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Publication numberUSRE29607 E
Publication typeGrant
Application numberUS 05/692,744
Publication dateApr 11, 1978
Filing dateJun 4, 1976
Priority dateMar 18, 1969
Publication number05692744, 692744, US RE29607 E, US RE29607E, US-E-RE29607, USRE29607 E, USRE29607E
InventorsClaude P. Fauran, Guy M. Raynaud, Rene A. Oliver, Colette A. Douzon
Original AssigneeDelalande S. A.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Antidepressants, myorelaxants, tranquilizers, sedatives, analgesics, anticonvulsants, antipyretics, antiinflammatory, and uricosuric
US RE29607 E
Abstract
Compounds of the formula ##STR1## in which R is H, .[.Cl, F, CH3 or CF3 .]. .Iadd.m-F, p-F, o-F, p-Cl, p-CH3, m-CH3 or m-CF3 .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.
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Claims(5)
    What we claim is: .[.1. A compound of the formula .Iadd. ##STR6##.Iaddend. in which R is selected from the group consisting of hydrogen,
  1. 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##
  2. .Iaddend. .Iadd. 4. A compound of the formula .Iadd. ##STR8##
  3. .Iaddend. .Iadd. 5. A compound of the formula .Iadd. ##STR9##.Iaddend. in which R is selected from the group consisting of p-methyl and
  4. m-methyl. .Iadd. 6. A compound of the formula .Iadd. ##STR10##
  5. .Iaddend. .Iadd. 7. A compound of the formula .Iadd. ##STR11##.Iaddend.
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-CH3, m-CH3 or m-CF3. .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 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 C.

Yield=80%

Empirical formula=C11 H10 F3 NO3

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                                 FoundCode No.R   formula wt.  C.                    percent                        C  H  N  C  H  N__________________________________________________________________________67360H   C10 H11 NO3            192.20                129 75  62.16                           5.74                              7.25                                 62.20                                    5.87                                       7.4068292m-F C10 H10 FNO3            211.19                 96 87  56.87                           4.77                              6.63                                 56.88                                    4.92                                       6.7969155p-F C10 H10 FNO3            211.19                116 68  56.87                           4.77                              6.63                                 56.97                                    4.77                                       6.8369275o-F C10 H10 FNO3            211.19                 94 60  56.87                           4.77                              6.63                                 56.75                                    4.73                                       6.676922 p-Cl    C10 H10 ClNO3            227.64                104 55  52.75                           4.43                              6.15                                 53.01                                    4.53                                       6.0569204p-CH3    C11 H13 NO3            207.22                145 66  63.75                           6.32                              6.76                                 63.93                                    6.10                                       6.8869276m-CH.sub. 3    C11 H13 NO3            207.22                 76 70  63.75                           6.32                              6.76                                 63.70                                    6.43                                       6.78.[. 9217o-CH3    C11 H13 NO3            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__________________________________________________________________________         PtosisHypothermia   Rat     Mouse   Ulcers     Effect, Effect, Effect, Effect,Code No. Dose1      C.         Dose1             percent                 Dose1                     percent                         Dose1                             percent__________________________________________________________________________67360 200 -3.3         200 70  200 55  --  --68121 100 -3.3         --  --  100 45  100 7768292 100 -2.6         100 75  100 50  100 856922  --  --  100 45  100 55  --  --69201 100 -2.9         --  --  --  --  --  --69276 --  --  --  --  --  --  100 50__________________________________________________________________________ 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 rodCode No. Traction test, ED50                      test, ED50______________________________________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______________________________________                       PotentialisationActimetric cage Evasion test                       penthiobarbital           Effect,       Effect,     Effect,Code No.   Dose1           percent Dose1                         percent                               Dose1                                     percent______________________________________67360    90     50      200   70    200   8068121   100     70      --    --     80   50______________________________________ 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            5068121        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. Dose1            percent Dose1                          percent                                Dose1                                      percent______________________________________67360    --      --      140   50    --    --68121    120     50      100   50    100   8068292    --      --      100   70    100   606922     --      --      100   100   --    --69155    --      --      100   65    --    --______________________________________ 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         >160068121         140068292         15006922          105069155         120069204         >400069276         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.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2437388 *Feb 16, 1946Mar 9, 1948 Z-oxazolidone compounds and proc
US3133932 *May 25, 1959May 19, 1964Deere & CoProduction of 2-oxazolidinones
US3641036 *Mar 17, 1970Feb 8, 1972Delalande SaDe ivatives of 5-carbamoyloxymethyl-3-substitutea dd-oxazoli1 0 01 dinoncess of thereof preparation and their therapeutic application
US3655687 *Mar 16, 1970Apr 11, 1972Delalande SaDerivatives of 5-hydroxymethyl-3-substituted-2-oxazolidinones process of preparation thereof and therapeutic application
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4977173 *Jul 7, 1989Dec 11, 1990E. I. Du Pont De Nemours And CompanyAminomethyl oxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents
US4985429 *Mar 15, 1990Jan 15, 1991E. I. Du Pont De Nemours And CompanyAminomethyl oxooxazolidinyl cycloalkylbenzene derivatives useful as antibacterial agents
US5032605 *Mar 15, 1990Jul 16, 1991Du Pont Merck Pharmaceutical CompanyAminomethyl oxooxazolidinyl oxa or thia cycloalkylbenzene derivatives useful as antibacterial agents
US5036092 *Mar 15, 1990Jul 30, 1991Du Pont Merck PharmaceuticalEffective against antibiotic resistant streptococci and staphylococci
US5036093 *Mar 15, 1990Jul 30, 1991Du Pont Merck PharmaceuticalAminomethyl oxooxazolidinyl azacycloalkylbenzene derivatives useful as antibacterial agents
US5039690 *Mar 15, 1990Aug 13, 1991Du Pont Merck Pharmaceutical CompanyAminomethyl oxooxazolidinyl oxa or thia cycloalkylbenzene derivatives useful as antibacterial agents
US5182403 *Apr 23, 1992Jan 26, 1993The Upjohn CompanyBactericides, treatment of AIDS
US5225565 *Apr 23, 1992Jul 6, 1993The Upjohn CompanyAntibacterial 3-(fused-ring substituted)phenyl-5β-amidomethyloxazolidin-2-ones
US5231188 *May 13, 1992Jul 27, 1993The Upjohn CompanyTricyclic [6.5.51]-fused oxazolidinone antibacterial agents
US5254577 *Aug 14, 1992Oct 19, 1993The Du Pont Merck Pharmaceutical CompanyAminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
US5523403 *May 22, 1995Jun 4, 1996The Upjohn CompanyTropone-substituted phenyloxazolidinone antibacterial agents
US5654428 *Jun 6, 1995Aug 5, 1997Pharmacia & Upjohn CompanySubstituted heteroarylphenyloxazolidinones
US5654435 *Jun 6, 1995Aug 5, 1997Pharmacia & Upjohn CompanySubstituted arylphenyloxazolindinones
US5756732 *Jun 6, 1995May 26, 1998Pharmacia & Upjohn CompanySubstituted heteroarylphenyloxazolidinones
US5801246 *Jun 6, 1995Sep 1, 1998Pharmacia & Upjohn CompanyBactericides
EP0184170A2Nov 30, 1985Jun 11, 1986E.I. Du Pont De Nemours And CompanyAminomethyl oxooxazolidinyl benzene derivatives useful as antibacterial agents
Classifications
U.S. Classification548/232, 514/906, 514/916
International ClassificationC07D263/24
Cooperative ClassificationC07D263/24
European ClassificationC07D263/24