Derivatives of 5-hydroxymethyl-3-substituted-2-oxazolidinones, process of preparation thereof and therapeutic application

Abstract

Compounds of the formula ##STR1## in which R is H, .[.Cl, F, CH.sub.3 or CF.sub.3 .]. .Iadd.m-F, p-F, o-F, p-Cl, p-CH.sub.3, m-CH.sub.3 or m-CF.sub.3 .Iaddend.. The compounds are prepared by cyclizing with ethyl carbonate, a compound of the formula ##STR2## The compounds have anti-depressive, myorelaxing, tranquilizing, sedative, analgesic, anti-convulsive, anti-pyretic, anti-inflammatory and uricosuric activities.

Description

The present invention concerns novel derivatives of 5-hydroxymethyl-3-substituted-2-oxazolidinones, their process of preparation and their therapeutic application.

The compounds according to the present invention correspond to the general formula: ##STR3## in which R represents .[.a hydrogen atom, a halogen atom, an alkyl radical having 1 to 4 carbon atoms or a trifluoromethyl radical..]. .Iadd.m-F, p-F, o-F, p-Cl, p-CH.sub.3, m-CH.sub.3 or m-CF.sub.3. .Iaddend.

The process for the preparation of the compounds according to the present invention comprises cyclising, by the action of ethyl carbonate, a 1-phenylamino-2,3-propanediol of the general formula: ##STR4## in which R has the same significance as in Formula I.

The following preparation is given, by way of non-limitative example, to illustrate the present invention.

EXAMPLE

5-hydroxymethyl-3-(m-trifluoromethyl phenyl)-2-oxazolidinone. (Code No. 68121)

59 G. OF 1-(M-TRIFLUOROMETHYL PHENYLAMINO)-2,3-PROPANEDIOL AND 118 G. OF ETHYL CARBONATE ARE INTRODUCED INTO A DISTILLATION APPARATUS. The mixture is progressively heated to about 110.degree. C. when dissolution is obtained. Then, 12 ml. of a 5% solution of sodium methylate in methanol is added thereto. The distillation of the ethanol formed during the course of the reaction is then observed. Upon completion thereof any excess ethyl carbonate is removed under reduced pressure and the residue obtained is crystallized in isopropyl ether.

Melting point=80.degree. C.

Yield=80%

Empirical formula=C.sub.11 H.sub.10 F.sub.3 NO.sub.3

Elementary analysis.--Calculated percent: C, 50.58; H, 3.86; N, 5.36. Found percent: C, 50,74; H, 3.76; N, 5.56.

The compounds listed in the following table have been prepared according to the process of the above example:

TABLE I __________________________________________________________________________ ##STR5## Elementary analysis, percent Empirical Mol M.P. Yield, Calculated Found Code No. R formula wt. .degree. C. percent C H N C H N __________________________________________________________________________ 67360 H C.sub.10 H.sub.11 NO.sub.3 192.20 129 75 62.16 5.74 7.25 62.20 5.87 7.40 68292 m-F C.sub.10 H.sub.10 FNO.sub.3 211.19 96 87 56.87 4.77 6.63 56.88 4.92 6.79 69155 p-F C.sub.10 H.sub.10 FNO.sub.3 211.19 116 68 56.87 4.77 6.63 56.97 4.77 6.83 69275 o-F C.sub.10 H.sub.10 FNO.sub.3 211.19 94 60 56.87 4.77 6.63 56.75 4.73 6.67 6922 p-Cl C.sub.10 H.sub.10 ClNO.sub.3 227.64 104 55 52.75 4.43 6.15 53.01 4.53 6.05 69204 p-CH.sub.3 C.sub.11 H.sub.13 NO.sub.3 207.22 145 66 63.75 6.32 6.76 63.93 6.10 6.88 69276 m-CH.sub. 3 C.sub.11 H.sub.13 NO.sub.3 207.22 76 70 63.75 6.32 6.76 63.70 6.43 6.78 .[. 9217 o-CH.sub.3 C.sub.11 H.sub.13 NO.sub.3 207.22 64 69 63.75 6.32 6.76 63.71 6.37 6.88.]. __________________________________________________________________________

The compounds of Formula I experimentally exert anti-depressive. myorelaxing, tranquillising, sedative, analgesic, anti-convulsive, anti-pyretic, anti-inflammatory and uricosuric activities. Moreover, their toxic effects on animals in the laboratory are little marked.

(1) Anti-depressive properties.--The compounds of Formula I are capable of opposing hypothermia and the ptosis provoked by reserpine in the rat and the mouse, as well as the ulcers provoked by reserpine in the rat. Moreover, they oppose the catalepsy provoked by prochlorperazine in the rat.

By way of example, several results obtained are listed in the following table:

TABLE II __________________________________________________________________________ Ptosis Hypothermia Rat Mouse Ulcers Effect, Effect, Effect, Effect, Code No. Dose.sup.1 .degree. C. Dose.sup.1 percent Dose.sup.1 percent Dose.sup.1 percent __________________________________________________________________________ 67360 200 -3.3 200 70 200 55 -- -- 68121 100 -3.3 -- -- 100 45 100 77 68292 100 -2.6 100 75 100 50 100 85 6922 -- -- 100 45 100 55 -- -- 69201 100 -2.9 -- -- -- -- -- -- 69276 -- -- -- -- -- -- 100 50 __________________________________________________________________________ .sup.1 Expressed in mg./kg./p.o.

(II) Myorelaxing properties.--The compounds of Formula I provoke in the mouse the loss of the righting reflex and inhibit the traction reflexes and the maintenance on a rotating rod.

By way of example, the results obtained with two compounds of Formula I are listed in the following table:

TABLE III ______________________________________ Rotating rod Code No. Traction test, ED.sub.50 test, ED.sub.50 ______________________________________ 67360 300 mg./kg./p.o. 160 mg./kg./p.o. 68121 110 mg./kg./p.o. ______________________________________

(III) Tranquillising and sedative action.--These effects are shown by a diminution of exploration curiosity in the enclose of an actimetric cage and of escape in an open field. The compound of Formula I reduce the aggressiveness provoked in the passage of an electric current and lower the body temperature of animals. The narcotic effects of penthiobarbital are equally reinforced.

The results obtained with two compounds of Formula I are listed in the following table:

TABLE IV ______________________________________ Potentialisation Actimetric cage Evasion test penthiobarbital Effect, Effect, Effect, Code No. Dose.sup.1 percent Dose.sup.1 percent Dose.sup.1 percent ______________________________________ 67360 90 50 200 70 200 80 68121 100 70 -- -- 80 50 ______________________________________ .sup.1 Expressed in mg./kg./p.o.

(IV) Analgesic activity.--This activity is particularly pronounced against the painful stretching provoked in the mouse by the intraperitoneal administration of phenyl benzoquinone or acetic acid.

The results obtained with two compounds of Formula I are shown in the following table:

TABLE V ______________________________________ Protection against phenylbenzoquinone Dose in Effect, Code No. mg./kg./p.o. percent ______________________________________ 67360 90 50 68121 45 50 ______________________________________

(V) Anti-convulsive properties.--The compounds of Formula I exert in the mouse an antagonism against the lethal effects of cardiazol, strychnine and nicotine. They equally show activity against the tonic hyperextension of an excessive electric shock.

By way of example, the results obtained with several compounds of Formula I are listed in the following table:

TABLE VI ______________________________________ Antagonism against Cardizol Strychnine Nicotine Effect, Effect, Effect, Code No. Dose.sup.1 percent Dose.sup.1 percent Dose.sup.1 percent ______________________________________ 67360 -- -- 140 50 -- -- 68121 120 50 100 50 100 80 68292 -- -- 100 70 100 60 6922 -- -- 100 100 -- -- 69155 -- -- 100 65 -- -- ______________________________________ .sup.1 Expressed in mg./kg./p.o.

(VI) Anti-pyretic action.--This action is manifested by a diminution of the experimental fever provoked by the administration of barm in the cat.

(VII) Anti-inflammatory effect.--The under-plantar oedema provoked in the rat by the administration of carraghenine is diminished by the compounds of the present invention.

(VIII) Uricosuric action.--After repeated oral administration in the rat, the compounds of Formula I provoke an augmentation of the urinary eliminations of uric acid.

In consequence of the results shown above, and the values appearing in the following table, the difference between the pharmacologically-active dose and the lethal dose is sufficiently great to enable the compounds of Formula I to be utilised in therapeutics.

TABLE VII ______________________________________ Code No. LD50 P.O. (mouse,) mg./kg. ______________________________________ 67360 >1600 68121 1400 68292 1500 6922 1050 69155 1200 69204 >4000 69276 1850 ______________________________________

The compounds of Formula I are indicated in the case of depression and neurosis by depressive and anxious components. They equally possess a favourable effect against contractural and inflammatory pains, with or without hyperthermia.

They may be administered in the form of tablets and gelules containing 50 to 250 mg. of active ingredient.

Hence, according to the present invention there is also provided a therapeutic composition comprising a compound of Formula I together with a therapeutically-acceptable carrier.

Claims

chlorine, fluorine, methyl and trifluoromethyl..]..[.2. A compound as claimed in claim 1, in which R is chlorine or fluorine..]..Iadd. 3. A compound of the formula.Iadd. ##STR7##

.Iaddend..Iadd. 4. A compound of the formula.Iadd. ##STR8##

.Iaddend..Iadd. 5. A compound of the formula.Iadd. ##STR9##.Iaddend. in which R is selected from the group consisting of p-methyl and

m-methyl..Iadd. 6. A compound of the formula.Iadd. ##STR10##

.Iaddend..Iadd. 7. A compound of the formula.Iadd. ##STR11##.Iaddend.