolyl) -oxazole Carbamoyl-5-methyl-2-(o-tolyl)-oazole 4-abmy--ehl2(-rilooehlhnl-xzl I-Carbainoy 1-2-(m-chlorophenyl )-5-methy 1-oxazole 11-Ccarb amoy 1-2-C o-fluoropheny1) -5-methy 1-oxazolo 11..Cycohxylcarbamoyl-2-(p-f1uorophel)-.-methy1-oxazole 4Carbamoyl-2-(o-ehlorophenyl)-5-mothy1oxazole 1-Carbamoy-5-ethy1-2-(p-ter.butylphenl)-oxazole

41-Cy clohexy lcarbamoy 1-2(Cm-methoxypheny 5-propy 1-oxazole 1 2-(m-Chlorophenyl)- oxazole 2-mClrpey)4(-yrxyrplabmy)5iorpl oxazole 1-C 2-Acetoxyethylcarbamnoyl)-5-methyl-2-phenl-oxazole

10477.23 1

6.9 8 2nr3

2-Acetoxypropy icarbamoyl )-5-methy 1-2-pheny 1-oxazole 1-2-phenyl-oxazole 4-Dicyclohexylcarbanoy 1-5-othyl-2- (p-methoxyphenyl-Oxazole 1 -Diethylcarbazmoyl-2-( 3,5-dimethylphenyl)-5-propyl-oxazole 5-Mthyl-2-phony 1- 4-oxazolecarbohy droxamic acid 5-Methyl-2-(p-toy1)-4-oxazolcarbohydroxamic acid 2-(o-ChloroDhenvl)-5-methyl-4-oxazalecarboh-vdroxamic acid 5-Etbyl1-2-( p-methoxyphenyl )-4-oxazolecarbohbydroxamic acid 1 I-oxazolecarbohydroxamic acid 1-2-pheny 1-I-oxazolecarboxy lic acid isopropy lidene- hydirazide 1-2-phony1-4-oxazolecarb oxy lic acid 4-methy lbenzy lidene hydrazide 2-Phenyl-5-propyl-4-oxazolecarboxylic acid cyclohexylidene hydrazide 4-Methy 1-2-phony 1-5-oxazolecarb oxylic acid hydrazide 4-Methy 1-2-phenyl-5-penty icarbamoyl-oxazole lcarb amoy 1- 1 -methy 1-2-(Cp-methoxypheny1) -oxazole 5-Al1ylcarbamioy1- 14-methy 1-2-phony 1-oxazole 3-Hydroxypropy icarbamoy 1) -L-methy 1-2-phony 1-oxazole amoyl-4-methy 1-2-pheny 1-oxazole clohexy learb amoy 1-4-ethy 1-2- (m-methoxypheny1)-oxazole 1-4-Imethy 1-2-C m-trifluoromethy ipheny1) -oxazolo 1-2 -(o-fluoropheny1) -k-mothy 1-oxazole -Cyc lohexy lcarb anoy 1-2 fluoropheny1) -4-methy 1-oxazole 5-Carbamoyl-2-C o-chlorophenyl)-4-methyl-oxazole 4-Methyl-1-piperazinylcarbonyl)-2-pheflyl-oxazolS amoy 1-4-ethyl-2-( p-terb uty ipheny1) -oxazole

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lcarb amoy m-methoxypheny 1)-'4.,propyl-oxazole 2-Ace-toxypropylcarbamoyl) 1 -methyl-2-phenyl-oxazole Dicyclohexy icarbanoy 1-I-ethyl-2-( p-methoxypheny 1)-oxazole 4 -Methyl-2-phony 1-5-oxazolecarbohydroxamic acid '4-Nethyl-2-(p-tolyl)-5-oxazoecarbohydroxamice acid 2-Cp-Chlorophenyl)-L4-methy1..5- oxazolecarbohydroxamic acid AI-Ethyl-2 p-methoxypheny 5-oxazole carb ohydroxamic acid 2 -Phenyl- 1 4-propyl-5-oxazolecarboxylic acid isopropylidene hy drazide 4-M'ethyl-2-phenyl-5-'oxazolecarboxylic acid-1 J-methylbenzyli- dene hydrazide 2-Pheny 1-41 -propy 1-5-oxazolecarb oxylic acid cy clohexy hidene hydrazide 4-Carbanoyl -5-methyl-2- Cm-nitropheny1) -oxazole 4-Carb anxoY -5-methyl-2-( p-nitrophenyl) -oxazole 1 -Carbamoyl-2 -(p-cyanophenyl )-S-isopropy 1-oxazole 5-Carbamoyl-2- Cp-carboxypheny 1) 1 -ethyloxazole 'I-Carbamoy 1-2- Cp-carboxypheny1) -5-ethy 1-oxazole 2-(p-Carbamoylphenyl 2-C 2-(m-Aminophenyl)- 1

2-(m-Aminophenyl )-5-carbamoyl-4-ethyl-oxazole 2-C p-Aminopheny1) -5-carbanioyl-Ii-methy 1-oxazole 2-C 0-Acetaininophenyl -J-carbamoyl-5-methy 1-oxazole 2-C m-Acetarninopheny 1) -4-carbamoy 1-5-methy 1-oxazole 2- (p-Acetaminopheny1) -4-carbamoyl-5-methy 1-oxazole

12 12 477,23 1

6.9 8 2 n3

2-(o-Acetaminophenyl)-5-carbamoyl-4-methyl-oxazole

4-Carbamoyl-5-methyl-2-(m-sulfamoylphenyl)-oxazole

4-Carbamoyl-5-methyl-2-(p-sulfamoylphenyl)-oxazole

The starting 4- and 5- carbalkoxyoxazole derivates were

prepared following the methods described by Chiaki Tanaka and Norio Saito in Vakagaku Zasshi 82, 136, 1962 (Chem.

Abs. 58 3407 d, 1962 and Chem. Abs. 58, 3407 h, 1962).

From these carbalkoxyoxazole derivatives the correspond-

ing acyl halides were obtained by means of the usual

procedures, i.e. by hydrolysis of the carbalkoxy group and subsequent reaction with a thionyl or phosphorus halide.

The melting points of the starting ozazolecarboxylic acids

derivatives of Examples 1-14 are given hereinbelow.

STARTING COMPOUND OF M.p. 0 C (SOLVENT OF RECRY

EXAMPLE STALLIZATION

1 52-54 (Light petroleum)

2 133-35 (diethyl ether/ hexane)

3 4 91-93 (hexane)

STARTING COMPOUND OF M,PoC (SOLVENT O RECRYSTALL-

EMPLE IZATION)

70-73 (hexane

6-7-8 141-44 (diethyl ether/hexane)

9-10-11 118-21 (diethyl ether/hexane)

12-13-14 159-62 (diethyl ether/hexane)

13 477,231

Claims (1)

1. 6.9 8 2

   The claims defining the invention are as follows: 1. A compound of the formula

   II A R2

   wherein A is cyclohexyl, thienyl or a radical

   wherein R represents one or more substituents each of them

   independently selected from hydrogen, lower alkyl, halogen,

   halogen-lower alkyl, lower alkoxy, nitro, cyano, amino,

   sulfamoyl, carbamoyl, acetamido or carboxy; one of the

   radicals R 1 and R2 represents a lower alkyl group and the

   other a group R3 -cog-

   wherein R3 is independently selected from hydrogen, lower alkyl, lower alkenyl, cycloalkyl, aryl, aryl-lower alkyl, hydroxy-lower alkyl, carboxylic-acyloxy-lower alkyl, hydroxy amino, lower alkylideneaminu, cycloalkylideneamino, aralkyl-

   ideneamino, R4 is independently selected from hydrogen, lowe alkyl, lower alkenyl, cycloalkyl, aryl, aryl-lower alkyl, hydroxy-lower alkyl, carboxylic-acyloxy -lower alkyl, or R3 and R4 taken together may also form with the nitrogen atom a 5 to 7 membered saturated heterocyclic ring which may contain one other heteroatom selected from N, O and S.

   14 477.231

   6.9 8 2 m

   2. A process for preparing a compound of the formula

   R

   wherein A, R 1 and R 2 have the above meanings, which comprises

   reacting a compound of the formula

   A wherein A has the same meanings as before, and one of the

   group R5 and R 6 is lower alkyl and the other a group of the formula

   C -R

   wherein R7 may be a halogen atom or a lower alkoxy group,

   with an amine of the formula

   /R4 -3

   in which R 3 and R 4 have the meanings given in dalm 1.

   A 5 477,231 8\ 0

   6,9B2 3

   as 3. A compound according to Claim 1, suibsu'atiaI1Y herein described with reference to any onc of the Examples. 4. A process according to Claim 2, substantially- as Examples. herein described with reference to any one of the

   DATED: 16 july, 1976. PHILLIPS ORM~ONDE FITZPATRICK Attorneys for: GRUFPO LEPETIT S.p.A. 4a P

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