EP1272485A1 - 1,2,3,4-tetrahydroisochinolinderivate, verfahren zu ihrer herstellung und ihre verwendung als fungizide - Google Patents

1,2,3,4-tetrahydroisochinolinderivate, verfahren zu ihrer herstellung und ihre verwendung als fungizide

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Publication number
EP1272485A1
EP1272485A1 EP01921468A EP01921468A EP1272485A1 EP 1272485 A1 EP1272485 A1 EP 1272485A1 EP 01921468 A EP01921468 A EP 01921468A EP 01921468 A EP01921468 A EP 01921468A EP 1272485 A1 EP1272485 A1 EP 1272485A1
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Prior art keywords
formula
compounds
radical
represent
atom
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EP01921468A
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English (en)
French (fr)
Inventor
Didier Babin
Yannick Benedetti
Fabienne Chatreaux
John Bernard Weston
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Aventis Pharma SA
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Aventis Pharma SA
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

  • the present invention relates to new derivatives of 1, 2, 3, 4-tetrahydroisoquinoline, their preparation process and their application as fungicides.
  • Ri, R 2 , R 3 , R5 and R 6 identical or different from each other in any position on the rings which carry them, represent a hydrogen atom, a halogen atom, an alkyl radical, O -alkyl, S (0) n -alkyl, alkenyl, O-alkenyl, S (0) n -alkenyl, alkynyl, O-alkynyl, S (0) n -alkynyl containing up to 8 carbon atoms, optionally substituted by one or more halogen atoms, n representing the number 0, 1 or 2, or represent a radical N0 2 , NH 2 or C ⁇ N, R X / R 2 / R 3 on the one hand and R 5 and R 6 on the other hand being able to form cycles two by two,.
  • R 7 represents a hydrogen atom or an OH, OSO3H or OPO (OH) 2 radical,
  • R 4 A represents a radical R 4 which can take one of the values indicated above for Ri, R 2 , R3, R5 or R 6 , and can also represent an unsubstituted or substituted heterocycle, an aryl or O-aryl group containing up to 14 unsubstituted or substituted carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms unsubstituted or substituted by an aryl optionally substituted by one or more halogen atoms and which may also represent an oxygen or nitrogen chain linked to the phenyl or heteroaryl nucleus by an oxygen or nitrogen atom, A and B identical or different from each other represent a d atom hydrogen or an oxygen or nitrogen chain linked to the phenyl nucleus by an oxygen or nitrogen atom,
  • C and D which are identical or different from each other, represent a hydrogen or halogen atom or an alkyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms or form together with the carbons which carry them a ring optionally substituted by one or more halogen atoms, one or more alkyl radicals containing up to 8 carbon atoms or together form a double bond, excluding the compounds of formula (IA) :
  • At least one of the substituents R 4 A, R 5 , R 6 or R 7 of the heteroaryl radical represents a hydrogen atom.
  • addition salts with acids there may be mentioned those formed with mineral acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acids or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic acid, citric, maleic, fumaric, succinic, tartaric, alkanesulfonic, such as methane or ethane sulfonic acids, arylsulfonic such as benzene or paratoluenesulfonic acids.
  • Substituents A and B are preferably in position 5 or 7.
  • the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, or cyclic radical.
  • the halogen is preferably fluorine or chlorine, or bromine
  • C and D form a cyclic radical
  • it may for example be a cyclopropyl radical optionally substituted by a fluorine atom or a dimethyl gem
  • the aryl radical is preferably the phenyl radical
  • the heterocycle radical may contain one or more heteroatoms, it is preferably a 5 or 6-membered radical optionally containing one or two double bonds, and one or more nitrogen atoms, for example
  • radicals being able to be substituted, they can especially be radicals
  • a more particular subject of the invention is the compounds of formula (I) defined above in which R 7 represents an OH, OS0 3 H or OPO (OH) 2 radical.
  • a more specific subject of the invention is the compounds of formula (I), in which A or B does not represent a hydrogen atom.
  • r represents the number 0 or 1
  • s represents an integer varying from 0 to S
  • W represents an oxygen atom or a radical -N (Rn) -
  • Ru representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms
  • Ru can also form a ring with the nitrogen atom which carries it and another atom in the chain (CO) r (CH 2 ) S -Z
  • Z represents a hydrogen atom , a radical S0 3 H or OSO3H, PO (OH) 2 or OPO (OH) 2 , or C0 2 H as well as the alkali, alkaline earth or amine salts of these radicals, or a radical
  • R 8 and R 9 representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, Rio representing an alkyl radical containing up to 8 carbon atoms, R 8 and R 9 may form a ring optionally containing a other heteroatom, and being optionally substituted, or else Z represents an optionally substituted heterocyclic radical.
  • OSO 3 H O- sugar (pyranose, furanose), a radical
  • a more particular subject of the invention is the compounds of formula (I), in which represents a nitrogen atom.
  • a and B can represent a chain NHCOOR'i, NHCOR'2, NH-CONR ' 3 R' 4 ,
  • R'i, R ' 2 , R' 3 and R ' 4 representing alkyl radicals containing up to 8 carbon atoms NHC0C0 2 H, NH-C0 2 P (0) (OH) 2 , NHS0 3 H, NHP0 3 H 2 , as well as the alkali, alkaline earth and amine salts of the latter two compounds
  • R 4A represents an oxygen or nitrogen chain, it is preferably one of the preferred values indicated above for A and B, or else one of the 5 or 6-membered heterocycles containing one or more atoms of nitrogen and one or more double bonds.
  • a more particular subject of the invention is the compounds of Examples 3, 6, 10, 12 and 13.
  • the compounds of formula (I) have interesting antifungal properties; they are particularly active on Candida albicans and other Candida such as Candida glabrata, krusei, tropicalis, pseudotropicalis and parapsilosis, on Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger Cryptococcus provisionoformans, Microsporum canis, Trichophyton rubrun, Trichophyton mentagrophyton.
  • the compounds of formula (I) can be used as medicaments in humans or animals, in particular for combating digestive, urinary, vaginal or skin candidiasis, cryptococcosis, for example neuromeningeal, pulmonary or skin cryptococcosis, bronchopulmonary and pulmonary aspergillosis and invasive aspergillosis of the immunocompromised.
  • the compounds of the invention can also be used in the prevention of fungal diseases in congenital or acquired immune depressed.
  • the compounds of the invention are not limited to pharmaceutical use, they can also be used as fungicides in fields other than pharmaceutical.
  • the subject of the invention is therefore, as antifungal compounds, the compounds of formula (I).
  • a subject of the invention is also the compounds of formula (I) as well as their pharmaceutically acceptable salts, as medicaments.
  • the invention particularly relates to pharmaceutical compositions containing as active ingredient. at least one compound of formula (I) or one of its pharmaceutically acceptable salts.
  • These compositions can be administered by the oral, rectal, parenteral route or by the local route as a topical application to the skin and the mucous membranes, but the preferred route is the oral route.
  • the active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, cyclodextrins, vehicles aqueous or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, cyclodextrins, vehicles aqueous or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • compositions can also be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example sterile pyrogen-free water.
  • the dose administered is variable depending on the condition treated, the subject concerned, the route of administration and the product considered. It can be, for example, between 50 mg and 300 mg per day orally, in adults for the product of Example 3 or of Example 6.
  • the subject of the invention is also a method characterized in that a compound of formula (II) is subjected:
  • Y represents a mesyl or tosyl radical and the other substituents retain their previous meaning due to the action of a compound of formula (III)
  • the subject of the invention is also a method characterized in that a compound of formula (IV) is subjected:
  • alci, alk 2 and alk 3 represent an alkyl radical containing up to 8 carbon atoms, RI, R2, R3 and X retain their previous meaning, to the action of a compound of formula (V):
  • the invention further relates to a variant of the preceding methods, characterized in that a compound of formula (VI) is subjected:
  • the compounds of formula (VI) are new products prepared as indicated below in the experimental part.
  • PREPARATION 1 3- [4- [2,4-dihydro-2- (1-methylpropyl) -3-oxo 3H-1,2,4-triazol-4-yl] phenyl] -2 (E) -propenal .
  • Stage A 1, 1-dimethylethyl 2- [[[(4-iodophenyl) -amino] -carbonyl] -hydrazine-carboxylate.
  • a mixture of 20 g of l-iodo-4-isocyanoto-benzene and 100 ml of tetrahydrofuran (THF) is cooled to 0 ° C., then introduced at a temperature below -10 ° C., 11.84 g of tert-butylcarbazate (BOCNHNH 2 ) in 100 ml of THF.
  • THF tetrahydrofuran
  • Stage B N- (4-iodophenyl) -hydrazinecarboxamide.
  • the mixture is stirred at reflux for 2 hours 30 minutes, a mixture containing 30 g of product from the previous stage, 250 ml of THF and 30 ml of a 6N hydrochloric acid solution. Cool to 0 ° C and add 150 ml of ethyl ether. Agitation is carried out for 1 hour 30 minutes at 0 ° C. We spin, rinse and dry. 22.69 g of sought product is obtained.
  • Stage D 2, -dihydro-4- (4-iodophenyl) -2- (1-methylpropyl) -3H- 1,2,4-triazol-3-one.
  • Stage E 3- [4- [2,4-dihydro-2- (1-methylpropyl) -3-OXO-3H- 1,2,4-triazol-4-yl] phenyl] -2 (E) -propenoate methyl.
  • Stage G 3- [4- [2,4-dihydro-2- (1-methylpropyl) -3-oxo-3H- 1,2,4-triazol-4-yl] phenyl] -2 (E) -propenal .
  • PREPARATION 3 3- [4- [2,4-dih ⁇ dro-2- ((1S, 2R) -2-h ⁇ drox ⁇ -l-methylpropyl) -3-oxo-3H-1,2,4 / triazol-4-yl ] phenyl] -2 (E) - propenal.
  • Stlade B 2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -4- (4-iodophenyl) -3H-1, 2, 4-1riazol-3 -one.
  • the mixture is brought to 110 ° C. for 2 hours 30 minutes.
  • stage C of preparation 1 0.861 g of 2,4-dihydro-4- (4-iodophenyl) -3H-1, 2, 4-triazol-3- one (stage C of preparation 1), 8 ml of methyl isobutyl ketone, 0.829 g of K2CO3 , 86 mg of Aliquat 336 and 0.913 g of product from the previous stage. Leave to return to room temperature, add water, decant, wash with water.
  • Stage C 3- [4- [2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -3-oxo-3H-1,2,4-triazol-4-yl ] phenyl] -2 (E) - methyl propenoate.
  • Stage D 2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -4- [4- (3-hydroxy-1 (E) -propenyl) hényl] -3H-1 , 2, 4-triazol-3-one.
  • Stage F preparation 1 By operating as above (Stage F preparation 1), the desired product was obtained.
  • Stage E 3- [4- [2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methyl-propyl) -3-oxo-3H-1,2,4-triazol-4 -yl] phenyl] -2 (E) -propenal.
  • Stage C Cis ( ⁇ ) 6- [[2- (2,4 dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1, 3-dioxolan-4-yl] - ethoxy] -1, 2, 3, 4-tetrahydro- 2- [3-tributylstannyl) -2 (E) -propenyl] -isoquinoleine.
  • EXAMPLE 1 2,4-dihydro-4- [4- [3- [6- [[(cis) -2- (2,4-dichlorophenyl) -2- (1H-imidazol-1- ⁇ lmethyl) - 1, 3-dioxolan-4-yl] - methoxy] -1,2,3,4-tetrahydro-2-isoquinoleinyl] -1 (E) -propenyl] - phenyl] -2- (1-methylpropyl) -3H- 1, 2, 4-triazol-3-one.
  • EXAMPLE 2 4- [4- [3- [6- [[(cis) -2- (2,4-dichloro ⁇ henyl) -2- (1H- imidazol-1-ylmethyl) -1,3-dioxolan-4- ⁇ l] methoxy] -1,2,3,4- tetrahydro-2-isoquinoleinyl] -1 (E) -propenyl] phenyl] -2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -3H- 1, 2, 4-triazol-3-one
  • Stage B cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl ) -1,3- dioxolan-4-yl] -methoxy] -5-nitro-1, 2,3, 4-tetrahydro-isoquinoleine
  • Stage C cis-2- [3 - (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl ) -1,3- dioxolan-4-yl] -methoxy] -1, 2, 3, 4-tetrahydro-5-isoquinoline-amine.
  • EXAMPLE 4 cis-7-chloro-2- [3- (4-chlorophenyl) -2 (E) - propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1, 3-dioxan-4-yl] -methoxy] -1,2,3,4-tetrahydro-isoquinoline.
  • EXAMPLE 5 cis-1- [2- [3- (4-chlorophen ⁇ l) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1- ⁇ l -methyl) -1, 3-dioxolan-4-yl] -methoxy] -1,2,3,4-tetrahydro-isoquinolinyl] -2-pyrrolidinone.
  • Stage B cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1, 3-dioxolan- 4-yl] -methoxy] -1, 2, 3, 4-tetrahydro-7-isoquinolineamine.
  • EXAMPLE 7 cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6,7-bis- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1- yl-meth ⁇ l) -1, 3-dioxolan-4-yl] -methoxy] -1,2,3,4-tee rahydro-isoquinoline.
  • EXAMPLE 8 cis-2- [2-trans- (4-chlorophen ⁇ l) -cyclopropyl] - methyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl] -methoxy] -1,2,3,4-tetrahydroisoquinoline.
  • EXAMPLE 9 cis-2- [3- [4- [(2-methoxyethoxy) methoxy] phenyl] - 2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H- imidazol-1-yl-methyl) -1,3-dioxolan-4-yl] -methoxy] -1,2,3,4-tetrahydro-isoquinoline.
  • EXAMPLE 10 cis-4- [3- [6- [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxan-4-yl] - methoxy] -1,2,3,4- tetrahydro-2-isoquinolinyl] -1 (E) -propenyl] -phenol.
  • a solution comprising 592 mg of product obtained in Example 10 in 20 ml of chloride is cooled to 0 ° C. methylene then add 960 ⁇ l of carbon tetrachloride, 24 mg of dimethylaminopyridine and 732 ⁇ l of diisopropyl ethylamine then drop by drop 628 ⁇ l of dibenzylphosphite.
  • mice weighing 18 to 22 g are used. We give them administers a quantity of Candida Albicans 44858 into the tail vein at the rate of 10 6 CFU per mouse (CFU: colony-forming unit). The mice are separated into 5 batches of 5 mice and they are treated as follows: One hour after infection
  • mice are treated with the product P 25 mg / kg orally group 2: the mice are treated with the product P intraperitoneally at a rate of 25 mg / kg - group 3: the mice are treated with the fluconazole ( 25mg / kg orally).
  • mice are treated with fluconazole (25 mg / kg intraperitoneally).
  • group 5 the mice do not receive any antifungal treatment.
  • the product at the dose used in the 2 modes of administration used has excellent activity.
  • test was carried out with an administration ' ' under order than those obtained with fluconazole.
  • MIC Minimum inhibitory concentration
  • Candida albicans cells are prepared as indicated in the Journal of Antimicrobial chemotherapy 38, 579-587, washed 3 times with 0.1 M phosphate solution and used immediately to determine the minimum inhibitory concentration (MIC).
  • the MICs are determined by the modification of a microtiter plate according to the standard method of the National Committee for clinical laboratory standards.
  • RPMI-1640 is used as medium, and L-glutamine buffered to pH7 with a 0.15 M solution of MOPS (3- [N-morpholino] propane sulfonic acid).
  • MOPS 3- [N-morpholino] propane sulfonic acid
  • Candida albicans cells (1.5 X 10 3 cells / ml) are added to the wells of a 96-well plate containing RPMI-1640 and dilutions of antifungal agents. The results are read 48 hours after incubation at 35 ° C. and the MIC or minimum inhibitory concentration which inhibits the growth of Candida albicans cells is determined.
  • Minimum fungicide concentration 1.5 X 10 3 cells / ml
  • the plates are shaken and 10 ⁇ L of aliquot are removed from the wells which are placed on rectangular disks containing dextrose agar. The plates are incubated for 48 hours at 35 ° C; The minimum fungicidal concentration and the concentration of the antifungal agent at which the number of colony forming units is zero.

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EP01921468A 2000-04-05 2001-04-04 1,2,3,4-tetrahydroisochinolinderivate, verfahren zu ihrer herstellung und ihre verwendung als fungizide Withdrawn EP1272485A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0004324 2000-04-05
FR0004324A FR2807434B1 (fr) 2000-04-05 2000-04-05 Nouveaux derives de la 1,2,3,4-tetrahydroisoquinoleine, leur procede de preparation et leur application comme fongicides
PCT/FR2001/001004 WO2001074808A1 (fr) 2000-04-05 2001-04-04 Nouveaux derives de la 1,2,3,4-tetrahydroisoquinoleine, leur procede de preparation et leur application comme fongicides

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EP1272485A1 true EP1272485A1 (de) 2003-01-08

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US (1) US20030187267A1 (de)
EP (1) EP1272485A1 (de)
JP (1) JP2003529599A (de)
AU (1) AU2001248456A1 (de)
CA (1) CA2405126A1 (de)
FR (1) FR2807434B1 (de)
IL (1) IL152072A0 (de)
MX (1) MXPA02009764A (de)
WO (1) WO2001074808A1 (de)

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FR2824325B1 (fr) * 2001-05-04 2003-08-15 Aventis Pharma Sa Nouveaux derives d'azole ou de triazole, leur procede de preparation et leur application comme fongicides
FR2824324B1 (fr) * 2001-05-04 2003-08-15 Aventis Pharma Sa Nouveaux derives d'azole ou de triazole, leur procede de preparation et leur application comme medicaments anti-fongiques
ITMI20032020A1 (it) * 2003-10-17 2005-04-18 Italfarmaco Spa Nuovi agenti antifungini azolici con diminuita interazione con i citocromi metabolici
AR080375A1 (es) 2010-03-05 2012-04-04 Sanofi Aventis Procedimiento para la preparacion de 2-(cicloheximetil)-n-{2-[(2s)-1-metilpirrolidin-2-il] etil}-1,2,3,4-tetrahidroisoquinolina- 7-sulfonamida
US9040539B2 (en) * 2010-05-19 2015-05-26 Sandoz Ag Process for the preparation of chiral triazolones
US20130345177A1 (en) * 2011-03-04 2013-12-26 Dafra Pharma Research & Development Bvba Oleyl Phosphocholine for the Treatment of Mycosis
EP2852589B1 (de) 2012-05-22 2021-04-28 Autifony Therapeutics Limited Triazole als kv3 inhibitoren

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JP2003529599A (ja) 2003-10-07
MXPA02009764A (es) 2003-03-27
CA2405126A1 (fr) 2001-10-11
FR2807434A1 (fr) 2001-10-12
WO2001074808A1 (fr) 2001-10-11
FR2807434B1 (fr) 2002-10-18
IL152072A0 (en) 2003-05-29
AU2001248456A1 (en) 2001-10-15
US20030187267A1 (en) 2003-10-02

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