FR2766485A1 - 2:Alkoxy phenyl triazolone derivatives - Google Patents
2:Alkoxy phenyl triazolone derivatives Download PDFInfo
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- FR2766485A1 FR2766485A1 FR9709341A FR9709341A FR2766485A1 FR 2766485 A1 FR2766485 A1 FR 2766485A1 FR 9709341 A FR9709341 A FR 9709341A FR 9709341 A FR9709341 A FR 9709341A FR 2766485 A1 FR2766485 A1 FR 2766485A1
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- 125000005036 alkoxyphenyl group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- -1 hydroxy fluoroalkyl Chemical group 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- LZTSCEYDCZBRCJ-UHFFFAOYSA-N 1,2-dihydro-1,2,4-triazol-3-one Chemical class OC=1N=CNN=1 LZTSCEYDCZBRCJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000032683 aging Effects 0.000 claims description 3
- 208000026139 Memory disease Diseases 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 2
- 230000001575 pathological effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- 208000019022 Mood disease Diseases 0.000 claims 1
- 230000007717 exclusion Effects 0.000 claims 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000003236 psychic effect Effects 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 102000010909 Monoamine Oxidase Human genes 0.000 description 14
- 108010062431 Monoamine oxidase Proteins 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- FYEUHDBLBXQIOV-UHFFFAOYSA-N ethyl 3-acetamidopropanoate Chemical compound CCOC(=O)CCNC(C)=O FYEUHDBLBXQIOV-UHFFFAOYSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- UFZKWTITXBRSPK-UHFFFAOYSA-N (4-phenylmethoxyphenyl)hydrazine Chemical compound C1=CC(NN)=CC=C1OCC1=CC=CC=C1 UFZKWTITXBRSPK-UHFFFAOYSA-N 0.000 description 1
- 0 *C(N(*)C1=O)=NN1c(cc1)ccc1O* Chemical compound *C(N(*)C1=O)=NN1c(cc1)ccc1O* 0.000 description 1
- XTIGGAHUZJWQMD-UHFFFAOYSA-N 1-chloro-2-methoxyethane Chemical compound COCCCl XTIGGAHUZJWQMD-UHFFFAOYSA-N 0.000 description 1
- DDGRAFHHXYIQQR-UHFFFAOYSA-N 1-chloro-3-(chloromethyl)benzene Chemical compound ClCC1=CC=CC(Cl)=C1 DDGRAFHHXYIQQR-UHFFFAOYSA-N 0.000 description 1
- WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-PPJXEINESA-N 2-((114C)cyclohexatrienyl)ethanamine Chemical compound NCC[14C]1=CC=CC=C1 BHHGXPLMPWCGHP-PPJXEINESA-N 0.000 description 1
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 101150050192 PIGM gene Proteins 0.000 description 1
- 101000650578 Salmonella phage P22 Regulatory protein C3 Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 101001040920 Triticum aestivum Alpha-amylase inhibitor 0.28 Proteins 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- JLYXXMFPNIAWKQ-UHFFFAOYSA-N γ Benzene hexachloride Chemical compound ClC1C(Cl)C(Cl)C(Cl)C(Cl)C1Cl JLYXXMFPNIAWKQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention a pour objet des composés dérivés de la 2,4-dihydro-3H-1,2,4-triazol-3-one, leur procédé de préparation et leur application en thérapeutique.The present invention relates to compounds derived from 2,4-dihydro-3H-1,2,4-triazol-3-one, their method of preparation and their therapeutic application.
On connaît de la demande de brevet japonais 2015069 certains composés dérivés de la 2,4-dihydro-3H-1,2,4-triazol-3-one. From Japanese Patent Application 2015069 certain compounds derived from 2,4-dihydro-3H-1,2,4-triazol-3-one are known.
Ces composés sont utiles en tant qu'anti-inflammatoires.These compounds are useful as anti-inflammatories.
La présente invention a pour objet des composés dérivés de la 2,4-dihydro-3H-1,2,4-triazol-3-one, de formule générale (I),
dans laquelle
R, représente un groupe alkyle comprenant 1 à 4 atomes de carbone,
R2 représente un atome d'hydrogène ou un groupe RaORb-, où Ra est un groupe alkyle comprenant 1 à 4 atomes de carbone et Rb est un groupe alkylène comprenant 1 à 4 atomes de carbone,
R3 représente un groupe alkyle comprenant 1 à 6 atomes de carbone, un groupe hydroxyalkyle, un groupe fluoroalkyle, un groupe hydroxyfluoroalkyle, un groupe phényle ou un groupe phényle substitué soit par un halogène soit par un groupe méthylènedioxy, à l'exclusion des composés où simultanément, R3 est un groupe alkyle comprenant de 1 à 4 atomes de carbone, R est un atome d'hydrogène et Rl est un groupe alkyle comprenant 2 à 4 atomes de carbone.The present invention relates to compounds derived from 2,4-dihydro-3H-1,2,4-triazol-3-one of the general formula (I),
in which
R, represents an alkyl group comprising 1 to 4 carbon atoms,
R2 represents a hydrogen atom or a RaORb- group, where Ra is an alkyl group comprising 1 to 4 carbon atoms and Rb is an alkylene group comprising 1 to 4 carbon atoms,
R3 represents an alkyl group comprising 1 to 6 carbon atoms, a hydroxyalkyl group, a fluoroalkyl group, a hydroxyfluoroalkyl group, a phenyl group or a phenyl group substituted with either a halogen or a methylenedioxy group, with the exception of compounds where simultaneously, R 3 is an alkyl group having 1 to 4 carbon atoms, R is a hydrogen atom and R 1 is an alkyl group having 2 to 4 carbon atoms.
Dans le cadre de l'invention les termes ci-après ont les significations suivantes - un groupe alkyle est un groupe aliphatique, saturé, linéaire ou ramifié, - un groupe alkylène est un groupe aliphatique saturé divalent, linéaire ou ramifié, - un halogène est un atome pris dans le groupe chlore, fluor, brome, iode, - un groupe fluoroalkyle est un groupe alkyle tel que défini ci-dessus comprenant 1 à 6 atomes de carbone, l'un au moins des atomes de carbone étant substitué par un à 3 atomes de fluor, - un groupe hydroxyalkyle est un groupe alkyle comprenant 1 à 6 atomes de carbone tel que défini ci-dessus, l'un des atomes de carbone étant substitué par un groupe hydroxy, - un groupe hydroxyfluoroalkyle est un groupe fluoroalkyle tel que défini ci-dessus, dont l'un des atomes de carbone est substitué par un groupe hydroxy.In the context of the invention the following terms have the following meanings - an alkyl group is a saturated, linear or branched aliphatic group, - an alkylene group is a divalent saturated aliphatic group, linear or branched, - a halogen is an atom taken from the group chlorine, fluorine, bromine, iodine, a fluoroalkyl group is an alkyl group as defined above comprising 1 to 6 carbon atoms, at least one of the carbon atoms being substituted with one to 3 fluorine atoms, - a hydroxyalkyl group is an alkyl group comprising 1 to 6 carbon atoms as defined above, one of the carbon atoms being substituted with a hydroxyl group, - a hydroxyfluoroalkyl group is a fluoroalkyl group such as as defined above, one of whose carbon atoms is substituted by a hydroxy group.
Selon l'invention, les atomes d'halogène préférés sont le chlore et le fluor.According to the invention, the preferred halogen atoms are chlorine and fluorine.
Les composés de formule (I) où Rl est un groupe méthyle sont préférés. Parmi ces composés, ceux où R représente un groupe éthyloxyméthyle sont tout particulièrement préférés.Compounds of formula (I) wherein R1 is a methyl group are preferred. Among these compounds, those in which R represents an ethyloxymethyl group are very particularly preferred.
Les composés de formule (I) peuvent comporter un ou deux atomes de carbone asymétriques. Ils peuvent donc exister sous forme d'énantiomères ou de diastéréoisomères purs ou de mélange de ces différentes formes, y compris de mélanges racémiques. Ces différentes formes ainsi que leurs mélanges font partie de l'invention.The compounds of formula (I) may comprise one or two asymmetric carbon atoms. They can therefore exist in the form of enantiomers or pure diastereoisomers or mixtures of these different forms, including racemic mixtures. These different forms and their mixtures are part of the invention.
Les composés de formule (I) peuvent être préparés selon le procédé représenté dans le schéma général de synthèse en annexe.The compounds of formula (I) may be prepared according to the process represented in the general synthetic scheme in the appendix.
Selon ce procédé on fait réagir un composé de formule (II),
dans laquelle Rl et R sont définis comme ci-dessus, soit avec un composé de formule R3X, dans laquelle R3 est défini comme ci-dessus et X représente un atome d'halogène ou un groupement labile tel que méthylsulfonylox.y (mésyloxy) ou p-toluènesulfonyloxy (tosyloxy), en présence d'une base telle que le carbonate de potassium, dans un solvant tel que l'acétone ou le méthyléthylcétone, soit avec un composé de formule R30H, dans laquelle R3 est défini comme ci-dessus, en présence de triphénylphosphine et de diéthylazodicarboxylate dans un solvant tel que le tétrahydrofurane.According to this process a compound of formula (II) is reacted,
wherein R1 and R3 are defined as above, either with a compound of formula R3X, wherein R3 is defined as above and X represents a halogen atom or a leaving group such as methylsulfonylox.y (mesyloxy) or p-toluenesulfonyloxy (tosyloxy), in the presence of a base such as potassium carbonate, in a solvent such as acetone or methyl ethyl ketone, or with a compound of formula R 3 OH, in which R 3 is defined as above, in the presence of triphenylphosphine and diethylazodicarboxylate in a solvent such as tetrahydrofuran.
La méthode de préparation des composés de formule (II) consiste à faire réagir un composé de formule (III), où Y est un atome d'hydrogène ou un atome d'halogène tel que le chlore ou le brome, avec un dérivé de N-carboxyimidate d'éthyle de formule (IV), où Rl est défini comme précédemment, pour obtenir le 2,4-dihydro-3H-1,2,4-triazol-3-one correspondant de formule (I.b), qui est traité par un composé de formule
R2X dans laquelle R et X sont définis comme précédemment, en présence d'une base telle que NaOH pour donner le composé de formule (I.a), qui est enfin déprotégé par hydrogénation catalytique. Les composés de formule (IV) décrits ci-dessus peuvent être obtenus par réaction d'un dérivé de chlorhydrate d'imidate de formule (V), où R; est tel que défini précédemment, obtenu à partir du nitrile correspondant selon
A.W. Dox, Org. Synth., Vol 1., page 5, avec du chloroformiate d'éthyle, en présence de triéthylamine, dans un solvant tel que le dichlorométhane.The method for preparing the compounds of formula (II) consists of reacting a compound of formula (III), where Y is a hydrogen atom or a halogen atom such as chlorine or bromine, with a derivative of N -ethylcarboxyimidate of formula (IV), where R1 is defined as above, to give the corresponding 2,4-dihydro-3H-1,2,4-triazol-3-one of formula (Ib), which is treated by a compound of formula
Wherein R and X are defined as above, in the presence of a base such as NaOH to give the compound of formula (Ia), which is finally deprotected by catalytic hydrogenation. The compounds of formula (IV) described above can be obtained by reaction of an imidate hydrochloride derivative of formula (V), where R; is as defined above, obtained from the corresponding nitrile according to
AW Dox, Org. Synth., Vol 1., page 5, with ethyl chloroformate, in the presence of triethylamine, in a solvent such as dichloromethane.
Le composé de formule générale (III) dans laquelle Y représente un atome d'hydrogène est disponible dans le commerce. Les composés de formule générale (III) dans laquelle Y représente un atome d'halogène tel que le chlore ou le brome sont préparés selon Freeman et al., Dyed Pigm. The compound of general formula (III) wherein Y represents a hydrogen atom is commercially available. Compounds of general formula (III) wherein Y represents a halogen atom such as chlorine or bromine are prepared according to Freeman et al., Dyed Pigm.
17, (1991), 2, pages 83 à 100. 17, (1991), 2, pp. 83-100.
Un autre objet de l'invention est relatif aux composés de formule (II),
qui sont notamment utiles comme intermédiaires de synthèse des composés de formule (I), pour lesquels Rl et R2 ont les mêmes significations que précédemment.Another subject of the invention relates to the compounds of formula (II),
which are especially useful as synthesis intermediates of the compounds of formula (I), for which R1 and R2 have the same meanings as above.
Les exemples suivants illustrent la présente invention.The following examples illustrate the present invention.
Dans les noms composés, le tiret "-" fait partie du mot, et le tiret " " ne sert que pour la coupure en fin de ligne ; il est à supprimer en l'absence de coupure et ne doit être remplacé ni par un tiret normal ni par un espace.In compound names, the hyphen "-" is part of the word, and the hyphen "" is only used for the cut at the end of the line; it must be deleted in the absence of a break and must not be replaced by a standard hyphen or a space.
Exemple 1 : 5-Méthyl-2-[4-(phénylméthoxy)phényl]-2,4-dihydro- 3H-1,2,4-triazol-3-one 1.1. N-éthoxycarbonyléthylacétimidate
On refroidit à +40C, à l'aide d'un bain de glace, une suspension de 25 g (200 mmol) de chlorhydrate d'éthylacétimidate dans 350 ml de dichlorométhane. On ajoute à ce mélange 59 ml (420 mmol) de triéthylamine, puis on ajoute goutte à goutte 19 ml (200 mmol) de chloroformiate d'éthyle en solution dans 40 ml de dichlorométhane. On agite la solution à +40C pendant 3 heures puis on filtre sur fritté. Enfin on évapore le solvant sous pression réduite.Example 1: 5-Methyl-2- [4- (phenylmethoxy) phenyl] -2,4-dihydro-3H-1,2,4-triazol-3-one 1.1. N-éthoxycarbonyléthylacétimidate
A suspension of 25 g (200 mmol) of ethylacetimidate hydrochloride in 350 ml of dichloromethane is cooled to + 40 ° C. using an ice-bath. 59 ml (420 mmol) of triethylamine are added to this mixture, and then 19 ml (200 mmol) of ethyl chloroformate dissolved in 40 ml of dichloromethane are added dropwise. The solution is stirred at + 40 ° C. for 3 hours and then sintered. Finally the solvent is evaporated under reduced pressure.
On récupère 25 g d'une huile (rendement=788). 25 g of an oil are recovered (yield = 788).
1.2. 5-Méthyl-2-[4-(phénylméthoxy)phényl]-2, 4-dihydro- 3H-1,2,4-triazol-3-one
On met en solution 30,8 g (144 mmol) de 4-benzyloxyphényl~ hydrazine et 25 g (158 mmol) de N-éthoxycarbonyléthyl~ acétimidate, préparé précédemment, utilisé sans autre purification, dans 430 ml de toluène à température ambiante.1.2. 5-Methyl-2- [4- (phenylmethoxy) phenyl] -2,4-dihydro-3H-1,2,4-triazol-3-one
30.8 g (144 mmol) of 4-benzyloxyphenylhydrazine and 25 g (158 mmol) of N-ethoxycarbonylethylacetimidate, prepared previously, used without further purification, are dissolved in 430 ml of toluene at room temperature.
On chauffe pendant 3 heures à 45 OC. On ajoute 22 ml (158 mmol) de triéthylamine, puis on chauffe pendant 15 heures à 90 "C. On refroidit la solution à température ambiante. On lave la phase organique par une solution aqueuse d'acide chlorhydrique N, puis par une solution aqueuse saturée de chlorure de sodium. On sèche la phase organique sur sulfate de magnésium, on filtre et évapore le solvant sous pression réduite.It is heated for 3 hours at 45 ° C. 22 ml (158 mmol) of triethylamine are added, then the mixture is heated for 15 hours at 90 ° C. The solution is cooled to room temperature The organic phase is washed with an aqueous solution of N hydrochloric acid and then with an aqueous solution saturated with sodium chloride The organic phase is dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure.
On récupère 15,7 g de produit (rendement=39%). 15.7 g of product are recovered (yield = 39%).
Point de fusion : 234-235"C. Melting point: 234-235 ° C.
Exemple 2 : 4-(2-Méthoxyéthyl)-5-méthyl-2-[4-(phényl méthOxy)phényl]-2,4-dihydro-3H-1,2,4-triazol-3-one
On ajoute 1,7 g (6 mmol) de 5-Méthyl-2-Ç4-(phénylméthoxy) phényl] -2, 4-dihydro-3H-1, 2, 4-triazol-3-one, obtenu à l'exemple 1, en solution dans 10 ml de diméthylformamide goutte à goutte à 0,35 g (7,2 mmol) d'hydrure de sodium en suspension dans 5 ml de diméthylformamide à température ambiante. A la fin du dégagement gazeux on ajoute 0,62 g
(6,6 mmol) de chloroéthyl méthyléther en solution dans 2 ml de diméthylformamide. On chauffe la solution pendant 20 heures à 100"C. On refroidit avant d'ajouter 200 ml d'eau.Example 2: 4- (2-Methoxyethyl) -5-methyl-2- [4- (phenylmethyl) phenyl] -2,4-dihydro-3H-1,2,4-triazol-3-one
1.7 g (6 mmol) of 5-methyl-2- [4- (phenylmethoxy) phenyl] -2,4-dihydro-3H-1,2,4-triazol-3-one are obtained, obtained in the example 1, dissolved in 10 ml of dimethylformamide dropwise at 0.35 g (7.2 mmol) of sodium hydride suspended in 5 ml of dimethylformamide at room temperature. At the end of the evolution of gas, add 0.62 g
(6.6 mmol) of chloroethyl methyl ether dissolved in 2 ml of dimethylformamide. The solution is heated for 20 hours at 100 ° C. It is cooled before adding 200 ml of water.
On extrait la phase aqueuse trois fois avec 70 ml d'acétate d'éthyle. On lave les phases organiques réunies par une solution aqueuse saturée de chlorure de sodium et on les sèche sur sulfate de magnésium. On filtre sur fritté et évapore le solvant sous pression réduite. On chromatographie le résidu sur gel de silice en éluant par un mélange heptane / acétate d'éthyle : 75 / 25. Enfin le produit obtenu est recristallisé dans l'éther isopropylique.The aqueous phase is extracted three times with 70 ml of ethyl acetate. The combined organic phases are washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. It is sintered and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane / ethyl acetate mixture: 75/25. Finally, the product obtained is recrystallized from isopropyl ether.
On récupère 1,05 g de produit (rendement=52%). 1.05 g of product is recovered (yield = 52%).
Point de fusion : 92-93"C. Melting point: 92-93 ° C.
Exemple 3 : 2-(4,4,4-Trifluorobutoxyphényl)-4-(2-méthoxy éthyl)-5-méthyl-2,4-dihydro-3H-1,2,4-triazol-3-one 3.1. 2-(4-Hydroxyphényl)-4-(2-méthoxyéthyl)-5-méthyl-2,4dihydro-3H-1,2,4-triazol-3-one
On met 5 g (14,7 mmol) de 4-(2-Méthoxyéthyl)-5-méthyl-2
[4-(phénylméthOxy)phényl]-2,4-dihydro-3H-1,2,4-triazol-3-one, obtenu à l'exemple 2, en solution dans 250 ml d'acétate d'éthyle et on ajoute 1 g de palladium 10% sur charbon 50% humide. On purge sous azote puis on met sous une pression d'hydrogène de 200 mbar pendant 48 heures à température ambiante. On filtre sur célite et rince le fritté avec de l'acétate d'éthyle. Enfin On concentre sous pression réduite.Example 3 2- (4,4,4-Trifluorobutoxyphenyl) -4- (2-methoxyethyl) -5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one 3.1. 2- (4-Hydroxyphenyl) -4- (2-methoxyethyl) -5-methyl-2,4dihydro-3H-1,2,4-triazol-3-one
5 g (14.7 mmol) of 4- (2-methoxyethyl) -5-methyl-2 are added
[4- (phenylmethyloxy) phenyl] -2,4-dihydro-3H-1,2,4-triazol-3-one, obtained in Example 2, dissolved in 250 ml of ethyl acetate and added 1 g of 10% palladium on 50% wet charcoal. Purge under nitrogen and then put under a hydrogen pressure of 200 mbar for 48 hours at room temperature. Filtered over celite and rinsed the sintered with ethyl acetate. Finally, it is concentrated under reduced pressure.
On récupère 3,5 g de produit (rendement=928). 3.5 g of product are recovered (yield = 928).
Point de fusion : lll-113"C. Melting point: 113-113 ° C.
3.2. 2-(4,4,4-Trifluorobutoxyphényl)-4-(2-méthoxy éthyl) -5-méthyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one
On met en suspension 0,42 g (1,68 mmol) de 2-(4-hydroxy~ phényl) -4- (2-méthoxyéthyl)-5-méthyl-2, 4-dihydro-3H- l,2,4-triazol-3-one, 0,32 ml (1,68 mmol) de 1-bromo-4,4,4-trifluorobutane et 0,46 g (3,36 mmol) de carbonate de potassium dans 20 ml de diméthylformamide. Après une nuit d'agitation à température ambiante, le milieu réactionnel est additionné d'eau et extrait à l'acétate d'éthyle. La phase organique, après séparation et lavage plusieurs fois à l'eau, est séchée sur sulfate de sodium et le solvant évaporé sous pression réduite. On chromatographie le résidu sur gel de silice en éluant par un mélange heptane / acétate d'éthyle : 1 / 1. Enfin le produit obtenu est recristallisé dans l'éther isopropylique.3.2. 2- (4,4,4-Trifluorobutoxyphenyl) -4- (2-methoxyethyl) -5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one
0.42 g (1.68 mmol) of 2- (4-hydroxy-phenyl) -4- (2-methoxyethyl) -5-methyl-2,4-dihydro-3H-1,2,4 are suspended. -triazol-3-one, 0.32 ml (1.68 mmol) of 1-bromo-4,4,4-trifluorobutane and 0.46 g (3.36 mmol) of potassium carbonate in 20 ml of dimethylformamide. After stirring overnight at room temperature, the reaction medium is added with water and extracted with ethyl acetate. The organic phase, after separation and washing several times with water, is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane / ethyl acetate mixture: 1 / 1. Finally, the product obtained is recrystallized from isopropyl ether.
On récupère 160 mg de produit (rendement=27%)
Point de fusion : 119-120 C. 160 mg of product is recovered (yield = 27%)
Melting point: 119-120C.
Exemple 4 : 2-[4-[ (3-Chlorophény1)méthoxyjphényl- 4-(2-méthOxyéthy)-5-méthyl-2,4-dihydro-3H-1,2,4-triazol-3-one
On met en suspension 0,6 g (2,4 mmol) de 2-(4-Hydroxyphényl) 4-(2-méthOxyéthyl)-5-méthyl-2,4-dihydro-3H-1,2,4-triazol-3- one, obtenu à l'exemple 3, 0,68 ml (4,5 mmol) de chlorure de 3-chlorobenzyle et 0,795 g (5,75 mmol) de carbonate de potassium dans 20 ml d'acétone. On porte pendant 48 heures à la température de reflux. On filtre sur fritté et évapore le solvant sous pression réduite. On chromatographie le résidu sur gel de silice en éluant avec un mélange heptane / acétate d'éthyle : 40 / 60.Example 4: 2- [4- [(3-Chlorophenyl) methoxy] phenyl-4- (2-methoxyethyl) -5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one
0.6 g (2.4 mmol) of 2- (4-Hydroxyphenyl) -4- (2-methoxyethyl) -5-methyl-2,4-dihydro-3H-1,2,4-triazole are suspended. 3- one, obtained in Example 3, 0.68 ml (4.5 mmol) of 3-chlorobenzyl chloride and 0.795 g (5.75 mmol) of potassium carbonate in 20 ml of acetone. It is heated for 48 hours at reflux temperature. It is sintered and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane / ethyl acetate mixture: 40/60.
On récupère 0,69 g de produit (rendement=77%). 0.69 g of product is recovered (yield = 77%).
Point de fusion : 109-111 C. Melting point: 109-111 C.
Exemple 5 :4- :4-(2-Méthoxyéthyl)-5-méthyl-2-[4-(4,4,4-trifluoro- 3-hydroxybutoxy)phényl]-2,4-dihydro-3H-1,2,4-triazol-3-one
On met en suspension 0,6 g (2,4 mmol) de 2-(4-Hydroxyphényl) 4- (2-méthoxyéthyl) -5-méthyl-2, 4-dihydro-3H-l, 2,4- triazol-3-one, obtenu à l'exemple 3, utilisé sans autre purification, 0, 978 ml (3,28 mmol) de tosylate de
(R)-4,4,4-trifluoro-3-hydroxybutyle et 0,795 g (5,75 mmol) de carbonate de potassium dans 20 ml de méthyléthylcétone. On porte pendant 48 heures à la température de reflux. On filtre sur fritté et évapore le solvant sous pression réduite. On chromatographie le résidu sur gel de silice en éluant avec un mélange heptane / acétate d'éthyle : 40 / 60.
Example 5: 4- [4- (2-Methoxyethyl) -5-methyl-2- [4- (4,4,4-trifluoro-3-hydroxybutoxy) phenyl] -2,4-dihydro-3H-1,2 , 4-triazol-3-one
0.6 g (2.4 mmol) of 2- (4-Hydroxyphenyl) -4- (2-methoxyethyl) -5-methyl-2,4-dihydro-3H-1,2,4-triazole are suspended. 3-one, obtained in Example 3, used without further purification, 0, 978 ml (3.28 mmol) of tosylate of
(R) -4,4,4-trifluoro-3-hydroxybutyl and 0.795 g (5.75 mmol) of potassium carbonate in 20 ml of methyl ethyl ketone. It is heated for 48 hours at reflux temperature. It is sintered and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane / ethyl acetate mixture: 40/60.
On récupère 0,55 g de produit (rendement=61%).0.55 g of product is recovered (yield = 61%).
Point de fusion : 125-127"C. Melting point: 125-127 ° C.
Quelques exemples de composés selon l'invention sont rassemblés dans le tableau suivant avec leurs caractéristiques physiques.
<tb> <SEP> Point <SEP> de
<tb> NO <SEP> R; <SEP> R <SEP> R3 <SEP> fusion <SEP> ( C)
<tb> <SEP> 1 <SEP> CH3 <SEP> H <SEP> C, > H5CH <SEP> 234-235 <SEP>
<tb> <SEP> 2 <SEP> CH3 <SEP> CH3OCH2CH <SEP> C <SEP> HcCH <SEP> 92-93 <SEP>
<tb> <SEP> 3 <SEP> CH3 <SEP> H <SEP> 3C1-CtHECHn <SEP> 222-224 <SEP>
<tb> <SEP> CH3 <SEP> CHOCHCH <SEP> CH, <SEP> CH(CH-)-CH <SEP> 54-56 <SEP>
<tb> <SEP> 5 <SEP> CH <SEP> CH3OCHCH <SEP> CF, <SEP> (CH <SEP> ) <SEP> CH <SEP> 119-120 <SEP>
<tb> <SEP> 6 <SEP> CH3 <SEP> CH3OCH-.CH- <SEP> 3Cl-CH5CH <SEP> 109-111 <SEP>
<tb> <SEP> oH <SEP> +32
<tb> <SEP> 7 <SEP> CH <SEP> CH,OCH,CH <SEP> i <SEP> 125-127 <SEP> (c=1,
<tb> <SEP> F3 <SEP> Méthanol)
<tb> <SEP> 8 <SEP> CH3 <SEP> CH3OCHCH. <SEP> 4
<tb> <tb><SEP><SEP> Point of
<tb> NO <SEP>R;<SEP> R <SEP> R3 <SEP> Merge <SEP> (C)
<tb><SEP> 1 <SEP> CH3 <SEP> H <SEP>C,> H5CH <SEP> 234-235 <SEP>
<tb><SEP> 2 <SEP> CH3 <SEP> CH3OCH2CH <SEP> C <SEP> HcCH <SEP> 92-93 <SEP>
<tb><SEP> 3 <SEP> CH3 <SEP> H <SEP> 3C1-CtHECHn <SEP> 222-224 <SEP>
<tb><SEP> CH3 <SEP> CHOCHCH <SEP> CH <SEP> CH (CH -) - CH <SEP> 54-56 <SEP>
<tb><SEP> 5 <SEP> CH <SEP> CH3OCHCH <SEP> CF <SEP> (CH <SEP>) <SEP> CH <SEP> 119-120 <SEP>
<tb><SEP> 6 <SEP> CH3 <SEP> CH3OCH-.CH- <SEP> 3Cl-CH5CH <SEP> 109-111 <SEP>
<tb><SEP> oH <SEP> +32
<tb><SEP> 7 <SEP> CH <SEP> CH, OCH, CH <SEP> i <SEP> 125-127 <SEP> (c = 1,
<tb><SEP> F3 <SEP> Methanol)
<tb><SEP> 8 <SEP> CH3 <SEP> CH3OCHCH. <SEP> 4
<Tb>
Les composés de l'invention ont fait l'objet d'essais pharmacologiques permettant de déterminer leur effet inhibiteur de la monoamine oxydase.The compounds of the invention have been the subject of pharmacological tests for determining their inhibitory effect of monoamine oxidase.
Ces essais consistent à mesurer l'activité in vitro de la monoamine oxydase-A (MAO-A) et de la monoamine oxydase-B (MAO-B).These assays consist of measuring the in vitro activity of monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B).
Les mesures des activités MAO-A et MAO-3 ont été réalisées en utilisant comme source d'enzyme un homogénat de cerveau de rat. La méthode utilisée, décrite par C. Fowler et M.Measurements of MAO-A and MAO-3 activities were performed using as a source of enzyme a rat brain homogenate. The method used, described by C. Fowler and M.
Strolin-benedetti, dans J. Neurochem., 40, 1534-1541 (1983), consiste à préincuber l'enzyme 20 minutes à 37 OC en présence ou en l'absence des inhibiteurs étudiés. Au terme de cette période, la réaction est démarrée par l'addition de [14C] sérotonine (5-HT, 125 HM), pour la mesure de l'activité de la MAO-A ou de [14C]phényléthylamine (PEA, 8 pM), pour la mesure de l'activité de la MAO-B. Après 5 minutes d'incubation à 37"C en présence de [14C]5-HT et une minute à 37"C en présence de [14C]PEA, la réaction est arrêtée par addition d'acide chlorhydrique. Les métabolites des amines sont alors extraits et la radioactivité est quantifiée par comptage en scintillation liquide.Strolin-benedetti, in J. Neurochem., 40, 1534-1541 (1983), consists in preincubating the enzyme for 20 minutes at 37 ° C. in the presence or in the absence of the inhibitors studied. At the end of this period, the reaction is started by the addition of [14C] serotonin (5-HT, 125 HM), for the measurement of the activity of MAO-A or [14C] phenylethylamine (PEA, 8 pM), for measuring the activity of MAO-B. After 5 minutes of incubation at 37 ° C in the presence of [14 C] 5-HT and one minute at 37 ° C in the presence of [14 C] PEA, the reaction is stopped by the addition of hydrochloric acid. The metabolites of the amines are then extracted and the radioactivity is quantified by liquid scintillation counting.
L'activité inhibitrice vis à vis de la MAO-B est donnée par la constante d'inhibition Ki (MAO-B).The inhibitory activity with respect to MAO-B is given by the inhibition constant Ki (MAO-B).
Pour les composés de l'invention les plus actifs, les Ki
(MAO-B) varient généralement entre 9 et 39 nM.For the most active compounds of the invention, the Ki
(MAO-B) generally range from 9 to 39 nM.
Pour les composés de l'invention, les K (MAO-A) se situent à des valeurs supérieures à 1AM. For the compounds of the invention, the K (MAO-A) values are greater than 1 AM.
Il apparaît donc que les composés de l'invention ont une activité inhibitrice de la MAO-B puissante et sélective.It thus appears that the compounds of the invention have a potent and selective MAO-B inhibitory activity.
Les composés de l'invention peuvent donc être utilisés pour la préparation de médicaments inhibiteurs de la monoamine oxydase B, ces médicaments trouvent leur emploi en thérapeutique notamment dans le traitement des troubles neurologiques liés au vieillissement pathologique, des troubles mnésiques, des troubles de l'humeur, de la schizophrénie, de la psychiatrie, du ralentissement psychique lié au vieillissement, de certaines formes de dépression et de la maladie de Parkinson.The compounds of the invention can therefore be used for the preparation of drugs that inhibit monoamine oxidase B. These medicaments find use in therapeutics, particularly in the treatment of neurological disorders related to pathological aging, memory disorders, disorders of the mood, schizophrenia, psychiatry, age-related mental retardation, certain forms of depression, and Parkinson's disease.
Les composés de l'invention peuvent être présentés, en association avec des excipients, sous forme de compositions formulées en vue de l'administration par voie orale, parentérale ou rectale, par exemple sous forme de comprimés, dragées, capsules, solutions, suspensions ou suppositoires.The compounds of the invention may be presented, in combination with excipients, in the form of compositions formulated for oral, parenteral or rectal administration, for example in the form of tablets, dragees, capsules, solutions, suspensions or suppositories.
Par voie orale, la dose de principe actif administrée par jour peut atteindre 50 mg/kg, en une ou plusieurs prises. Par voie parentérale, elle peut atteindre 5 mg/kg/jour et par voie rectale 10 mg/kg/jour. Orally, the dose of active ingredient administered per day can reach 50 mg / kg, in one or more doses. Parenterally, it can reach 5 mg / kg / day and rectally 10 mg / kg / day.
Annexe
<tb> <SEP> t+oNHNH2
<tb> CIII) <SEP> $ÉNNH2 <SEP> NH
<tb> <SEP> Mo <SEP> 02C2M5 <SEP> Co)JvC02CZH5 <SEP> < V)RiÀ <SEP> Jt <SEP> A
<tb> <SEP> v <SEP> (IV) <SEP> Nll <SEP> triéthylamine
<tb> <SEP> PhCH3
<tb> <SEP> R1 <SEP> O
<tb> <SEP> À1
<tb> <SEP> I
<tb> <SEP> ( <SEP> I <SEP> .b) <SEP> Co <SEP> j3/N <SEP> > (NH
<tb> <SEP> CI.b)
<tb> <SEP> v <SEP> } <SEP> NaH <SEP> N,Ndiméthytforrriemide
<tb> <SEP> qr <SEP> I <SEP> A
<tb> <SEP> RZX
<tb> <SEP> (I.a)0/
<tb> <SEP> CI.a) <SEP> À0
<tb> <SEP> r
<tb> <SEP> Pd/ <SEP> C
<tb> <SEP> sN4R1
<tb> <SEP> (II) <SEP> R2
<tb> <SEP> 0 <SEP> 2
<tb> <SEP> RX <SEP> K2CO <SEP> acétone <SEP> ou <SEP> méthyéthytacétone
<tb> <SEP> ou
<tb> <SEP> I <SEP> ou
<tb> <SEP> RJOH/ <SEP> PPh3 <SEP> / <SEP> diéthyazodicarbaxytate <SEP> tétrahydrofurane
<tb> <SEP> y1
<tb> <SEP> ( <SEP> XNoX <SEP> NR2
<tb> <SEP> /04
<tb> <SEP> R3
<tb> <tb><SEP> t + oNHNH2
<tb> CIII) <SEP> $ ÉNNH2 <SEP> NH
<tb><SEP> Mo <SEP> 02C2M5 <SEP> Co) JvC02CZH5 <SEP><V) RiÀ <SEP> Jt <SEP> A
<tb><SEP> v <SEP> (IV) <SEP> NII <SEP> triethylamine
<tb><SEP> PhCH3
<tb><SEP> R1 <SEP> O
<tb><SEP> TO1
<tb><SEP> I
<tb><SEP>(<SEP> I <SEP> .b) <SEP> Co <SEP> j3 / N <SEP>> (NH
<tb><SEP> CI.b)
<tb><SEP> v <SEP>} <SEP> NaH <SEP> N, Ndimethytforrriemide
<tb><SEP> qr <SEP> I <SEP> A
<tb><SEP> RZX
<tb><SEP> (Ia) 0 /
<tb><SEP> CI.a) <SEP> À0
<tb><SEP> r
<tb><SEP> Pd / <SEP> C
<tb><SEP> sN4R1
<tb><SEP> (II) <SEP> R2
<tb><SEP> 0 <SEP> 2
<tb><SEP> RX <SEP> K2CO <SEP> Acetone <SEP> or <SEP> Methyethytacetone
<tb><SEP> or
<tb><SEP> I <SEP> or
<tb><SEP> RJOH / <SEP> PPh3 <SEP> / <SEP> diethylazodicarbaxylate <SEP> tetrahydrofuran
<tb><SEP> y1
<tb><SEP>(<SEP> XNoX <SEP> NR2
<tb><SEP> / 04
<tb><SEP> R3
<Tb>
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9709341A FR2766485B1 (en) | 1997-07-23 | 1997-07-23 | 2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
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| FR9709341A FR2766485B1 (en) | 1997-07-23 | 1997-07-23 | 2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
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| Publication Number | Publication Date |
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| FR2766485A1 true FR2766485A1 (en) | 1999-01-29 |
| FR2766485B1 FR2766485B1 (en) | 2002-05-24 |
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| FR9709341A Expired - Fee Related FR2766485B1 (en) | 1997-07-23 | 1997-07-23 | 2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002006272A1 (en) * | 2000-07-18 | 2002-01-24 | Sanofi-Synthelabo | Polyfluoroalkyltriazole derivatives, preparation and therapeutic use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0275742A1 (en) * | 1986-12-19 | 1988-07-27 | Synthelabo | 5-Hydroxymethyl derivatives of 2-oxazolidinones, their preparation and their therapeutical use |
| WO1991008201A1 (en) * | 1989-11-24 | 1991-06-13 | Delalande S.A. | (hetero) 4-arylmethoxy phenyl diazole derivatives, method for preparing same, and their therapeutical applications |
| EP0504574A1 (en) * | 1991-03-22 | 1992-09-23 | Wakamoto Pharmaceutical Co., Ltd. | 1,2,4-Oxadiazole derivatives having monoamine oxidase B enzyme-inhibitory activity and method for preparing same |
| EP0655445A1 (en) * | 1993-11-26 | 1995-05-31 | Synthelabo | 1,3,4-oxadiazol-2(3H)-one Derivates, their preparation and their use as monoamine oxidase inhibitors |
-
1997
- 1997-07-23 FR FR9709341A patent/FR2766485B1/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0275742A1 (en) * | 1986-12-19 | 1988-07-27 | Synthelabo | 5-Hydroxymethyl derivatives of 2-oxazolidinones, their preparation and their therapeutical use |
| WO1991008201A1 (en) * | 1989-11-24 | 1991-06-13 | Delalande S.A. | (hetero) 4-arylmethoxy phenyl diazole derivatives, method for preparing same, and their therapeutical applications |
| EP0504574A1 (en) * | 1991-03-22 | 1992-09-23 | Wakamoto Pharmaceutical Co., Ltd. | 1,2,4-Oxadiazole derivatives having monoamine oxidase B enzyme-inhibitory activity and method for preparing same |
| EP0655445A1 (en) * | 1993-11-26 | 1995-05-31 | Synthelabo | 1,3,4-oxadiazol-2(3H)-one Derivates, their preparation and their use as monoamine oxidase inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 108, no. 5, 1 February 1988, Columbus, Ohio, US; abstract no. 37731p, HUSAIN M. I. ET AL.: "synthesis of some new substituted mercaptotriazoles and thiazolidones and their monoamine oxidase inhibitory and anticonvulsant properties" page 627; column 2; XP002062426 * |
| CHEMICAL ABSTRACTS, vol. 97, no. 21, 22 November 1982, Columbus, Ohio, US; abstract no. 174489j, JAISWAL, R. K.: "Anticonvulsant activity and monoamine oxidase inhibitory properties of substituted 1,2,4-triazoles" page 28; column 2; XP002062427 * |
| INDIAN J. CHEM. SECT. B, vol. 26B, no. 3, 1987, pages 251 - 254 * |
| RES. COMMUN. CHEM. PATHOL. PHARMACOL., vol. 37, no. 3, 1982, pages 499 - 502 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002006272A1 (en) * | 2000-07-18 | 2002-01-24 | Sanofi-Synthelabo | Polyfluoroalkyltriazole derivatives, preparation and therapeutic use thereof |
| FR2811989A1 (en) * | 2000-07-18 | 2002-01-25 | Sanofi Synthelabo | POLYFLUOROALKYTRIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2766485B1 (en) | 2002-05-24 |
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