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EP1423393A1 - Anellierte indol- und heteroindolderivate, deren herstellung und verwendung als antitumormittel - Google Patents

Anellierte indol- und heteroindolderivate, deren herstellung und verwendung als antitumormittel

Info

Publication number
EP1423393A1
EP1423393A1 EP02767436A EP02767436A EP1423393A1 EP 1423393 A1 EP1423393 A1 EP 1423393A1 EP 02767436 A EP02767436 A EP 02767436A EP 02767436 A EP02767436 A EP 02767436A EP 1423393 A1 EP1423393 A1 EP 1423393A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
chain
straight
branched
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02767436A
Other languages
German (de)
English (en)
French (fr)
Inventor
Heinz Weinberger
Thomas Beckers
Mathias Schmidt
Silke Baasner
Bernd Nickel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10143079A external-priority patent/DE10143079A1/de
Application filed by Zentaris AG filed Critical Zentaris AG
Publication of EP1423393A1 publication Critical patent/EP1423393A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/14—Ortho-condensed systems

Definitions

  • the invention relates to new substituted indole and heteroindole derivatives of the general formula I.
  • German patent application dated April 28, 2000 (patent ASTA Medica AG with Priv.-Doz. Dr. Mahboobi) describes a process for the preparation of 2-acylindoles via the corresponding 2-lithio-indoles.
  • R1 is hydrogen, unsubstituted or completely or partially identical or differently substituted (C6-C14) aryl, unsubstituted or completely or partially identical or differently having at least one to four N, NH, O and / or S ring members (C1-C13) - Heteroaryl, unsubstituted or completely or partly identical or differently substituted (C3-C8) -cycloalkyl, or unsubstituted or completely or partly identical or differently substituted straight-chain or branched (C1-C20) -alkyl;
  • A, B, C or D independently represent a carbon atom substituted by R2-R5 or a nitrogen atom;
  • R2, R3, R4, and R5 independently of one another a free electron pair (if binding partner A, B, C or D stand for a nitrogen atom), hydrogen, halogen, cyano, nitro, hydroxy, straight-chain or branched (C1-C6) alkyl, straight chain or branched (C1-C6) alkyl substituted with one or more halogen atoms, straight chain or branched (C1-C6) alkoxy, straight chain or branched (C1-C6) alkoxy substituted with one or more halogen atoms, straight chain or branched (C1-C6) - alkylenedioxy, (C1-C6) -alkylcarbonyloxy, (C1-C6) -alkoxycarbonyloxy, (C1-C6) - alkylthio, (C1-C6) -alkylsulfinyl, (C1-C6) -alkylsulfonyl, carboxy, Carboxy- (C
  • R6 unsubstituted or completely or partially identical or differently substituted (C6-C14) -aryl, unsubstituted or completely or partially identical or differently or differently containing at least one to four N, NH, O and / or S ring members (C1-C13) heteroaryl, unsubstituted or completely or partly identical or differently substituted (C3-C8) -cycloalkyl, unsubstituted or completely or partly identical or differently substituted straight-chain or branched (C1-C20) -alkyl, the same or different substituents being selected from the group consisting of Hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, (C1-C6) -alkyl, (C1-C6) -alkoxy, carboxy, with one or more halogen atoms, the same or differently substituted (C1-C6) -alkyl , with one or more halogen atoms, identical or differently
  • Y represents an oxygen atom or a nitrogen atom (NR7) substituted by the radical R7, where
  • R7 unsubstituted or completely or partially identical or differently substituted (C6-C14) -aryl, unsubstituted or completely or partially identical or differently or at least one to four N, NH, O and / or S having ring members (C1-C13) heteroaryl, unsubstituted or completely or partly identical or differently substituted (C3-C8) -cycloalkyl, unsubstituted or completely or partly identical or differently substituted straight-chain or branched (C1-C20) -alkyl, page 4
  • substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, carboxy, with one or several halogen atoms of the same or differently substituted (C1-C6) alkyl, with one or more halogen atoms of the same or differently substituted (C1-C6) alkoxy, straight-chain or branched (C2-C6) alkenyl, straight-chain or branched (C2-C6) - Alkynyl, (C3-C8) -cycloalkyl, straight-chain or branched (C1-C6) - alkoxy, straight-chain or branched (C1-C6) -alkylenedioxy, (C1-C6) - alkoxy- (C1-C6) -alkyl, straight-chain or branched mono- (C1-C6) -al
  • n 0 or 1
  • Z represents a carbon atom (C-R8) substituted by the radical R8, where
  • R8 unsubstituted or completely or partially identical or differently substituted (C6-C14) aryl, unsubstituted or completely or partially identical or differently or at least one to four (C1-C13) heteroaryl containing N, NH, O and / or S as ring members, unsubstituted or completely or partly identical or differently substituted (C3-C8) -cycloalkyl, unsubstituted or completely or partly identical or differently substituted straight-chain or branched (C1-C20) -alkyl, the same or different substituents being selected from the group consisting of Hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, carboxy, with one or more halogen atoms, the same or differently substituted (C1-C6) alkyl , with one or more halogen atoms page 5
  • Z represents a nitrogen atom
  • compounds are characterized in that R1 is hydrogen, R2, R3, R4 and R5 independently of one another are hydrogen, halogen or (C1-C6) alkoxy, R6 is unsubstituted or completely or partially identical or differently substituted straight-chain or branched (C1-C20) -alkyl or for unsubstituted or completely or page 6
  • Y is an oxygen atom or the radical N-R7, where R7 is unsubstituted or completely or partially identical or differently substituted (C6-C14 )
  • the above-mentioned compounds according to the invention are provided for use as medicaments.
  • medicaments containing at least one of the abovementioned compounds according to the invention together with customary pharmaceutical auxiliaries, diluents and / or carriers are provided.
  • R1, R2, R3, R4, R5, R6, A, B, C and D are defined as mentioned at the beginning,
  • R9 is hydrogen, unsubstituted or substituted by one or more halogen atoms, straight-chain or branched (C1-C6) -alkylcarbonyl, straight-chain or branched (C1-C6) -alkoxycarbonyl, substituted (C6-C14) -aryl- (C1) -alkyl, straight-chain or is branched (C1-C6) -alkylsulfonyl and unsubstituted or (C1-C6) -alkyl-substituted (C6-C14) -arylsulfonyl,
  • halogen atom e.g. a fluorine, chlorine or bromine atom, (C1-C6) alkoxy, imidazole and
  • M represents Li, Mg-R10,
  • R10 is a halogen atom, e.g. represents a chlorine, bromine or iodine atom
  • R1, R2, R3, R4, R5, R6, R8, R9, A, B, C, D, E and X are defined as mentioned at the beginning,
  • R1, R2, R3, R4, R5, R6, R8, A, B, C, D and X are defined as mentioned at the outset and Z is a carbon atom substituted by a radical R8,
  • R1, R2, R3, R4, R5, R6, R9, A, B, C, D and Y are defined as mentioned above, Z represents a nitrogen atom and
  • R10 is hydrogen, straight-chain or branched (C1-C6) -alkyl, straight-chain or branched (C1-C6) -alkyl substituted with one or more halogen atoms, straight-chain or branched (C1-C6) -alkoxy substituted with one or more halogen atoms, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylsulfinyl, (C1 -C6) alkylsulfonyl, (C1-C6) alkoxy- (C1-C6) alkyl, (C6-C14) aryl, (C6-C14) aryl- (C1-C6) alkyl, (C6-C14 ) -Aryl- (C1-C6) -alk
  • R1, R2, R3, R4, R5, R6, R9, A, B, C, D and X are defined as mentioned at the outset, Z is a nitrogen atom and R10 is a hydrogen atom,
  • R11 and R12 independently of one another are nucleofugic leaving groups such as a halogen atom, e.g. is a chlorine, bromine or iodine atom, (C1-C6) alkoxy or imidazolide.
  • a halogen atom e.g. is a chlorine, bromine or iodine atom, (C1-C6) alkoxy or imidazolide.
  • R1, R2, R3, R4, R5, R9, A, B, C and D are defined as mentioned at the beginning, with
  • R1, R2, R3, R4, R5, R6, R9, A, B, C and D are defined as mentioned at the beginning, with
  • R1, R2, R3, R4, R5, R6, A, B, C and D are defined as mentioned at the beginning, are cyclized with N, N'-carbonyldiimidazole to give the indole or heteroindole derivatives of the general formula V.
  • R1, R2, R3, R4, R5, R6, A, B, C and D are defined as mentioned at the outset and R9 is a hydrogen atom with optionally substituted ones
  • Phenylacetic acid halides in the presence of, for example, sodium hydride
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • the compounds of general formula I obtained which occur as a racemate can be converted into their optical antipodes according to methods known per se and compounds of general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, eg by chromatography and / or fractional crystallization, into their diastereomers which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Esters or amides forming optically active substance.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use, into their pharmacologically and physiologically tolerable salts with inorganic or organic acids.
  • acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid,
  • the compounds of the formula I contain an acidic group such as a carboxyl group, they can, if desired, be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • Reagent A1 methyl magnesium chloride, 3.0 M solution in tetrahydrofuran
  • Reagent A2 phenyl magnesium bromide, 3.0 M solution in diethyl ether
  • Reagent A3 3-methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran
  • Reagent A4 4-methoxyphenylmagnesium bromide, 0.5 M solution in tetrahydrofuran
  • Reagent A5 4-chlorophenyl magnesium bromide, 1.0 M solution in diethyl ether
  • Reagent A6 2-thienyllithium, 1.0 M solution in tetrahydrofuran
  • Method B One-pot variant: synthesis of the imidazol-1-yl- (1 H -indol-2-yl) -methanone and subsequent reaction with organometallic reagents in situ Page 17
  • the organic phase was separated off and the aqueous phase was extracted three times with ethyl acetate (2 ml / mmol each). After drying the combined organic phases over magnesium sulfate, the solvent was removed on a rotary evaporator and the residue was recrystallized from alcohol.
  • Reagent B1 2-methoxyphenyl magnesium bromide, 1.0 M solution in tetrahydrofuran
  • Reagent A3 3-methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran Page 18
  • Reagent A1 methyl magnesium chloride, 3.0 M solution in tetrahydrofuran
  • Reagent B4 ethyl magnesium chloride, 3.0 M solution in tetrahydrofuran
  • Reagent A2 phenyl magnesium bromide, 3.0 M solution in diethyl ether Page 19
  • Reagent A3 3-methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran
  • Method D Direct reaction of the 1 / - / - indol-2-yl-methanone oximes prepared with V, / V-carbonyldiimidazole
  • V, / V-carbonyldiimidazole The following oxadiaza derivatives were synthesized in accordance with regulation C1, but were further reacted in accordance with C2 without purification.
  • A, C, D, R, R1, R6 and X have the meaning according to the above-described Examples Nos. 1-324 and Y each represents NH;
  • A, C, D, R, R1, R6 and X have the meaning according to Examples No. 1-324 described above and Y each represents N-CH 3 ,
  • A, C, D, R, R1, R6 and X have the meaning according to Examples No. 1-324 described above and Y each represents NC H 5 ;
  • A, C, D, R, R1, R6 and X have the meaning according to the above-described Examples Nos. 1-324 and Y each represents N-CeH 5 ;
  • A, C, D, R, R1, R6 and X have the meaning according to Examples No. 1-324 described above and Y each represents N-2- (CH 3 0) -C 6 H ;
  • A, C, D, R, R1, R6 and X have the meaning according to Examples No. 1-324 described above and Y each represents N-3- (CH 3 0) -C 6 H 4 ;
  • A, C, D, R, R1, R6 and X have the meaning according to the above-described Examples Nos. 1-324 and Y each represents N-4- (CH 3 0) -C 6 H 4 .
  • Reagent E1 phenylhydrazine
  • A, C, D, R, R1, R6, R8 and X each have the meaning according to Examples Nos. 2635 to 3842 mentioned above, where Y is in each case S (O);
  • A, C, D, R, R1, R6, R8 and X each have the meaning according to the above-mentioned Examples Nos. 2635 to 3842, where Y in each case means SO 2 .
  • the substances D-70260, D-70744, D-80815, D-80816 and D-80819 were tested in a proliferation test (Scudiero, et al., Cancer Res. , 48: 4827-33, 1987) on established tumor cell lines for their anti-proliferative activity.
  • the test used determines the mitochondrial dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number.
  • the cell lines used are the human cell lines HeLa / KB (CCL17), SK-OV-3 (HTB77), MCF-7 (HTB22) and the murine leukemia cell line L1210 (CCL219). These are very well characterized, established cell lines obtained from ATCC and taken in culture.
  • FIG. 1 Graphical representation of the concentration-dependent anti-proliferative activity of D-80816 (Example F3) in the XTT cytotoxicity test on the cell lines HeLa / KB, SK-OV-3, MCF-7 and L1210 (A).
  • Example 2 Effect of D-80816 (Ex. F3) in the hollow fiber model in vivo
  • the cell lines HeLa / KB, MCF-7 and L1210 were cultivated in hollow fibers which were implanted ip or sc (Hollingshead et al., Life Sciences 57, 131-41, 1995) .
  • the test substance D-80816 is given four times in a dose of 100 mg / kg ip.
  • the fibers are explanted and the cell vitality of the tumor cells contained is determined using an XTT assay.
  • D-80816 a maximum inhibition of 100% indicates in all cell lines, and implantation sites in a general toxicity of LD5 o> 1000 mg / kg (ip).
  • RKO The RKOp27 cell system was used as a model for studying the cell cycle-specific effect (M.Schmidt et al. Oncogene19 (20): 2423-9, 2000).
  • RKO is a human colon carcinoma line in which the cell cycle inhibitor p27 K ⁇ p1 induced expression by means of the Ecdyson expression system and leads to a cell cycle arrest specifically in G1 (Fig. 2).
  • a non-specific substance inhibits proliferation regardless of whether the RKO cell is locked in G1 or not.
  • cell cycle-specific substances such as tubulin inhibitors are only cytotoxic if cells are not locked and the cell cycle is followed.
  • D-80816 shows a cell cycle-specific effect, ie a concentration-dependent anti-proliferative effect can only be measured in cells that are not induced and not locked in G1 of the cell cycle (Fig. 3). Therefore, a defined molecular mechanism of action of D-80816 and derivatives can be assumed.
  • Fig. 2 Schematic representation of the induced expression of p27 / kip1, which leads to a cell cycle arrest in G1, and the chronological sequence of the treatment of cells +/- inductor (Muristeron A) and test substance.
  • the adherent growing tumor cell lines HeLa / KB, SK-OV-3, MCF-7, L1210 and RKO were cultivated under standard conditions in the fumigation incubator at 37 ° C, 5% CO2 and 95% humidity.
  • the cells are detached with trypsin / EDTA and pelleted by centrifugation.
  • the cell pellet is then resuspended in the respective culture medium in the corresponding cell number and converted into a 96-well microtiter plate.
  • the plates are then cultivated overnight in the fumigation incubator.
  • the test substances are prepared as 10 mM stock solutions in DMSO and diluted with culture medium in the appropriate concentrations on test day 2.
  • the tumor cell lines HeLa / KB, MCF-7 and L1210 are placed in polyvinylidene fluoride hollow fibers (5x10 6 cells / ml) and in the physiological compartments of the nude mouse (intraperitoneally, ip or subcutaneously, sc) transplanted. Each experimental animal receives a total of 6 hollow fibers transplanted (3 ip and 3 sc) with the Page 104
  • a group of 6 animals is treated with the test substance (i.p., once a day for a total of 4 days) (ok?). Animals that are treated with the solvent tylose alone serve as a control group.
  • the hollow fibers are explanted one day after the last substance application.
  • the proportion of metabolically active, vital cells is determined for each hollow fiber using the XTT assay (see above).
  • the anti-tumor activity of the test substance in% inhibition relative to the control is determined from this.
  • the assay is carried out in 96-well plates. By inducible expression of p27 k ⁇ p1 , the cells are completely arrested for growth, but do not die. By comparing the effectiveness on induced and non-induced cells, conclusions can be drawn about the mechanism of action (cell cycle specificity) of the therapeutic agents. Uninduced cells are sown in about four times the number of cells, since there is no division during the assay compared to uninduced cells (2x10 4 cells / well induced, approx. 0.6x10 4 cells / well not induced). The controls are untreated cells (+/- induction). Induction takes place with 3 M Muristeron A. On the 1st day, the cells are exposed (+/- Muristeron A) and incubated for 24 hours at 37 ° C. On day 2, the test substance is added (control DMSO) and incubated for a further 48 h at 37 ° C. before a standard XTT assay is carried out (see above).
  • the compounds according to the invention can be used as medicaments in the treatment of diseases, in particular tumor diseases, in mammals, in particular humans.
  • Suitable dosage forms are:
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP02767436A 2001-09-03 2002-08-27 Anellierte indol- und heteroindolderivate, deren herstellung und verwendung als antitumormittel Withdrawn EP1423393A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10143079 2001-09-03
DE10143079A DE10143079A1 (de) 2001-09-03 2001-09-03 Cyclische Indol- und Heteroindolderivate, deren Herstellung und Verwendung als Arzneimittel
PCT/EP2002/009539 WO2003020731A1 (de) 2001-09-03 2002-08-27 Cyclische indol-und heteroindolderviate, deren herstellung und verwendung als arzneimittel

Publications (1)

Publication Number Publication Date
EP1423393A1 true EP1423393A1 (de) 2004-06-02

Family

ID=32239891

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02767436A Withdrawn EP1423393A1 (de) 2001-09-03 2002-08-27 Anellierte indol- und heteroindolderivate, deren herstellung und verwendung als antitumormittel

Country Status (15)

Country Link
EP (1) EP1423393A1 (es)
JP (1) JP2005508898A (es)
KR (1) KR20040029463A (es)
CN (1) CN1551885A (es)
AR (1) AR036776A1 (es)
BR (1) BR0212300A (es)
CA (1) CA2458399A1 (es)
HU (1) HUP0401446A3 (es)
IL (1) IL160441A0 (es)
MX (1) MXPA04002034A (es)
NO (1) NO20040831L (es)
NZ (1) NZ531642A (es)
PL (1) PL370210A1 (es)
RU (1) RU2004110412A (es)
ZA (1) ZA200401290B (es)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111362891A (zh) * 2020-04-01 2020-07-03 杭州福斯特药业有限公司 一种乙酰基四氢呋喃的生产装置及生产方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03020731A1 *

Also Published As

Publication number Publication date
JP2005508898A (ja) 2005-04-07
IL160441A0 (en) 2004-07-25
CN1551885A (zh) 2004-12-01
HUP0401446A2 (hu) 2004-11-29
NO20040831L (no) 2004-04-13
HUP0401446A3 (en) 2006-11-28
BR0212300A (pt) 2004-10-13
CA2458399A1 (en) 2003-03-13
MXPA04002034A (es) 2004-07-08
AR036776A1 (es) 2004-10-06
PL370210A1 (en) 2005-05-16
ZA200401290B (en) 2004-03-23
NZ531642A (en) 2005-01-28
RU2004110412A (ru) 2005-03-20
KR20040029463A (ko) 2004-04-06

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