+

WO1996033991A1 - DERIVES D'ACIDE β-NONYLHYDROXAMIQUE - Google Patents

DERIVES D'ACIDE β-NONYLHYDROXAMIQUE Download PDF

Info

Publication number
WO1996033991A1
WO1996033991A1 PCT/JP1996/001093 JP9601093W WO9633991A1 WO 1996033991 A1 WO1996033991 A1 WO 1996033991A1 JP 9601093 W JP9601093 W JP 9601093W WO 9633991 A1 WO9633991 A1 WO 9633991A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
acid
ethyl
reaction
Prior art date
Application number
PCT/JP1996/001093
Other languages
English (en)
Japanese (ja)
Inventor
Susumu Sato
Tomoyuki Shibata
Kazuhiko Tamaki
Kazuhiko Tanzawa
Tomowo Kobayashi
Kosaku Fujiwara
Original Assignee
Sankyo Company, Limited
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
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU53478/96A priority Critical patent/AU5347896A/en
Publication of WO1996033991A1 publication Critical patent/WO1996033991A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms

Definitions

  • the present invention has excellent gelatinase inhibitory activity, and is a novel hydroxamic acid useful as an anticancer agent, an angiogenesis inhibitor, a cancer invasion inhibitor or a cancer metastasis inhibitor.
  • a novel hydroxamic acid useful as an anticancer agent, an angiogenesis inhibitor, a cancer invasion inhibitor or a cancer metastasis inhibitor.
  • Matrix metallobin tinase is an enzyme that degrades protein components constituting connective tissues and the like. Gelatinase belongs to this group and degrades type IV collagen which is a major component of basement membrane. Gelatinase increases the expression level of its enzyme or activates it when a blood vessel is formed in a cancer tissue or when the cancer metastasizes. It is said that cancer cells play an important role in destroying the basement membrane of normal tissue cells (Will iam G. Stetler—Stevenson, Sadie Aznavoorian, and Lance A). Liotta; Annual Review of Cell Biology, vol. 9, 541-573 (1993)).
  • gelatinase inhibitors are expected to suppress angiogenesis and cancer metastasis in cancer tissues, and are considered to be useful for the prevention and treatment of cancer diseases.
  • hydroxamic acid was found to be a compound having a potent and selective inhibitory effect on gelatinase.
  • a derivative having a nonyl group at the ⁇ -position was found.
  • the compound found in the present invention is much more than the above-mentioned [[4-hydroxyamino-2R-isobutyl-3S— (thin phenthiomethyl) succinyl] -1L-phenylalanine] methylamide.
  • the enzyme has high selectivity for the target enzyme.
  • novel hydroxamic acid derivative of the present invention has the general formula
  • R ′ represents a 2-phenyl group
  • R 2 represents an alkyl group having 1 to 4 carbon atoms, a cycloalkyl-alkyl group having 4 to 12 carbon atoms, or 7 to 14 carbon atoms.
  • R 3 and FT each represent an aralkyl group wherein R 3 is selected from the following group A: Represents an alkyl group having 1 to 4 carbon atoms which may be substituted with up to 6 substituents, wherein R 4 represents a hydrogen atom, or together with R 3 , R and the nitrogen atom to which they are bound In addition, it represents a heterocyclyl group (which may be substituted with a substituent selected from the following group B). And a salt thereof.
  • a hydroxyl group which may be protected an amino group which may be protected, a carboxyl group which may be protected, an aminocarbonyl group and a phenyl group.
  • the present invention also provides a pharmaceutical composition for suppressing cancer, inhibiting angiogenesis, inhibiting cancer invasion or inhibiting cancer metastasis, comprising an effective amount of the above compound together with a pharmaceutically acceptable carrier or excipient. is there.
  • the present invention is a method for treating or preventing a mammal, which comprises administering an effective amount of the compound to a mammal for treating cancer or preventing cancer metastasis.
  • the present invention is also the use of the above compound for treating cancer or preventing cancer metastasis.
  • Examples of the “alkyl group having 1 to 4 carbon atoms” for R 2 include methyl, ethyl, ⁇ -propyl, isobromo, ⁇ -butyl, isobutyl, S-butyl, and t-butyl groups. — A butyl group.
  • Examples of the cycloalkyl monoalkyl group J having 4 to 12 carbon atoms for R 2 include cyclmethyl pyrmethyl, cyclobutyl pyrethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclobentylethyl, cyclobentylbrobi.
  • Examples of the “aralkyl group having 7 to 14 carbon atoms” of R 2 include a benzyl group, a phenyl group, a naphthylmethyl group and the like, and an alkyl group such as methyl and ethyl on these aromatic rings, and an alkoxy group such as methoxy and ethoxy.
  • Examples of the above-mentioned groups having a substituent such as the following are preferable, and an unsubstituted benzyl group is preferable.
  • R 2 Preferred as R 2 as a whole are t-butyl, cyclohexylmethyl and benzyl, more preferably t-butyl.
  • ⁇ alkyl group having 1 to 4 carbon atoms '' of the ⁇ alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 6 substituents selected from the following group A '' of R 3 .
  • the same as those described for the “alkyl group having 1 to 4 carbon atoms” for R 2 are preferable, and are preferably ethyl, isobrovir, t-butyl group, and more preferably, isobrovir, t-butyl group.
  • R 3 is a substituent of ⁇ optionally substituted with 1 to 6 substituents selected from the following group A, an alkyl group having 1 to 4 carbon atoms ''.
  • the protecting group for the ⁇ hydroxyl group '' include alkyl groups such as methyl and ethyl, formyl, acetyl, propionyl, butyryl, isobutyryl, bentanoyl, vivaloyl, nodylrelyl, isovaleryl, octamyl, lauroyl, myristyl, and tridecanol.
  • Aliphatic groups such as alkylcarbonyl groups such as palmitoyl and stearoyl, lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl, and unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl Aromatic groups such as benzoyl, ⁇ -naphthoyl, and naphthoyl; tetrahydrochloride -2-yl, 3-bromotetrahydrohydran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiovirane-2-yl, 4-methoxytetrahydrothiopyran-4- Tetrahydrofuranyl or tetrahydrothiranyl group such as tetrahydrofuran-2-yl, tetrahydrofuran-2-yl or tetrahydrofuran-2-yl Tri-tetrahydrofuranyl or tetra
  • Tri-lower alkylsilyl groups substituted with one or two aryl groups such as lower alkylsilyl groups, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisobromovirsilyl, and phenyldiisobrovirsilyl, etc.
  • a lower alkoxymethyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, bromoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxyhexyl;
  • Lower such as xymethyl
  • Alkoxymethyl groups such as halogeno-lower alkoxymethyl such as lucodizated lower alkoxymethyl group, 2,2,2-trichloromouth ethoxymethyl and bis (2-chloroethoxy) methyl
  • 1-ethoxyxyl, 1 -Substituted ethyl groups such as lower alkoxylated ethyl groups such as (isopropoxy) ethyl and halogenated ethyl groups such as 2,2,2-trichloroethyl;
  • Lower alkyl groups substituted with one to three aryl
  • R 3 is a substituent of ⁇ optionally substituted with 1 to 6 substituents selected from the following group A, an alkyl group having 1 to 4 carbon atoms ''.
  • the protecting group for the “amino group” is not limited as long as it is generally used as a protecting group for an amino group. Preferably, it is formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, bivaloyl, ⁇ , and 'relyl.
  • Alkylcarbonyl groups such as isovaleryl, cistanyl, lauroyl, myristol, tridecanoyl, nopermitoyl, stearoyl, and halogeno lower alkyls such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl.
  • Alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with alkylsilyl groups; alkenyloxycarbonyl groups such as vinyloxycarbonyl and aryloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl; 3, 4-dimethoxybenzyl An aralkyl group which may be substituted with one or two lower alkoxy or nitro groups such as xyloxycarbonyl, 2-nitrobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl; trimethylsilyl; Trialkylsilyl groups, such as triethylsilyl, isopropyldimethylsilyl, butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisobrovirsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropyl Silyl
  • R 3 is a substituent of ⁇ optionally substituted with 1 to 6 substituents selected from the following group ⁇ , an alkyl group having 1 to 4 carbon atoms ''.
  • ⁇ an alkyl group having 1 to 4 carbon atoms ''.
  • the protecting group for the ⁇ carboxyl group '' a protecting group in the reaction and a protecting group for blocking the drug when administered to a living body are shown.
  • -Halogeno lower alkyl groups such as 2-fluoroethyl, 2,2-dibromoethyl; benzyl, phenyl, 3-phenylbromo, ⁇ -naphthylmethyl, ⁇ -naphthylmethyl, diphenylmethyl, triphenylmethyl, ⁇ -naphthyldiphenyl
  • Lower alkyl groups substituted with one to three aryl groups such as methyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4, 5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxybenzyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4 -Cyanobenzyldiphenylmethyl, lower alkyl such as bis (2-nitrophenyl) methyl, biveronyl, lower alk
  • R 3 an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 6 substituents selected from the following group A”: a bis (hydroxymethyl) methyl group as a whole (Ie, a 2-hydroxy-1-hydroxymethylethyl group) and a 2-hydroxy-11,1-bis (hydroxymethyl) ethyl group.
  • heterocyclyl group of the “heterocyclyl group (optionally substituted by a substituent selected from the following group B)” formed by R 3 , R 4 and N together, preferably 1
  • One pyrrolidinyl is a 1-piperidino group.
  • the "protecting group” of the “optionally protected hydroxyl group” is preferably an aliphatic acetyl group (particularly an acetyl group).
  • the "protecting group” of the “optionally protected hydroxyalkyl group” is preferably an aliphatic acetyl group (especially an acetyl group).
  • Heterocyclyl group (which may be substituted with a substituent selected from the following group B)” formed by R 3 and N together is preferably 2-hydroxymethyl-1- 1 Monopyrrolidinyl, 2-hydroxymethyl-1-hydroxypyrrolidinyl group.
  • the compound of the present invention can be converted into a salt, and such a salt is preferably an alkali metal salt such as a sodium salt, a potassium salt, or a lithium salt, or an alkaline earth salt such as a calcium salt or a magnesium salt.
  • a salt is preferably an alkali metal salt such as a sodium salt, a potassium salt, or a lithium salt, or an alkaline earth salt such as a calcium salt or a magnesium salt.
  • Metal salts such as metal salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc .; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, Enylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexyl I 0
  • Lamine salt N, N'-Dibenzylethylenediamine salt, Chlorobromine salt, Proforce salt, Diethanolamine salt, N-Benzylofenethynamine salt, Piperazine salt, Tetramethylammonium Salts, amine salts such as organic salts such as tris (hydroxymethyl) amino methane salt; hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; Inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkane sulfonates such as methanesulfonate, trifluromethanesulfonate, and ethanesulfonate; benzenesulfonate; -Arylsulfonate such as toluenesulfonate, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate etc.
  • the compound of the present invention may absorb water, leave water, or become a hydrate when left in the air, and such salts are also included in the present invention.
  • R 1 is a 2-phenyl group
  • R 2 is an alkyl group having 1 to 4 carbon atoms, a cycloalkyl monoalkyl group having 4 to 12 carbon atoms, or an aralkyl group having 7 to 14 carbon atoms.
  • R 3 is an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 6 substituents selected from the following group A, and R 4 is a hydrogen atom
  • a hydroxyl group which may be protected an amino group which may be protected, a carboxyl group which may be protected, an aminocarbonyl group, a phenyl group,
  • R 3 force a compound which is 2-hydroxy-1-hydroxymethylethyl group
  • the compound (1) of the present invention can be produced according to the following process chart.
  • R ′, R 2 , R 3 and FT have the same meanings as described above, and X 1 and X 2 represent a leaving group (preferably a halogen atom, more preferably a chlorine or bromine atom.
  • X 3 represents a protecting group for an amino group (preferably a t-butyloxycarbonyl group or a benzyloxycarbonyl group); t Bu represents a t-butyl group; n represents a benzyl group.
  • This step is a step for producing an amide compound from the compound (2) and the compound (3) (commercially available or produced by the method described below).
  • a method in which a compound (2) is mixed with an acid anhydride in an inert solvent in the presence of a condensing agent and a base and then the compound (3) is reacted, or 2) an inert solvent is used.
  • a compound (2) is reacted with a haloformate, an acid halide and the like in the presence of a base in the agent to react the compound (3).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is an aliphatic solvent such as hexane, hebutane, lignin, or petroleum ether.
  • Hydrocarbons aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxan, dimethoxetane, and diethylene glycol dimethyl ether; acetone, Methyl ethyl ketone, methyl is
  • amides particularly dimethyl In the case of 2), they are ethers (especially tetrahydrofuran).
  • the condensing agent to be used is not particularly limited as long as it is used for ordinary amidation, but di-lower alkyl azodicarboxylate-triphenylphosphine such as acetyldicarboxylate phenyldiphenylphosphine is used.
  • N-lower alkyl-5-arylisoxazolidin-3'-sulfonates such as N-ethyl-5-phenylisoxazolidum-3'-sulfonate ⁇ , ⁇ '-Dicycloalkylcarbodiimides, such as N, N, ⁇ '-dicyclohexylcarbodiimide (DCC), diheteroaryldiselenides, such as di-2-pyridyldiselenide, trifenyl Triarylphosphines such as phosphine, arylsulfonyltriazolides such as benzene-sulfonyltriazolide, 2-chloro-1-methylbiphenyldiamide Diarylphosphorylazides such as 2-halo-1-lower alkylbiridinium halides and diphenylphosphorylazide (DPPA), and ⁇ , ⁇ '-carbonyldiimidazole (CDI)
  • haloformate examples include methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, tert-butyl chloroformate, methyl bromoformate, ethyl ethyl bromoformate, isobutyl bromoformate, tert-butyl bromoformate, and the like.
  • it is isobutyl chloroformate.
  • Examples of the acid halide acid to be used include acetate chloride, brobionate chloride, pino, 'phosphate chloride, acetate bromide, propionate bromide, and vivalic acid promide.
  • Vivalic acid chloride acetate chloride, brobionate chloride, pino, 'phosphate chloride, acetate bromide, propionate bromide, and vivalic acid promide.
  • bases used include triethylamine, triptylamine, diisopropylvirethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, ⁇ , ⁇ -dimethylaniline, ⁇ , ⁇ -jetylaniline, 1,5 -Diazabicyclo [4.3.0] Non-5-ene, 1,4-Diazabicyclo [2.2.2] Octane (DABC0), 1,8-Diazavicik ⁇ [5.4.0] Pendek-7-ene (DBU) And organic bases, such as triethylamine and di-methylmorpholine. 1 I
  • 1-hydroxybenzotriazole may be added to the reaction solution to promote the reaction or to produce the product in high yield. You can get things.
  • the reaction temperature varies depending on the compound, the reagent, etc., but is usually 0 to 50 ° C., preferably room temperature
  • the reaction time varies depending on the compound, the reagent, the reaction temperature, etc. It is usually 5 to 24 hours, preferably 15 to 20 hours.
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually 150 to 5 CTC, preferably -20 to room temperature
  • the reaction time is the compound, the reagent and the reaction.
  • the reaction time is usually 5 to 60 minutes, preferably 10 to 30 minutes, and the reaction between the compound (3) and the mixed acid anhydride is performed. In the stage, it is usually 5 to 24 hours, preferably 15 to 20 hours.
  • reaction solution is poured into dilute hydrochloric acid, and extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., and the extract is washed with water and then with saturated saline. Later, it is obtained by distillation.
  • a water-immiscible solvent for example, benzene, ether, ethyl acetate, etc.
  • This step is a step of producing a dicarboxylic acid compound by removing the benzyl group of the ester contained in the amide compound obtained in the first step in an inert solvent.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is an aliphatic solvent such as hexane, hebutane, lignin, or petroleum ether.
  • Hydrocarbons methanol, ethanol, n-blovanol, isopropanol, ⁇ -butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, Alcohols such as methylacetate sorb; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane; Preferably, alcohols (particularly methanol or ethanol Isopropanol Solvent mixture).
  • Examples of the reducing agent to be used include a catalyst such as palladium black, palladium carbon, platinum, and Raney nickel.
  • a catalyst such as palladium black, palladium carbon, platinum, and Raney nickel.
  • palladium carbon (10%) or palladium black is used. (0%), it is preferable to use ammonium formate, and to use palladium black, hydrogen is preferably used as a hydrogen source.
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually 0 to 50 ° C, preferably room temperature.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 5 minutes to 15 hours, preferably 30 minutes to 8 hours.
  • the catalyst is removed by filtration, and the filtrate is concentrated to about half of the total amount, and used as it is as a solution of the starting compound in the third step.
  • the solvent used in the second step may be used as it is or by appropriately adding ethanol.
  • Examples of the base to be used include triethylamine, tributylamine, diisoprovirethylamine, ⁇ -methylmorpholine, pyridine, pyridine, 4- ( ⁇ , ⁇ -dimethylamino) pyridine, ⁇ , ⁇ -dimethylaniline, ⁇ , ⁇ -Jetylaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene, 4-diazabicyclo [2.2.2] octane (DAB CO), 1,8-diazabicyclo [5.4.0] dex-7- And organic bases such as DBU.
  • it is biveridine.
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually 0 to 100 ° C, preferably room temperature to about 80 ° C.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 1 to 24 hours, preferably 2 to 20 hours.
  • the solvent is distilled off, and the reaction mixture is poured into a 5% aqueous solution of citric acid, extracted with a water-immiscible solvent such as benzene, ether, ethyl acetate, and the like. Extract, make the aqueous layer acidic with hydrochloric acid, and extract again with ethyl acetate. It is obtained by washing the ethyl acetate layer with water and distilling off the solvent. Usually, it is used as it is in the next step. If desired, it can be isolated and purified by various chromatography or recrystallization methods.
  • the solution is relatively fat-soluble and cannot be extracted with an aqueous solution of potassium carbonate, pour the reaction solution into a 5% aqueous solution of potassium hydrogen sulfate and extract with a water-immiscible solvent such as benzene, ether, or ethyl acetate. After concentration of the extract, the extract can be purified by silica gel chromatography.
  • This step is a step of reacting the compound (4) with the compound R′SH in an inert solvent to produce a lig compound (5).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is an aliphatic solvent such as hexane, hebutane, lignin, or petroleum ether.
  • Hydrocarbons aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether;
  • Preferred are ethers (particularly tetrahydrofuran).
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually from 0 to 100 ° C, preferably from 40 to the boiling point of the solvent.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 1 to 24 hours, preferably 5 to 10 hours.
  • reaction solution is poured into 5% aqueous potassium hydrogen sulfate, extracted with a water-immiscible solvent, such as benzene, ether, or ethyl acetate, and the solvent is distilled off from the extract.
  • a water-immiscible solvent such as benzene, ether, or ethyl acetate
  • compound (5) is reacted with hydroxyxylamine or 0- (t-butyldimethylsilyl) hydroxylamine in an inert solvent in the presence of a condensing agent and a base to give compound (1) of the present invention. ).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is an aliphatic solvent such as hexane, hebutane, lignin, or petroleum ether.
  • Hydrocarbons aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; formic acid Esters such as tyl, ethyl acetate, propyl acetate, butyl acetate, getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dixan, dimethoxetane, diethylene glycol dimethyl ether; ditroethane Compounds such as nitrobenzene and dinitrobenzene; Ni
  • the condensing agent to be used is not particularly limited as long as it is used for ordinary amidation. However, a di-lower alkyl azodicarboxylate-triphenylphosphonate such as acetyldicarboxylate-triphenylphosphine is used.
  • N-ethyl-5-phenylisoxazoles-3'-sulfonates such as N-lower alkyl-5-arylisoxazoles-3'-sulfonates
  • ⁇ , ⁇ '-dicycloalkyl carbodiimides such as N, ⁇ '-dicyclohexylcarpoimide (DCC), diheteroaryl diselenides such as di-2-pyridyldiselenide, trifenyl Triarylphosphines, such as phosphine
  • arylsulfonyltriazolides such as benzo-sulfonyltriazolide
  • 2-chloro-methylbiridini ® —Dylides such as dihalide phosphoryl azides (DPPA) such as dialkylphosphoryl azides (DPPA), ⁇ , ⁇ '-carbonyldiimidazole ( Imidazole derivatives such as CDI) and carposimid derivatives such
  • Examples of the base used include triethylamine, tributylamine, diisopropylvirethylamine, ⁇ -methylmorpholine, pyridine, 4- ( ⁇ , ⁇ -dimethylamino) pyridine, ⁇ , ⁇ -dimethylaniline, ⁇ , ⁇ -jetylaniline, 5- Diazabicyclo [4.3.0] Non-5-ene, 1,4-Diazabicyclo [2.2.2] Octane (DABC0), 1,8-Diazabicyclo [5.4.0] Pendek-7-E And organic bases such as butane (DBU), and preferably, ⁇ -methylmorpholine.
  • DBU butane
  • 1-hydroxybenzotriazole may be added to the reaction mixture to promote the reaction or to produce the compound in high yield, if desired. You can get things.
  • Hydroxyamine hydrochloride may be added simultaneously with the other reagents, but it is also possible to add the other reagents at 0 to 10 ° C, and after 1 hour with the base, or to add 0- (t-butyldimethyl methacrylate). When using (silyl) hydroxylamine, the amine can be similarly added one hour after the addition of the other reagents.
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually ⁇ 20 to 40 ° C., and preferably 0 to 10 ° C.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature, etc., but when hydroxylamine is used, it is usually 30 minutes to 5 hours after addition of hydroxylamine, preferably 1 to 2 hours. Yes, when 0- (t-butyldimethylsilyl) hydroxylamine is used, it is usually 10 to 36 hours after adding 0- (t-butyldimethylsilyl) hydroxylamine, preferably 1 to 36 hours. It lasts 2 to 24 hours.
  • the product is purified by various chromatographic or recrystallization methods.
  • R 3 has a hydroxyl group which may be protected and which is included in group A in the general formula (preferably, a protecting group is preferably an acyl group), the protecting group is further deprotected.
  • a protecting group is preferably an acyl group
  • the compounds of the present invention can also be prepared.
  • the removal of the protecting group can be carried out by a usual method.
  • the protecting group is an acyl group
  • the removal can be carried out using a base, and it is preferable to use a carbon dioxide lime in methanol. It is.
  • R 3 has an amino group which may be protected and a carboxyl group which may be protected and which are included in group A in the general formula, or R 3 , R 4 and the nitrogen to which they are bonded
  • the heterocyclyl group formed together with the atom has an optionally protected hydroxyl group or an optionally protected hydroxyalkyl group shown in the aforementioned group B
  • the compound of the present invention can also be produced by deprotection according to a conventional method.
  • This step is a step of producing a compound (7) by reacting the compound (6) with 4- (R) -pentyl-2-exoxazolidinone in an inert solvent in the presence of a base.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • Aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dithioxan, dimethoxetane, and diethylene glycol dimethyl ether; Is tetrahydrofuran.
  • Butyllithium is preferred as the base used.
  • the order of the reagents added to the solvent is as follows. A base is added to 4- (R) 1-benzyl-2-agexazolidinone, and then 10 to 30 minutes later, the compound (6) is added.
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually from 100 to 150 ° C.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 30 minutes to 5 hours, preferably 1 to 2 hours after the compound (6) is added to the reaction solution.
  • the solvent is distilled off, the reaction solution is poured into water, and extracted with a water-immiscible solvent such as benzene, ether, ethyl acetate, and the like.
  • the product obtained by distilling off is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatography or recrystallization methods.
  • This step is a step of reacting the amide compound obtained in the sixth step with a halogenating agent in an inert solvent in the presence of a Lewis acid and a base to produce compound (8).
  • the solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • Aliphatic hydrocarbons such as hexane, hebutane, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, tetrahydrofuran, zio ' 13
  • Ethers such as xane, dimethyloxetane and diethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; Suitably are halogenated hydrocarbons, especially methylene chloride.
  • the halogenating agent used is preferably bromo-succinic acid imide.
  • a combination of a Lewis acid and a base to be used a combination of dibutyl boron derivative and an organic amine such as triethylamine diisopropylethylamine is preferable.
  • the reaction can be performed without using a Lewis acid.
  • reaction temperature varies depending on the compound, reagent, etc., but when the starting compound is activated with a base and dibutyl borant float, when adding both reagents, raise the temperature to 178 ° C, then allow to cool to 0 ° C. To When adding N-bromosuccinic acid imid to the solution, bring it to -78 ° C again and react at the same temperature.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 30 to 120 minutes for the activation step, and preferably 30 to 60 minutes for the bromination step.
  • reaction solution is poured into aqueous potassium hydrogen sulfate, extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., and the extract is washed with hydrogen sulfite-reduced water, and the solvent is distilled off. It is obtained by doing.
  • a water-immiscible solvent for example, benzene, ether, ethyl acetate, etc.
  • compound (8) is hydrolyzed in an inert solvent in the presence of a base to produce compound (9).
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples thereof include methylene chloride, chloroform, carbon tetrachloride, and dichloromethane.
  • Halogenated hydrocarbons such as chloroethane, cyclobenzene, and dichlorobenzene, ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether;
  • a mixed solvent is preferable, and a mixed solvent of ethers (particularly tetrahydrofuran) and water is preferable.
  • a preferred one is lithium hydroxide. If desired, the reaction can be carried out using hydrogen peroxide in combination.
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually ⁇ 20 to 40 ° C., and preferably 0 to 10 ° C.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 30 minutes to 5 hours, preferably 1 to 2 hours.
  • the reaction solution is neutralized with 1 N hydrochloric acid, and after concentration, the reaction solution is poured into 0.5 N hydrochloric acid, and extracted with a water-immiscible solvent such as benzene, ether, ethyl acetate, and the like. After washing with, the solvent is distilled off from the extract. If desired, it can be isolated and purified by various chromatography or recrystallization methods.
  • This step is a step in which isobutene is reacted with compound (9) in an inert solvent in the presence of an acid catalyst to obtain an ester compound (10).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is an aliphatic solvent such as hexane, hebutane, lignin, or petroleum ether.
  • Hydrocarbons Aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene;
  • ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane and diethylene glycol dimethyl ether, and preferred are halogenated hydrocarbons (particularly dichloromethane).
  • Acid catalysts used include those used as acid catalysts in normal reactions. 3 ⁇
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid are preferred, and sulfuric acid is more preferred.
  • the reaction temperature varies depending on the compound, the reagent, and the like.
  • the reaction temperature is ⁇ 40 ° C. to 120 ° C.
  • the reaction is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. To 25 ° C.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 5 to 24 hours.
  • reaction solution is poured into saturated aqueous sodium hydrogen carbonate, extracted with a water-immiscible solvent, such as benzene, ether, or ethyl acetate.
  • a water-immiscible solvent such as benzene, ether, or ethyl acetate.
  • the extract is washed with water and saturated saline, and the solvent is removed. Obtained by distillation.
  • This step is a step of producing compound (11) by reacting compound (10) with dibenzyl malonate in an inert solvent in the presence of a base.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • Aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl Ethers such as ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; and amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide.
  • dimethylformamide is used.
  • the base used is preferably an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride or an alkali metal alkoxide such as potassium l-butoxide. Particularly, hydrogenated sodium and potassium t-butoxide.
  • the reaction temperature varies depending on the compound, the reagent and the like, but is usually ⁇ 20 ° C. to 40 ° C., preferably 0 to room temperature.
  • reaction time varies depending on the compound, reagents, reaction temperature, etc., but usually 5 to 2 when dibenzyl malonate is converted to a sodium salt with sodium hydride or potassium salt with potassium hydroxide. Minutes when the compound (10) is added and reacted at room temperature for 10 to 20 hours.
  • reaction solution is poured into 0.5 N hydrochloric acid, extracted with a water-immiscible solvent, for example, dichloromethane, ether, ethyl acetate, etc., and the extract is washed with saturated brine, and then the solvent is distilled off.
  • a water-immiscible solvent for example, dichloromethane, ether, ethyl acetate, etc.
  • This step is a step of hydrolyzing compound (11) in an inert solvent using an acid catalyst to produce compound (2), which is an important intermediate for producing aldehyde compound (1). It is.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene. Suitable halogenated hydrocarbons (particularly methylene chloride) are preferred.
  • the acid catalyst to be used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, but is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid.
  • a brensted acid such as an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and more preferably trifluroacetic acid.
  • the reaction temperature varies depending on the compound, the reagent, and the like, but is usually 0 ° C to 40 ° C, and preferably room temperature.
  • the reaction time varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 1 to 5 hours.
  • This step is a step of producing an amide compound by reacting the compound (13) with the compound (13) in an inert solvent in the presence of a condensing agent and a base.
  • This step can be performed in the same manner as in the first step.
  • This step is a step of producing compound (3) by reacting compound (14) with a protective group-removing agent in an inert solvent.
  • the removal of the protecting group can be carried out by a usual method,
  • the protecting group is a t-butoxycarbonyl group
  • it can be removed, for example, by treating with an acid.
  • the acid to be used is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, and is preferably an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid.
  • Organic acids such as trifluroacetic acid are used.
  • the solvent to be used is not particularly limited as long as it is used in a usual reaction.
  • the solvent include halogenated hydrocarbons such as methylene chloride and chloroform, and ethers such as tetrahydrofuran and dioxane.
  • Organic solvents are preferred.
  • reaction temperature and reaction time vary depending on the starting material, the solvent and the acid or base used, and are not particularly limited. However, the reaction is usually carried out at 0 to 50 ° C for 1 to 10 hours.
  • the protecting group is a benzyloxycarbonyl group
  • a method of removing by contacting with a reducing agent in a solvent preferably catalytic reduction at room temperature under a catalyst
  • the solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol, and isopropanol, dimethyl ether, tetrahydrofuran, and dioxane
  • alcohols such as methanol, ethanol, and isopropanol, dimethyl ether, tetrahydrofuran, and dioxane
  • ethers aromatic hydrocarbons such as toluene, benzene, and xylene
  • Aliphatic hydrocarbons such as sun and cyclohexane, esters such as ethyl acetate and propyl acetate, fatty acids such as acetic acid, and mixed solvents of these organic solvents and water are preferred.
  • the catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, or triflic acid. Enylphosphine rhodium monochloride and paradium monophosphate sulfate are used.
  • the pressure is not particularly limited, but it is usually 1 to 10 atm.
  • reaction temperature and reaction time vary depending on the starting material, solvent, type of catalyst, and the like, but are usually from 0 to 100 ° C. for 5 minutes to 24 hours.
  • the compound of the present invention When the compound of the present invention is used as an angiogenesis inhibitor, a cancer invasion inhibitor or a cancer metastasis inhibitor, it is administered in various forms.
  • the administration form include oral administration by tablets, capsules, granules, powders, syrups, etc. or parenteral administration by injections (intravenous, intramuscular, subcutaneous), eye drops, suppositories, etc. it can.
  • These various preparations are commonly used in the known pharmaceutical formulation technical fields such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspending agents, coating agents, etc. It can be formulated using known adjuvants. The amount used depends on the condition, age, body weight, administration method and dosage form, but usually 50 to 1000 mg per day can be administered to an adult.
  • gelatinase B was prepared from a serum-free culture of TNF ⁇ -added human fibrosarcoma cells, and substrate was labeled with radioisotope after labeling type I collagen prepared from rat tail with radioisotopes. It was measured by measuring the cleavage of gelatin using gelatinized by denaturation.
  • the structure of the compound of the present invention is very similar to that of the compound described in International Publication WO 90Z05719, but its gelatinase B inhibitory activity was unexpectedly strong.
  • the precipitated dicyclohexylurea was filtered off, and the obtained filtrate was poured into 0.5 Nt casing acid, and extracted with ethyl acetate.
  • the organic layer was washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate.
  • Benzyloxycarbonyl-L-tert-mouth isine (7.19 g) was dissolved in anhydrous tetrahydrofuran (300 ml) under a nitrogen atmosphere and cooled to 120 ° C.
  • N-Methylmorpholine (3.00 ml) and isobutyl chloroformate (3.50ral) were sequentially added to this solution, and the mixture was stirred at -20 ° C for 20 minutes.
  • a solution of 2-amino-1,3-propanediol (3.40 g) in dimethylformamide (70 ml) was added, and the mixture was stirred at -20 ° C for 16 hours.
  • reaction solution was poured into 0.5N hydrochloric acid and extracted with ethyl acetate.
  • Reference Example 11 (benzyloxycarbonyl-L-tert-mouth isine)-(2-acetoxy-11- (acetoxymethyl) ethyl) amide (4.10 g) was dissolved in methanol (90 ml). After adding palladium carbon (300 mg), the mixture was stirred at room temperature for 1.7 hours in a hydrogen atmosphere to undergo hydrogenolysis. The catalyst was filtered off, and the solution was concentrated under reduced pressure to obtain a crudely purified target compound. The obtained crude product was used for the next step (Reference Example 13) without further purification.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Composés de formule générale (1) ayant un excellent effet inhibiteur de la gélatinase et utiles comme agent cancérostatique, suppresseur de la néoformation de vaisseaux sanguins, suppresseur d'infiltration cancéreuse ou suppresseur de métastases cancéreuses. Dans ladite formule, R1 représente 2-thiényle, R2 représente alkyle, cycloalkylalkyle ou aralkyle, R3 représente alkyle possédant un ou plusieurs substituants sélectionnés dans le groupe A suivant: OH, NH¿2?, COOH, aminocarbonyle, phényle, etc.; et R?4¿ représente H, ou bien R3 et R4 forment ensemble un hétérocycle comportant éventuellement des substituants choisis dans le groupe B suivant: OH, HO-alkyle, etc..
PCT/JP1996/001093 1995-04-26 1996-04-23 DERIVES D'ACIDE β-NONYLHYDROXAMIQUE WO1996033991A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53478/96A AU5347896A (en) 1995-04-26 1996-04-23 Beta-nonylhydroxamic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/102011 1995-04-26
JP10201195 1995-04-26

Publications (1)

Publication Number Publication Date
WO1996033991A1 true WO1996033991A1 (fr) 1996-10-31

Family

ID=14315832

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/001093 WO1996033991A1 (fr) 1995-04-26 1996-04-23 DERIVES D'ACIDE β-NONYLHYDROXAMIQUE

Country Status (2)

Country Link
AU (1) AU5347896A (fr)
WO (1) WO1996033991A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005716A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
WO1990005719A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
EP0498665A1 (fr) * 1991-02-07 1992-08-12 British Biotech Pharmaceuticals Limited Dérivés de l'acide hydroxamique, procédé pour leur préparation et leur utilisation
WO1993009090A1 (fr) * 1991-11-06 1993-05-13 Yamanouchi Pharmaceutical Co., Ltd. Derive d'acide hydroxamique
WO1993020047A1 (fr) * 1992-04-07 1993-10-14 British Bio-Technology Limited Inhibiteurs de la collagenase et de la cytokine a base d'acide hydroxamique
WO1993021942A2 (fr) * 1992-05-01 1993-11-11 British Biotech Pharmaceuticals Limited Utilisation d'inhibiteurs de metalloprotease matricielle (mmp)
WO1995009841A1 (fr) * 1993-10-07 1995-04-13 British Biotech Pharmaceuticals Limited Derives d'acide hyroxamique utilises comme inhibiteurs de production de cytokine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005716A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
WO1990005719A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
EP0498665A1 (fr) * 1991-02-07 1992-08-12 British Biotech Pharmaceuticals Limited Dérivés de l'acide hydroxamique, procédé pour leur préparation et leur utilisation
WO1993009090A1 (fr) * 1991-11-06 1993-05-13 Yamanouchi Pharmaceutical Co., Ltd. Derive d'acide hydroxamique
WO1993020047A1 (fr) * 1992-04-07 1993-10-14 British Bio-Technology Limited Inhibiteurs de la collagenase et de la cytokine a base d'acide hydroxamique
WO1993021942A2 (fr) * 1992-05-01 1993-11-11 British Biotech Pharmaceuticals Limited Utilisation d'inhibiteurs de metalloprotease matricielle (mmp)
WO1995009841A1 (fr) * 1993-10-07 1995-04-13 British Biotech Pharmaceuticals Limited Derives d'acide hyroxamique utilises comme inhibiteurs de production de cytokine

Also Published As

Publication number Publication date
AU5347896A (en) 1996-11-18

Similar Documents

Publication Publication Date Title
EP1309594B1 (fr) Derives de benzimidazole, leur preparation et leur application en therapeutique
WO1991005784A1 (fr) Derive de pyrimidine bicyclique, procede de production et preparation pharmaceutique le contenant en tant qu'ingredient actif
WO1996033212A1 (fr) Nouveaux derives peptidiques
WO1995009864A1 (fr) Nouveau derive peptidique
JP2004517090A5 (fr)
HU230701B1 (hu) Hepatitis C inhibitor tripeptidek
US7186846B2 (en) Process for preparing a dipeptidyl peptidase IV inhibitor and intermediates employed therein
JP2010523502A (ja) ジペプチジルペプチダーゼｉｖの阻害剤としてのｎ−置換チオモルホリン誘導体およびその医薬的使用
JPH03176495A (ja) ドーパミン及びドーパミン誘導体の４―０―リン酸エステルの製造方法
JPS6146462B2 (fr)
CN115819319A (zh) 一种酰胺类化合物、其制备方法及其应用
JP4233262B2 (ja) カルバ糖アミン誘導体及びそれを用いるグリコシダーゼ阻害剤
JP2979139B2 (ja) Ｌ−パラボロノフェニルアラニンの製造方法
JP7331116B2 (ja) ＴＧＦ－βＲ１キナーゼ阻害剤としての５－（４－ピリジルオキシ）ピラゾール類化合物
JPH07224091A (ja) 新規ホスホン酸、それらを調製する方法及びそれらを 含有する薬剤組成物
WO1996033991A1 (fr) DERIVES D'ACIDE β-NONYLHYDROXAMIQUE
KR0144684B1 (ko) 디카르복실산의 모노에스테르 및 그의 제조방법
WO2017144015A1 (fr) Nouvelle toxine et procédé de préparation de son intermédiaire
JP2789365B2 (ja) ジカルボン酸モノエステルおよびその製造法
JP7336432B2 (ja) アザ糖とその中間体の合成
JPH08188546A (ja) カルコン誘導体
CN111349077A (zh) 一种哒嗪衍生物及其制备方法和医药用途
JPS59199693A (ja) インドリルグリシルセフアロスポリン誘導体
JPH10130257A (ja) β−ノニルヒドロキサム酸誘導体を有効成分とする医薬
JPH0912570A (ja) β−ノニルヒドロキサム酸誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN CZ HU KR MX NO NZ RU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载