FR2460940A2 - Antidepressant oxazolidinone(s) - with 5-hydroxymethyl -3-phenyl substituents - Google Patents
Antidepressant oxazolidinone(s) - with 5-hydroxymethyl -3-phenyl substituents Download PDFInfo
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- FR2460940A2 FR2460940A2 FR7917834A FR7917834A FR2460940A2 FR 2460940 A2 FR2460940 A2 FR 2460940A2 FR 7917834 A FR7917834 A FR 7917834A FR 7917834 A FR7917834 A FR 7917834A FR 2460940 A2 FR2460940 A2 FR 2460940A2
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- 239000000935 antidepressant agent Substances 0.000 title abstract description 3
- 229940005513 antidepressants Drugs 0.000 title abstract description 3
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title abstract 2
- 230000001430 anti-depressive effect Effects 0.000 title 1
- -1 3-chloro-5-fluorobenzyloxy Chemical group 0.000 claims abstract description 12
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- HMIAXVWVTBIGON-UHFFFAOYSA-N 2-chloro-1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C(Cl)=C1 HMIAXVWVTBIGON-UHFFFAOYSA-N 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- JXTKFWIYCRWWJD-UHFFFAOYSA-N (3-amino-5-chlorophenyl)methanol Chemical compound NC1=CC(Cl)=CC(CO)=C1 JXTKFWIYCRWWJD-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- VJTJBAMDTCIMOB-UHFFFAOYSA-N (3-chloro-5-fluorophenyl)methanol Chemical compound OCC1=CC(F)=CC(Cl)=C1 VJTJBAMDTCIMOB-UHFFFAOYSA-N 0.000 claims description 3
- LKBQUSJJIYIBDP-UHFFFAOYSA-N (3-chloro-5-nitrophenyl)methanol Chemical compound OCC1=CC(Cl)=CC([N+]([O-])=O)=C1 LKBQUSJJIYIBDP-UHFFFAOYSA-N 0.000 claims description 3
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 3
- YLQAJBKACBLUCM-UHFFFAOYSA-N 3-chloro-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1 YLQAJBKACBLUCM-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 150000003983 crown ethers Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- 229910004039 HBF4 Inorganic materials 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- REWFUSHVOGNMCQ-UHFFFAOYSA-N azanium;iron;chloride Chemical compound [NH4+].[Cl-].[Fe] REWFUSHVOGNMCQ-UHFFFAOYSA-N 0.000 claims description 2
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- MXUNKHLAEDCYJL-UHFFFAOYSA-N 5-(hydroxymethyl)-3-(3-methylphenyl)-1,3-oxazolidin-2-one Chemical compound CC1=CC=CC(N2C(OC(CO)C2)=O)=C1 MXUNKHLAEDCYJL-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960002309 toloxatone Drugs 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- ZJVGZPXKLAORCY-UHFFFAOYSA-N (3-chloro-4-nitrophenyl)methanol Chemical compound OCC1=CC=C([N+]([O-])=O)C(Cl)=C1 ZJVGZPXKLAORCY-UHFFFAOYSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- LSYOFPBORRARMF-UHFFFAOYSA-N 5-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical class OCC1CNC(=O)O1 LSYOFPBORRARMF-UHFFFAOYSA-N 0.000 description 1
- WVULNOZIAYBGLE-UHFFFAOYSA-N 5-(hydroxymethyl)-3-(4-hydroxyphenyl)-1,3-oxazolidin-2-one Chemical compound O=C1OC(CO)CN1C1=CC=C(O)C=C1 WVULNOZIAYBGLE-UHFFFAOYSA-N 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940077481 dl- 5-hydroxytryptophan Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000004540 pour-on Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/26—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups and being further substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
La demande de brevet principal n 77 13027 a pour objet des hydroxyméthyl-5 oxazolidinones-2 répondant à la formule
dans laquelle R représente un groupement nitro, un groupement alkoxy
o comportant de I a 3 atomes de carbone, un groupement méta-thioalkyle comportant de I à 3 atomes de carbone, un groupement méta-acyle comportant de 2 à 4 atomes de carbone, un atome de brome ou plusieurs groupements alkyle comportant de 1 à 4 atomes de carbone, Ro ne pouvant toutefeis être situé en position ortho.The main patent application No. 77 13027 relates to 5-hydroxymethyl-2-oxazolidinones corresponding to the formula
in which R represents a nitro group, an alkoxy group
o having from 1 to 3 carbon atoms, a meta-thioalkyl group comprising from 1 to 3 carbon atoms, a meta-acyl group containing from 2 to 4 carbon atoms, a bromine atom or several alkyl groups containing from 1 to 4 carbon atoms, Ro can not all be located in ortho position.
La présente demande concerne des composés de même structure répondant plus précisément à la formule
dans laquelle R représente - un groupement cyclopentyloxy, ou (chloro-3 fluoro-5) benzyloxy - un groupement -0-(CH2)n-X dans lequel X représente un atome de chlore ou de brome et n prend les valeurs 4, 5 et 6 ; ou - un groupement -0-(CH2)m-CN dans lequel m prend les valeurs 5 et 6.The present application relates to compounds of the same structure more precisely corresponding to the formula
in which R represents - a cyclopentyloxy group, or (3-chloro-5-fluoro) benzyloxy - a group -O- (CH2) nX in which X represents a chlorine or bromine atom and n takes the values 4, 5 and 6 ; or - a group -O- (CH2) m-CN in which m takes the values 5 and 6.
Le procédé selon l'invention pour la préparation des composés de formule (I) dans laquelle R représente un groupement -0-(CH2)n-X et un groupement (chloro-3 fluoro-5) benzyloxy consiste à condenser le composé de formule (II)
avec les dérivés halogénés de formules (III) et (IV)
Br-(CH2)n-X (III)
dans lesquellesn et X ont la même signification que dans la formule (I).The process according to the invention for the preparation of the compounds of formula (I) in which R represents a group -O- (CH 2) nX and a group (3-chloro-5-fluoro) benzyloxy consists in condensing the compound of formula (II )
with the halogenated derivatives of formulas (III) and (IV)
Br- (CH2) nX (III)
in which n and X have the same meaning as in formula (I).
Cette condensation s'effectue de préférence au reflux dans l'acétonîtrile en présence de carbonate de potassium. This condensation is preferably carried out under reflux in acetonitrile in the presence of potassium carbonate.
Le composé de formule (IV) ci-dessus est nouveau Il est obtenu par une synthese en plusieurs stades à partir de l'acide chloro-3 nitro-5 benzolque qui consiste à réduire ledit acide par le diborane pour obtenir le chloro-3 nitro-5 benzèneméthanol nouveau, qui est alors réduit par le mélange fer-chlorure d'ammonium pour donner l'amino-3- chloro-5 benzeneméthanol qui, mis en réaction avec le tétrafluoroborate tHBF4 à 50%) en présence de nitrite de sodium, donne le chloro-3 fluoro-5 benzèneméthanol également nouveau. Ce dernier composé traité par le chlorure de thionyle en milieu benzénique conduit au composé de formule (IV). The compound of formula (IV) above is new It is obtained by a synthesis in several stages from 3-chloro-5-nitro benzoic acid which consists in reducing said acid by diborane to obtain 3-chloro-nitro 5 benzenemethanol new, which is then reduced by the iron-ammonium chloride mixture to give the amino-3-chloro-5-benzenemethanol which, reacted with tetrafluoroborate tHBF4 at 50%) in the presence of sodium nitrite, gives the 3-chloro-5-fluorobenzenemethanol also new. This last compound treated with thionyl chloride in a benzene medium leads to the compound of formula (IV).
Le procédé selon l'invention pour la préparation des composes de formule (I) dans laquelle R représente le groupement cyclopentyloxy consiste à condenser le composé de formule (II) avec le bromocyclopentane. The process according to the invention for the preparation of the compounds of formula (I) in which R represents the cyclopentyloxy group consists in condensing the compound of formula (II) with bromocyclopentane.
Cette condensation s'effectue de préférence en solution dans le diméthylformamide, en présence d'hydrure de sodium. This condensation is preferably carried out in solution in dimethylformamide, in the presence of sodium hydride.
Le procédé selon l'invention par la préparation des composés de formule (I) dans laquelle R représente le groupement -0-(CH3)m-CN consiste a traiter les composés de formule (I) dans laquelle R représente les groupements 0- (CH2) 5-Br et -O-(CH2)6-Cl par le cyanure de potassium. The process according to the invention by the preparation of the compounds of formula (I) in which R represents the group -O- (CH 3) m-CN consists in treating the compounds of formula (I) in which R represents the groups O- ( CH2) 5-Br and -O- (CH2) 6-Cl by potassium cyanide.
Cette réaction s'effectue de préférence au reflux dans l'acétonitrile et en présence d'un catalyseur du type éther couronne (18-Crown-6). This reaction is preferably carried out under reflux in acetonitrile and in the presence of a crown ether catalyst (18-Crown-6).
Les préparations suivantes sont données à titre d'exemple pour
illustrer l'invention.The following preparations are given as examples for
illustrate the invention.
Exemple I [(Bromo-5 pentyloxy)-4 phénol -3 hydroxymethyl-5 oxazolidinone-2 (I)
numéro de code : 4
On porte à reflux pendant 3 heures un mélange de 10,4 g
d(hydroxy-4 phényl)-3 hydroxyméthyl-5 oxazolidinone-2 (II), de
13,5 ml de 1,5-dibromopentane et de 14 g de carbonate de potassium
dans 100 ml d'acétonitrile. Puis on filtre, évapore le filtrat,
reprend le résidu dans l'étherisopropylique, filtre le produit
cristallisé et le chromatographie sur une colonne de silice.EXAMPLE I 4- (5-Bromo-pentyloxy) phenol-5-hydroxymethyl-2-oxazolidinone (I)
code number: 4
Refluxed for 3 hours a mixture of 10.4 g
d (4-hydroxy-phenyl) -5-hydroxymethyl-2-oxazolidinone (II),
13.5 ml of 1,5-dibromopentane and 14 g of potassium carbonate
in 100 ml of acetonitrile. Then filter, evaporate the filtrate,
take up the residue in ether-isopropyl, filter the product
crystallized and chromatography on a silica column.
Elués par le mélange chloroforme 99 Z, méthanol 1 Z, on obtient
4 g de produit.Eluted with chloroform mixture 99% Z, 1% methanol,
4 g of product.
. point de fusion : 820C. . melting point: 820C.
. forme brute : C15H20BrNO4. . crude form: C15H20BrNO4.
analyse élémentaire : C H N
calcule (Z) : 50,29 5,63 3,91
trouvé (%) : 50,39 5,32 3,73
Par le même procédé, mais à partir des réactifs correspondants, on
obtient les composés de formule (I) figurant dans le tableau I
et portant les numéros de code 2, 3 et 7.elemental analysis: CHN
Calculates (Z): 50.29 5.63 3.91
found (%): 50.39 5.32 3.73
By the same process, but from the corresponding reagents,
obtain the compounds of formula (I) appearing in Table I
and bearing the code numbers 2, 3 and 7.
Exemple 2 (eyelopentyloxy-4 phényl)-3 hydroxyméthyl-5 oxazolidinone-2 (I).Example 2 (4-eyelopentyloxy-phenyl) -3-hydroxymethyl-5-oxazolidinone-2 (I).
numéro de code : 1
A une solution de 6,3 g d'(hydroxy-4 phe-nyl)-3 hydroxyméthyl-5
oxazolidinone-2 (II) dans 100 ml de diméthyl formamide, on ajoute
lentement 1,5 g d'hydrure de sodium à 50 %, puis lorsque le
dégagement gazeux a cessé, on ajoute 4,5 g de bromure de cyclo
pentyle et on porte 3 heures à 60 C. Puis on verse sur de l'eau,
filtre le produit forme et le recristallise dans un mélange
d'éther et d'alcool isopropylique. On obtient 2,7 g de produit.code number: 1
To a solution of 6.3 g of (4-hydroxy-phe-nyl) -3-hydroxymethyl-5
oxazolidinone-2 (II) in 100 ml of dimethyl formamide is added
1.5 g of sodium hydride at 50% and then
gaseous release ceased, 4.5 g of cyclo bromide was added
pentyl and bring it to 60 ° C. for 3 hours. Then pour on water,
filters the product forms and recrystallizes it into a mixture
ether and isopropyl alcohol. 2.7 g of product are obtained.
. rendement : 32 %
. point de fusion : 1040C.. yield: 32%
. melting point: 1040C.
. forme brute : C15HlgNO4. . crude form: C15HlgNO4.
. poids moléculaire : 277,31. . molecular weight: 277.31.
. analyse élémentaire : C H N
calcule (%) : 64,96 6,91 5,05
trouvé (%) : 64,66 6,96 4,94
Exemple 3 Ç(cyano-5 pentyloxy)-4 phényl]-3 hydroxyméthyl-5, oxazolidinone-2 (I)
numéro de code : 5
On porte à reflux pendant 73 heures un mélange de 3;6 g de
[(bromo-5 pentyloxy)-4 phényle -3 hydroxyméthyl-5 oxazolidinone-2
(I), obtenu à l'exemple 1, de 1,3 g de cyanure de potassium et de
0,25 g d'éther couronne (18-Crown-6) dans 80 ml d'acétonitrile.. elemental analysis: CHN
Calculates (%): 64.96 6.91 5.05
Found (%): 64.66 6.96 4.94
Example 3 (5-cyano-pentyloxy) -4-phenyl] -3-hydroxymethyl-5-oxazolidinone-2 (I)
code number: 5
The mixture is refluxed for 73 hours for 3 hours.
4- (5-bromo-pentyloxy) phenyl-5-hydroxymethyl-2-oxazolidinone
(I), obtained in Example 1, of 1.3 g of potassium cyanide and
0.25 g of crown ether (18-Crown-6) in 80 ml of acetonitrile.
Puis on filtre, reprend le résidu dans l'acétate d'éthyle, le
lave à l'eau, seche sur sulfate de sodium, évapore le solvant
et recristallise le résidu dans un mélange 50-50 d'éther et
d'alcool isopropylique.Then filtered, the residue is taken up in ethyl acetate, the
Wash with water, dry over sodium sulfate, evaporate the solvent
and recrystallizes the residue in a 50-50 mixture of ether and
of isopropyl alcohol.
. rendement : 53 %. . yield: 53%.
. point de fusion : 680C. . melting point: 680C.
. forme brute : C16H20N204 = 304,34. . crude form: C16H20N2O4 = 304.34.
. analyse élémentaire : C H N
calculé (%) : 63,14 6,62 9,21
trouve (%) : 63,02 6,42 8,98
Par le même procédé, mais à partir des réactifs correspondants, on
obtient le composé de formule (I) figurant dans le tableau I et
portant le numéro de code 6.. elemental analysis: CHN
Calculated (%): 63.14 6.62 9.21
found (%): 63.02 6.42 8.98
By the same process, but from the corresponding reagents,
obtain the compound of formula (I) in Table I and
bearing the code number 6.
Exemple 4 chloro-3 fluoro-5 chlorométhylbenzene (IV)
A une solution refroidie à 0 C de 75 g d'acide chloro-3 nitro-5 benzoique dans 800 ml de tétrahydrofuranne, on ajoute lentement 25 g debonohydrure de sodium et on laisse en contact 30 mn. Puis on ajoute lentement 100 ml d'éthérate de trifluorure de bore, et on laisse revenir à température ambiante (3 heures). On hydrolyse par de l'acide chlorhydrique dilué, et extrait par du chlorure de méthylène, sèche sur sulfate de soude et évapore le filtrat.Example 4 3-chloro-5-fluoro-chloromethylbenzene (IV)
To a solution cooled to 0 ° C. of 75 g of 3-chloro-5-nitro benzoic acid in 800 ml of tetrahydrofuran, 25 g of sodium borohydride are slowly added and the mixture is left in contact for 30 minutes. Then 100 ml of boron trifluoride etherate are slowly added and allowed to come to room temperature (3 hours). It is hydrolysed with dilute hydrochloric acid and extracted with methylene chloride, dried over sodium sulphate and the filtrate is evaporated.
On obtient 44 g de produit brut (le chloro-3- nitro-5 benzène méthanol), puis on dissout 3,4 g de ce produit dans 100 ml d'une solution 0,1 N de chlorure d'ammonium, ajoute 3,5 g de fer en poudre et porte le mélange pendant 90 mn à 650-700C. Puis on dilue par de l'acétate d'éthyle, filtre, décante la phase organique, la lave à l'eau, sèche sur sulfate de sodium et évapore le solvant. On obtient 2,4 g (85%) d'amino-3 chloro-5 benzèneméthanol que l'on dissout dans un mélange de 5 ml de tétrafluoroborate à 50% (HBF4) et 5 ml d'eau. On refroidit à OOC, et ajoute lentement une solution de 1,4 g de nitrite de soude dans 3 ml d'eau et on garde en contact à une température inférieure à OOC pendant 1 heure. Puis on filtre, lave le précipité obtenu à l'éther, et le met en suspension dans 100 ml de toluène et porte au reflux pendant 1 heure. Puis on dilue par de l'eau, extrait à l'acétate d'éthyle, décante la phase organique, sèche sur sulfate de sodium et évapore le solvant On obtient 1,8 g de chloro-3 fluoro-i benzène méthanol que l'on dissout dans 30 ml de benzène et 0,8 ml de chlorure de thionyle. Après 30 mn à température ambiante, on ajoute 1 ml de pyridine. Puis on lave à l'eau, sèche la phase organique sur sulfate de sodium et évapore le solvant, on obtient 1 g de composé (-IV) qui est utilisé brut dans la synthèse du composé de formule (I) correspondant, figurant dans le tableau I et portant le numéro de code 7.
TABLEAU I
Composés <SEP> Point <SEP> Analyse <SEP> élémantaire
<tb> <SEP> de <SEP> R <SEP> Formule <SEP> Poids <SEP> de <SEP> Rande- <SEP> Calculé <SEP> Trouvé
<tb> numéro <SEP> de <SEP> brute <SEP> moléculaire <SEP> fusion <SEP> mant
<tb> <SEP> code <SEP> C <SEP> % <SEP> C <SEP> H <SEP> N <SEP> C <SEP> H <SEP> N
<tb> <SEP> 1 <SEP> # <SEP> C15 <SEP> H19 <SEP> NO4 <SEP> 277,31 <SEP> 104 <SEP> 32 <SEP> 64,96 <SEP> 6,91 <SEP> 5,05 <SEP> 64,66 <SEP> 6,96 <SEP> 4,94
<tb> <SEP> 2 <SEP> 4-O-(CH2)4-Cl <SEP> C14H18ClNO4 <SEP> 299,75 <SEP> 96 <SEP> 33 <SEP> 56,09 <SEP> 6,05 <SEP> 4,67 <SEP> 55,92 <SEP> 5,82 <SEP> 4,63
<tb> <SEP> 3 <SEP> 4-O-(CH2)6-Cl <SEP> C16H22ClNO4 <SEP> 327,80 <SEP> 86 <SEP> 44 <SEP> 58,62 <SEP> 6,77 <SEP> 4,27 <SEP> 58,69 <SEP> 6,74 <SEP> 4,22
<tb> <SEP> 4 <SEP> 4-O-(CH2)5-Br <SEP> C15H20BrNO4 <SEP> 358,23 <SEP> 82 <SEP> 52 <SEP> 50,29 <SEP> 5,63 <SEP> 3,91 <SEP> 50,39 <SEP> 5,32 <SEP> 3,73
<tb> <SEP> 5 <SEP> 4-O-(CH2)5-CN <SEP> C16H20N2O4 <SEP> 304,34 <SEP> 68 <SEP> 53 <SEP> 63,14 <SEP> 6,62 <SEP> 9,21 <SEP> 63,03 <SEP> 6,42 <SEP> 8,98
<tb> <SEP> 6 <SEP> 4-O-(CH2)6-CN <SEP> C17H22N2O4 <SEP> 318,36 <SEP> 72 <SEP> 45 <SEP> 64,13 <SEP> 6,97 <SEP> 8,80 <SEP> 63,81 <SEP> 6,93 <SEP> 8,62
<tb> <SEP> 7 <SEP> # <SEP> C17H15ClFNO4 <SEP> 351,75 <SEP> 124 <SEP> 10 <SEP> 58,04 <SEP> 4,30 <SEP> 3,98 <SEP> 57,94 <SEP> 4,31 <SEP> 3,89
<tb> tes composés de formule (I) ont été étudiés chez l'animal de laboratoire et ont montré des activités dans le domaine psychotrope comme antidépresseurs potentiels.Compounds <SEP> Point <SEP> Analysis <SEP> Elementiary
<tb><SEP> of <SEP> R <SEP> Formula <SEP> Weight <SEP> of <SEP> Rande- <SEP> Calculated <SEP> Found
<tb> number <SEP> of <SEP> gross <SEP> molecular <SEP> fusion <SEP> mant
<tb><SEP> code <SEP> C <SEP>% <SEP> C <SEP> H <SEP> N <SEP> C <SEP> H <SEP> N
<tb><SEP> 1 <SEP>#<SEP> C15 <SEP> H19 <SE> NO4 <SEP> 277.31 <SEP> 104 <SEP> 32 <SEP> 64.96 <SEP> 6.91 <MS> 5.05 <SEP> 64.66 <SEP> 6.96 <SEP> 4.94
<tb><SEP> 2 <SEP> 4-O- (CH2) 4-Cl <SEP> C14H18ClNO4 <SEP> 299.75 <SEP> 96 <SEP> 33 <SEP> 56.09 <SEP> 6.05 <SEP> 4.67 <SEP> 55.92 <SEP> 5.82 <SEP> 4.63
<tb><SEP> 3 <SEP> 4-O- (CH 2) 6-Cl <SEP> C 16 H 22 ClNO 4 <SEP> 327.80 <SEP> 86 <SEP> 44 <SEP> 58.62 <SEP> 6.77 <SEP> 4.27 <SEP> 58.69 <SEP> 6.74 <SEP> 4.22
<tb><SEP> 4 <SEP> 4-O- (CH 2) 5-Br <SEP> C 15 H 20 BrNO 4 <SEP> 358.23 <SEP> 82 <SEP> 52 <SEP> 50.29 <SEP> 5.63 <SEP> 3.91 <SEP> 50.39 <SEP> 5.32 <SEP> 3.73
<sep>SEP>5-SEP> 4-O- (CH 2) 5-CN <SEP> C 16 H 20 N 2 O 4 <SEP> 304.34 <SEP> 68 <SEP> 53 <SEP> 63.14 <SEP> 6.62 <SEP> 9.21 <SEP> 63.03 <SEP> 6.42 <SEP> 8.98
<sep>SEP> 6 <SEP> 4-O- (CH 2) 6-CN <SEP> C 17 H 22 N 2 O 4 <SEP> 318.36 <SEP> 72 <SEP> 45 <SEP> 64.13 <SEP> 6.97 <SEP> 8.80 <SEP> 63.81 <SEP> 6.93 <SEP> 8.62
<tb><SEP> 7 <SEP>#SEP> C17H15ClFNO4 <SEP> 351.75 <SEP> 124 <SEP> 10 <SEP> 58.04 <SEP> 4.30 <SEP> 3.98 <SEP> 57.94 <SEP> 4.31 <SEP> 3.89
The compounds of formula (I) have been studied in laboratory animals and have shown activities in the psychotropic field as potential antidepressants.
Ces activités sont mises en évidence dans les tests suivants
Test A : potentialisation chez la souris des tremblements généralisés provoqués par une injection intrapéritonéale (200 mg/Kg) de dl-5-hydroxytryptophane, selon le protocole décrit par GOURET C. et RAYNAUD G. dans J. Pharmacol. (Paris) (1974), 5, 231.These activities are highlighted in the following tests
Test A: Potentiation in the mouse of generalized tremors caused by an intraperitoneal injection (200 mg / kg) of dl-5-hydroxytryptophan, according to the protocol described by GOURET C. and RAYNAUD G. in J. Pharmacol. (Paris) (1974), 5, 231.
Test B : antagonisme vis-à-vis du ptosis observé une heure après une injection intraveineuse (2 mg/Kg) de reserpine chez la souris selon le protocole décrit par COUREZ C. et THOMAS J. dans J. Pharmacol, (Paris),(1973), 4, 401.Test B: antagonism with respect to ptosis observed one hour after an intravenous injection (2 mg / kg) of reserpine in the mouse according to the protocol described by COUREZ C. and THOMAS J. in J. Pharmacol, (Paris), (1973), 4, 401.
Les résultats de ces deux tests ainsi que ceux d'une substance de référence, la TOLOXATONE, sont rassemblés dans le tableau Il ci- apres.The results of these two tests as well as those of a reference substance, TOLOXATONE, are summarized in Table II below.
Les toxicités ont été effectuées selon le protocole décrit par
Miller et Tainter dans "Proceeding of Society Experimental Biology and Medecine 1944, 57, 261".The toxicities were carried out according to the protocol described by
Miller and Tainter in "Proceeding of Society Experimental Biology and Medicine 1944, 57, 261".
Les résultats sont également consignés dans le tableau II. The results are also recorded in Table II.
TABLEAU
Il
he
<tb> <SEP> composé <SEP> Test <SEP> A <SEP> Test <SEP> B <SEP> Toxicité
<tb> testé <SEP> (I) <SEP> DE50 <SEP> mg/Kg/p.o <SEP> DE50 <SEP> mg/Kg/p.o <SEP> DL50 <SEP> souris
<tb> <SEP> numéro <SEP> de <SEP> code <SEP> 8 <SEP> jours/mg/Kg/p.o
<tb> <SEP> 1 <SEP> 3,5 <SEP> 6,2 <SEP> < <SEP> 1 <SEP> 00
<tb> <SEP> 2 <SEP> 1,6 <SEP> 2,5
<tb> <SEP> 3 <SEP> 12 <SEP> 13
<tb> <SEP> 4 <SEP> 8 <SEP> 12,5
<tb> <SEP> 5 <SEP> 1,6 <SEP> 1 <SEP> 1,4 <SEP> 1 <SEP> 000 <SEP> (40%)
<tb> <SEP> 6 <SEP> 7 <SEP> 6,8 <SEP> 1 <SEP> 000 <SEP> (602)
<tb> <SEP> 7 <SEP> 3,1 <SEP> 5
<tb> <SEP> TOLOXATONE <SEP> 60 <SEP> 50
<tb>
Comme il ressort des résultats exprimés dans le tableau Il ltecart entre les doses léthales et les doses pharmacologiquement actives est suffisant pour permettre l'utilisation des composés selon l'invention en thérapeutique.<tb><SEP> Compound <SEP> Test <SEP> A <SEP> Test <SEP> B <SEP> Toxicity
<tb> tested <SEP> (I) <SEP> DE50 <SEP> mg / Kg / in <SEP> DE50 <SEP> mg / Kg / in <SEP> LD50 <SEP> mice
<tb><SEP>SEP> number of <SEP> code <SEP> 8 <SEP> days / mg / Kg / in
<tb><SEP> 1 <SEP> 3.5 <SEP> 6.2 <SEP><<SEP> 1 <SEP> 00
<tb><SEP> 2 <SEP> 1.6 <SEP> 2.5
<tb><SEP> 3 <SEP> 12 <SEP> 13
<tb><SEP> 4 <SEP> 8 <SEP> 12.5
<tb><SEP> 5 <SEP> 1.6 <SEP> 1 <SEP> 1.4 <SEP> 1 <SEP> 000 <SEP> (40%)
<tb><SEP> 6 <SEP> 7 <SEP> 6.8 <SEP> 1 <SEP> 000 <SEP> (602)
<tb><SEP> 7 <SEP> 3.1 <SEP> 5
<tb><SEP> TOLOXATONE <SEP> 60 <SEP> 50
<Tb>
As can be seen from the results shown in Table II, the difference between lethal doses and pharmacologically active doses is sufficient to allow the use of the compounds according to the invention in therapy.
Les composés de formule (I) sont indiques pour le traitement des états dépressifs endogènes et éxogenes et seront administrés soit par voie orale sour forme de comprimés, de dragées ou gélules à une posologie pouvant aller jusqu'à 500 mg/jour de principe actif, soit sous forme de soluté injectable, à une posologie pouvant aller jusqu'à 50 mg/jour de principe actif, le solvant utilisé étant constitué par des mélanges binairesou ternaires contenant par exemple de l'eau, du propylene glycol, du polyéthylène glycol 300 ou 400 ou tout autre solvant physiologique. Les proportions relatives des différents constituants sont ajustées en fonction de la dose administrée. The compounds of formula (I) are indicated for the treatment of endogenous and exogenous depressive states and will be administered either orally in the form of tablets, dragees or capsules at a dosage of up to 500 mg / day of active principle, either in the form of an injectable solution, at a dosage of up to 50 mg / day of active ingredient, the solvent used being constituted by binary or ternary mixtures containing, for example, water, propylene glycol, polyethylene glycol 300 or 400 or any other physiological solvent. The relative proportions of the various constituents are adjusted according to the dose administered.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7917834A FR2460940A2 (en) | 1979-07-10 | 1979-07-10 | Antidepressant oxazolidinone(s) - with 5-hydroxymethyl -3-phenyl substituents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7917834A FR2460940A2 (en) | 1979-07-10 | 1979-07-10 | Antidepressant oxazolidinone(s) - with 5-hydroxymethyl -3-phenyl substituents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2460940A2 true FR2460940A2 (en) | 1981-01-30 |
| FR2460940B2 FR2460940B2 (en) | 1984-06-01 |
Family
ID=9227702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR7917834A Granted FR2460940A2 (en) | 1979-07-10 | 1979-07-10 | Antidepressant oxazolidinone(s) - with 5-hydroxymethyl -3-phenyl substituents |
Country Status (1)
| Country | Link |
|---|---|
| FR (1) | FR2460940A2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2003151A (en) * | 1977-08-26 | 1979-03-07 | Delande Sa | 5-hydroxymethyl ozazolidinones the method of preparing them and their application in therapeutics |
-
1979
- 1979-07-10 FR FR7917834A patent/FR2460940A2/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2003151A (en) * | 1977-08-26 | 1979-03-07 | Delande Sa | 5-hydroxymethyl ozazolidinones the method of preparing them and their application in therapeutics |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2460940B2 (en) | 1984-06-01 |
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