WO2006011499A1 - Nouveau dérivé d’arylamidine, sel de celui-ci et antifongique contenant celui-ci - Google Patents

Nouveau dérivé d’arylamidine, sel de celui-ci et antifongique contenant celui-ci Download PDF

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Publication number
WO2006011499A1
WO2006011499A1 PCT/JP2005/013702 JP2005013702W WO2006011499A1 WO 2006011499 A1 WO2006011499 A1 WO 2006011499A1 JP 2005013702 W JP2005013702 W JP 2005013702W WO 2006011499 A1 WO2006011499 A1 WO 2006011499A1
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compound
group
general formula
methyl
salt
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PCT/JP2005/013702
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English (en)
Japanese (ja)
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Kazuya Hayashi
Nobuhiko Nomura
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Toyama Chemical Co., Ltd.
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Priority to JP2006527815A priority Critical patent/JP5021308B2/ja
Publication of WO2006011499A1 publication Critical patent/WO2006011499A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

Definitions

  • Novel arylamidine derivatives and salts thereof, and antifungal agents containing them Novel arylamidine derivatives and salts thereof, and antifungal agents containing them
  • the present invention relates to a novel arylamidine derivative having antifungal activity, a salt thereof, and an antifungal agent containing them as an active ingredient.
  • amphotericin B has a very strong bactericidal action, but there are side effects such as nephrotoxicity, which limits its clinical use. Because flucytosine has problems such as resistance, it is rarely used alone. Micafungin is weakly active against the genus Talyptococcus. All other drugs are collectively referred to as azole antifungal agents, and their fungicidal action against fungi is currently the most commonly used due to the balance between efficacy and safety, which tends to be generally inferior to that of amphotericin B. (Non-patent document 2).
  • Non-patent Document 3 The problem of resistance has a serious impact on the management of patients with deeply growing mycosis.
  • Non-Patent Document 1 Clinical and Microorganism, Vol.17, pp.265-266, 1990
  • Non-Patent Document 2 Clinical and Microorganisms, Vol. 21, pp. 277-283, 1994
  • Non-Patent Document 3 Clinical and Microorganisms, 28th, 51-58, 2001
  • WO03 / 074476 discloses that allylamidine derivatives have strong antifungal activity and are useful as antifungal agents, but the side effects are further reduced, such as hygroscopicity and deliquescence. A compound with improved physical properties is desired.
  • R 1 is an amidino group which may be protected or substituted;
  • R 2 and R 3 are the same or different and each represents a hydrogen atom or a halogen atom, or a salt thereof, or an azole
  • the compound of general formula [1] in which R 1 is an amidino group, R 2 is a hydrogen atom and R 3 is a fluorine atom is an azole drug. It has strong activity against fungi including resistant fungi, exhibits high safety, does not exhibit deliquescence and hygroscopicity at all, has excellent chemical stability, and is suitable as a pharmaceutical drug substance. In addition, the present invention was completed by finding that it has an excellent activity against protozoa.
  • the compound of the present invention has strong activity against fungi including azole drug-resistant fungi, It exhibits high safety and excellent physical properties and is useful as an antifungal agent. In addition, it has excellent activity against protozoa and is also useful as an antiprotozoal drug.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
  • an alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec butyl
  • a linear or branched C alkyl group such as butyl, isobutyl, tert butyl, pentyl, isopentyl, hexyl, heptyl and octyl
  • a lower alkyl group is, for example, methyl, ethyl, propyl, isopropyl
  • a linear or branched C alkyl group such as butyl, sec butyl, isobutyl, tert butyl, pentyl and isopentyl;
  • Linear or branched C alkke such as Ninole, Arinole, Propeninole, Isopropeninole, Buteninole, Isobuteninole, Penteninole, Hexayl, Heptyl and Otatenyl
  • An aryl group means, for example, a group such as fur and naphthyl;
  • an alkyl group means an alkyl alkyl group such as, for example, benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl;
  • alkoxy groups include methoxy and ethoxy
  • a linear or branched C alkyloxy group such as xoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec butoxy, tert butoxy, pentyloxy and isopentyloxy;
  • an aralkyloxy group is, for example, Benzyloxy, Dihue
  • alkyl-alkyloxy group such as -methyloxy, trityloxy, phenethyloxy and naphthylmethyloxy
  • an alkoxyalkyl group is, for example, methoxymethyl
  • alkyloxy group examples include C cycloalkyloxy groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy;
  • a ruoxyalkyl group is, for example, an al C alkyloxy C alkyl group such as benzyloxymethyl and phenethyloxymethyl;
  • the acyl group is, for example, a linear or branched C alkanoyl group such as formyl group, acetyl, propiol and isovaleryl, or an al Cyl group such as benzyl carboyl.
  • Heterocyclic carbocyclic groups such as thiol, tenol, pyrrolidino carboyl and furoyl, and carboxy C alkyl such as 3 carboxypropanol and 4 carboxybutanol.
  • C 6 alkyloxycarbons such as 1-6 alkyl carboyl groups, 3- (methoxy carbol) propanol and 4 (methoxy carbol) butanols.
  • Succiol group Succiol group, glutaryl group, maleoyl group, phthaloyl group and amino acids (for example, glycine, alanine, norin, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, Linear, branched or branched at the N-terminus derived from glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline and hydroxyproline) A chained OC aminoalkanoyl group;
  • Alkyloxycarbonyl groups include, for example, methoxycarbon, ethoxycarbol, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tertbutoxycarbonyl and a straight-chain or branched C-alkyloxycarbonyl group such as tert-pentyloxypol;
  • An oral alkyloxycarbon group refers to, for example, a C cycloalkyloxycarbon group such as cyclopentyloxycarbon and cyclohexyloxycarbon.
  • An aralkyloxycarboxyl group refers to, for example, an aralkyloxycarboxyl group such as benzyloxycarbol and phenoxycarboxyl;
  • a carboxy group is a group such as a phenoxy carboxy group
  • an alkoxy group is a linear or branched C alkanoyl group such as an acetyloxy and propio-oxy group.
  • alloys such as benzoyloxy
  • the arylthio group is, for example, a group such as phenolthio;
  • the alkanesulfol group is, for example, C such as methanesulfol, ethanesulfol, and propanesulfol.
  • Alkanesulfol group for example, arylsulfonyl group is a group such as benzenesulfonyl, toluenesulfol and naphthalenesulfol; for example, alkanesulfooxyl group is, for example, methanesulfoloxyl And ethanesulfoloxy c
  • An alkanesulfo-oxy group; an arylsulfo-oxy group is, for example,
  • alkylthiocarbonyl group refers to, for example, a C alkylthiocarbonyl group such as methylthiocarbonyl and ethylthiocarbonyl; a cycloalkylidene group refers to
  • a group such as cyclopentylidene and cyclohexylidene; an alkylidene group such as benzylidene and naphthylmethylene; a dialkylaminoalkylidene group such as N, N dimethylaminomethylene and N, N a group such as a jetylaminomethylene; a dialalkylphosphoryl group, for example, a group such as dibenzylphosphoryl; a dialylphosphoryl group, for example, a group such as diphenylphosphoryl
  • the oxygen-containing heterocyclic group is, for example, a group such as tetrahydrofuryl and tetrahydrobiranyl; and the oxygen-containing heterocyclic alkyl group is, for example, 5-methyl-2-oxo-2H-1,3-dioxole-4 A group such as ethylmethyl; a sulfur-containing heterocyclic group, for example, a group such as tetrahydrocarbyl; a heterocyclic hydroxyl group, for example, 2-furfuroxycarboxyl And a group such as 8-quinolyloxycarbonyl; a nitrogen-containing bicyclic alkylidene group such as 3-hydroxy-4-pyridylmethylene; a substituted silyl group such as trimethylsilyl and triethylsilyl And a group such as tributylsilyl.
  • Each of the above groups further includes a halogen atom, an amino group that may be protected, a hydroxyl group that may be protected, a nitro group, a lower alkyl group, an alkyl group, an alkoxy group, an alkyloxy group, an aryl.
  • a group, an acyl group, or an oxo group may be substituted with one or more groups selected.
  • the amino protecting group includes all groups that can be used as protecting groups for ordinary amino groups.
  • W. Green et al. Protective 'Groups' In 'Organic' Synthesis (Protective Groups in Organic Synthesis) 3rd edition, 494-653, 1999, John Wiley & Sons, INC.
  • an acyl group an alkyl carboxy group, an aralkyl carboxy group, an aryl carboxy group, an aralkyl group, an alkoxy group.
  • Sialkyl group alkyloxyalkyl group, arylthio group, alkanesulfonyl group, arylaryl group, dialkylaminoalkylidene group, alkylidene group, nitrogen-containing heterocyclic alkylidene group, cycloalkylidene group, diarylphosphoryl group And a dialkyl phosphoryl group, an oxygen-containing heterocyclic alkyl group, and a substituted silyl group.
  • the hydroxyl protecting group includes all groups that can be used as protecting groups for ordinary hydroxyl groups.
  • W. Green et al. Protective 'Groups' In 'Organic' Synthesis ( Protective Groups in Organic Synthesis) 3rd edition, pages 17-245, 1999, John Wiley & Sons JNC.
  • an acyl group an alkyloxycarbon group, an aralkyloxycarbonyl group, a heterocyclic oxycarbon group, an alkyl group, an alkenyl group, an aralkyl group, an oxygen-containing heterocyclic group And sulfur-containing heterocyclic groups, alkoxyalkyl groups, aralkyloxyalkyl groups, alkanesulfonyl groups, arylsulfonyl groups and substituted silyl groups.
  • the amidino protecting group includes all groups that can be used as a protecting group for ordinary amidino groups.
  • an asilino group an alkyloxycarbonyl group, an aralkyloxycarbonyl group , Aryloxycarboro group, cycloalkyloxycarboxyl group, alkyl group, alkoxyalkyl group, aralkyloxyalkyl group, allylthio group, alkanesulfol group, allylsulfonyl group, alkylthiocarboxyl And -alkyl group, a dialkylaminoalkylidene group, an alkylidene group, a nitrogen-containing heterocyclic alkylidene group, a cycloalkylidene group, an oxygen-containing heterocyclic alkyl group, and a substituted silyl group.
  • Examples of the substituent of the amidino group include a hydroxyl group which may be substituted with an acyl group, and an alkoxy and aralkyloxy group which may be substituted.
  • Examples of the leaving group include a halogen atom, an alkanesulfoxy group, an arylsulfonyl group, and an acyloxy group.
  • Examples of the salt of the compound of the general formula [1] include hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid. Salts with mineral acids such as L; tartaric acid, formic acid, acetic acid, citrate, L lactic acid, succinic acid, maleic acid, fumaric acid, trichlorodiacetic acid and trifluoroacetic acid, and salts with organic carboxylic acids; and methanesulfone And salts with sulfonic acids such as acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • Preferable salts of the compound of the general formula [1] include pharmacologically acceptable salts, and hydrochloride is more preferable.
  • preferable compounds include the following compounds.
  • R 1 may be substituted with an acyl group, substituted with a hydroxyl group, or a compound that is an amidino group is preferred, or a compound that is an amidino group is more preferred. More preferred are compounds that are amidino groups.
  • R 2 and R 3 are the same or different and is a hydrogen atom or a fluorine atom is preferred.
  • trihydrochloride As a salt of a compound in which R 1 is an amidino group, R 2 or R 3 hydrogen atom, trihydrochloride is preferable.
  • the compound of the present invention is produced by a combination of methods known per se.
  • the compound of the present invention can be produced by the following production method.
  • the compound of the general formula [la] is generally the compound of the general formula [2]. It can be produced by reacting with a compound of the formula [4] and converting it to a compound of the general formula [3], and then reacting the compound of the general formula [3] with ammonia or an ammonium salt. This reaction is carried out according to the method described in the W096 / 16947 publication and the journal 'Ob' Organic 'Chemistry (J. Org. Chem.), Vol. 64, pp. 12-13, 1999, or the like. Just do it.
  • the compound of the general formula [3] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [4] in the presence of an acid.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • N, N — Amides such as dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, cycloform and dichloroethane
  • Fragrances such as benzene, toluene and xylene Group hydrocarbons
  • ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether
  • sulfoxides such as dimethyl sulfoxide
  • acetone and 2-butano Ketones such as
  • Examples of the acid used in this reaction include hydrogen chloride, hydrogen bromide, perchloric acid, p-toluenesulfonic acid, methanesulfonic acid, and the like.
  • It may be 1 to 200 times mol, preferably 5 to 100 times mol for the compound of 2].
  • the amount of the compound represented by the general formula [4] is preferably 2 to 1000 times that of the compound represented by the general formula [2].
  • This reaction may be carried out at 30 to 150 ° C, preferably 10 to 50 ° C for 30 minutes to 24 hours.
  • the compound of the general formula [la] can be produced by reacting the compound of the general formula [3] with ammonia or an ammonium salt.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • N N Amides such as dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • Aromatic carbonization such as benzene, toluene and xylene Hydrogens
  • ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether
  • -tolyls such as acetonitrile
  • sulfoxides such as dimethyl sulfoxide
  • Examples include heteroaromatics such as pyridine and water, and these may be used as a mixture.
  • ammonium salt examples include ammonium chloride, ammonium bromide and ammonium acetate, and the amount of ammonia or ammonium salt used is generally It may be 3 to 100 times mol, preferably 3 to 10 times mol for the compound of formula [3]. This reaction may be carried out at 0 to 150 ° C, preferably 20 to 120 ° C for 1 minute to 24 hours.
  • R 5 represents an optionally substituted acyl, lower alkyl or aralkyl group; R 2 and R 3 have the same meaning as described above.”
  • the compound of the general formula [lb] can also produce the compound power of the general formula [2].
  • a compound of the general formula [lc] can be produced by alkylating or acylating the compound of the general formula [lb].
  • the compound of general formula [la] can be produced by reducing the compound of general formula [lc].
  • the compound of the general formula [la] can be produced by reducing the compound of the general formula [lb].
  • the compound of the general formula [lb] is a compound of the general formula [2] in the presence or absence of a base, It can be produced by reacting with hydroxylamine or a salt thereof.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • N, N — Amides such as dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, cycloform and dichloroethane
  • Fragrances such as benzene, toluene and xylene Group hydrocarbons
  • ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether
  • sulfoxides such as dimethyl sulfoxide
  • acetone and 2-butano Ketones such as
  • hetero aromatics and water such as pyridine and the like, may be used which are mixed.
  • Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide and sodium tert-butoxide; sodium hydroxide, sodium hydroxide, potassium hydroxide Inorganic salts such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as tritylamine and pyridine.
  • metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide and sodium tert-butoxide
  • sodium hydroxide sodium hydroxide
  • potassium hydroxide Inorganic salts such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride
  • organic bases such as tritylamine and pyridine.
  • the amount of the base used may be 2 to 100 times mol, preferably 2 to 20 times monole to the compound of the general formula [2].
  • Examples of the salt of hydroxylamine include hydrochloride and sulfate.
  • the amount of hydroxylamine or a salt thereof used may be 2 to 100 times mol, preferably 2 to 20 times mol, of the compound of the general formula [2].
  • This reaction may be carried out at 0 to 150 ° C., preferably 30 to 150 ° C. for 1 minute to 24 hours.
  • the compound of the general formula [lc] can be produced by reacting the compound of the general formula [lb] with a reactive derivative or an alkylating agent in the presence or absence of a base.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • Halogenated hydrocarbons such as dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane, tetrahydrofuran, azole, di
  • Examples of the reactive derivative include acid anhydrides such as acetylylformyloxide, acetic anhydride, trifluoroacetic anhydride, and trifluoroacetic anhydride; organic carboxylic acids such as acetic acid, chloroethyl carbonate, and isobutyl carbonate.
  • Mixed acid anhydrides with monoalkyl esters of carbonic acid such as; Acid anhydrides of mixed acid anhydrides of organic carboxylic acids such as acetic acid with organic acids such as pivalic acid; Acid bromides such as acetyl chloride; and ⁇ Nitrophenyl ester, N hydroxy And active esters such as succinimide ester and N-hydroxyphthalimide ester.
  • a reactive derivative may be generated in the system using a coupling reagent!
  • Coupling reagents include, for example, carbodiimides such as N, N, monodicyclohexylcarbodiimide and Nethyl N ′-(3-dimethylaminopropyl) carbodiimide; carbo-diimidazole and other carbodiimides.
  • Acid azides such as diphenyl phosphoryl azide; acid cyanides such as jetyl phosphoryl cyanide; 2-ethoxy 1 ethoxycarbonyl 1, 2 dihydroquinoline; O benzotriazole 1-yl 1, 1, 3, 3—Tetramethyluronium hexafluorophosphate; and O— (7-azabenzotriazole 1-yl) -1, 1, 3, 3—Tetramethylol-um-hexa Examples include fluorophosphate.
  • alkylating agent examples include alkyl halides such as methyl iodide and thiol iodide; aralkyl halides such as benzyl chloride and benzyl bromide; and sulfate esters such as dimethyl sulfate. It is done.
  • Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, carbonate, Examples include inorganic salts such as sodium hydride, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as tritylamine and pyridine.
  • metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert butoxide and sodium tert butoxide
  • sodium hydroxide potassium hydroxide
  • carbonate examples include inorganic salts such as sodium hydride, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as tritylamine and pyridine.
  • the amount of the reactive derivative, coupling reagent, alkylating agent and base used is 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [lb].
  • This reaction may be carried out at 20-100 ° C, preferably 0-50 ° C for 1 minute to 24 hours.
  • the compound of the general formula [la] can be produced by subjecting the compound of the general formula [lb] to a reduction reaction.
  • the compound of the general formula [la] can be produced by subjecting the compound of the general formula [lc] to a reduction reaction.
  • Examples of the reduction reaction used here include a catalytic hydrogenation reaction using a metal catalyst and a reduction using a metal and an acid such as zinc acetate.
  • the solvent used is not particularly limited as long as it does not adversely affect the reaction.
  • Alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; amides such as N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone; methylene chloride, black mouth form And halogenated hydrocarbons such as dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether ; -Tolyls such as tonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate
  • Examples of the metal catalyst include palladium-carbon, palladium oxide, and palladium hydroxide.
  • Palladium catalysts such as nickel and palladium black, nickel catalysts such as Raney nickel, and acid-platinum, etc., and the amount used is 0.001 to the amount of the compound of the general formula [lb] or the compound of the general formula [lc].
  • the amount is 1 time (wZw), preferably 0.01 to 0.5 times (wZw).
  • reducing agents other than hydrogen examples include formic acid; formate salts such as sodium formate, ammonium formate, and triethylammonium formate; cyclohexene, and cyclohexadiene.
  • the amount may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [lb] or the compound of the general formula [lc].
  • the hydrogen pressure thereof may be normal pressure to 30 atm, preferably 2 to 10 atm.
  • the hydrogen pressure may be normal pressure
  • This reaction may be carried out at 0 to 200 ° C., preferably at 0 to 100 ° C. for 1 minute to 24 hours.
  • R 6 represents an optionally substituted lower alkyl or aralkyl group
  • RR 3 and R 4 have the same meaning as described above.
  • the compound of general formula [Id] can also produce the compound power of general formula [3]. Subsequently, the compound of general formula [la] can be produced by reducing the compound of general formula [Id].
  • the compound of the general formula [Id] can be produced by reacting the compound of the general formula [3] with the compound of the general formula [5] or a salt thereof.
  • Examples of the compound of the general formula [5] include O-methylhydroxylamine and O-benzylhydroxylamine.
  • Examples of the salt of the compound of the general formula [5] include hydrochloride and sulfate.
  • This reaction may be carried out according to production method 1-2.
  • the compound of the general formula [la] can be produced by reducing the compound of the general formula [Id]. This reaction can be carried out according to production method 2-3.
  • R 7 represents an optionally substituted lower alkyl, aralkyl, aryl, alkoxy, cycloalkyloxy or aralkyloxy group; R 2 and R 3 have the same meaning as described above.
  • the compound of the general formula [le] can be produced by reacting the compound of the general formula [la] with a reactive derivative in the presence or absence of a base.
  • This reaction may be carried out according to production method 2-2.
  • a salt thereof can also be used, and examples of the salt include the same salts as those described for the compound of the general formula [1].
  • the compound of the general formula [2] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
  • Examples of the compound of the general formula [8] include, for example, 4 cyanophenol and 4-cyanol 3 Examples include fluorophenol.
  • the compound of the general formula [7] can be produced by reacting the compound of the general formula [6] with the compound of the general formula [8] in the presence or absence of a base and then deprotecting the compound. .
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • N N Amides such as dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane
  • Aromatics such as benzene, toluene, and xylene Hydrocarbons
  • ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether
  • -tolyls such as acetonitrile
  • sulfoxy such as dimethyl sulfoxide S
  • ketones such as acetone and 2-butanone
  • esters such as acetic Echiru
  • hetero aromatics and water
  • Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium metoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, hydrogen carbonate Examples thereof include inorganic bases such as sodium, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as triethylamine, N, N diisopropylethylamine and pyridine.
  • metal alkoxides such as sodium methoxide, sodium metoxide, potassium tert butoxide and sodium tert butoxide
  • sodium hydroxide potassium hydroxide
  • hydrogen carbonate examples thereof include inorganic bases such as sodium, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as triethylamine, N, N diisopropylethylamine and pyridine.
  • the amount of the base used may be 1 to 10 times mol, preferably 1 to 3 times mono to the compound of the general formula [6].
  • the amount of the compound of general formula [8] used in this reaction is 1 for the compound of general formula [6].
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 1 minute to 24 hours.
  • the removal of the amino protecting group represented by R 8 is, for example, protected group in organic synthesis, brother 3fe, 494: If you follow the method described on page 653, 1999, etc. or a method similar to it.
  • the compound of the general formula [2] can be produced by reacting the compound of the general formula [7] with the compound of the general formula [9]. This reaction may be performed according to production method A-1.
  • the compound of the general formula [11] can be produced, for example, by using 4-piperidinemethanol as a raw material and combining known methods.
  • the compound of the general formula [10] can be produced by reacting the compound of the general formula [9] with the compound of the general formula [11], followed by deprotection. This reaction may be performed according to production method A-1.
  • the compound of the general formula [12] can be produced by converting the hydroxyl group of the compound of the general formula [10] into a leaving group by a conventional method.
  • the compound of the general formula [10] can be prepared in the presence or absence of a base, for example, methane sulfol chloride.
  • a base for example, methane sulfol chloride.
  • the reaction may be carried out with an arylsulfuric chloride such as alkanesulfochloride or p-toluenesulfonic acid chloride.
  • Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, hydrogen carbonate Examples thereof include inorganic bases such as sodium, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as triethylamine, N, N diisopropylethylamine and pyridine.
  • metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert butoxide and sodium tert butoxide
  • sodium hydroxide potassium hydroxide
  • hydrogen carbonate examples thereof include inorganic bases such as sodium, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as triethylamine, N, N diisopropylethylamine and pyridine.
  • the amount of the alkylsulfonyl chloride or arylsulfuryl chloride and the base used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [10].
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 1 minute to 24 hours.
  • the leaving group is a halogen atom
  • the compound of the general formula [10] can be converted to, for example, a salt of sodium chloride, thionyl bromide, boron tribromide and carbon tetrabromide trif-phosphine. You can react with them.
  • the amount of these reagents to be used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [10].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone Amides such as; Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Dioxane, Tetrahydrofuran, Carsol, Diethylene glycol dimethyl ether, Diethylene glycol jetyl Ether and ethylene glycol
  • ethers such as coal monomethyl ether; -tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide, and heteroaromatics such as pyridine. These may be used as a mixture.
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 1 minute to 24 hours.
  • the compound of the general formula [2] can be produced by reacting the compound of the general formula [12] with the compound of the general formula [8]. This reaction may be performed according to production method A-1.
  • Examples of the compound of the general formula [13] include 4 cyanophanol and 4-cyanol 3 —Fluorophenol and the like.
  • Examples of the compound of the general formula [15] include 3 bromo-1 propanol.
  • the compound of the general formula [14] can be produced by reacting the compound of the general formula [13] with the compound of the general formula [15]. This reaction may be performed according to production method A-1.
  • the compound of the general formula [9] can be produced by converting the hydroxyl group of the compound of the general formula [14] into a leaving group. This reaction may be performed according to production method B-2.
  • excipients and carriers usually used for formulation can be mixed with formulation adjuvants such as diluents, etc. according to conventional methods.
  • Tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, liquids, powders It can be administered orally or parenterally in the form of suppositories, suppositories, eye drops, nasal drops, ear drops, patches, ointments or injections.
  • the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, 0.01 to 1000 mg / kg is divided into several doses once a day by oral or parenteral (eg injection, infusion, rectal administration, etc.) It should be administered once a day.
  • Example 6 The compound of Example 6 was selected as the compound of the present invention.
  • a comparative compound the compound described in the example of WO03 / 074476, which has the most similar structure to the compound of the present invention, was selected. Their chemical structural formulas are shown below.
  • the susceptibility test against fungi was performed using a micro liquid dilution method.
  • RPMI1640 RPMI / MOPS adjusted to PH 7.0 with 0.165 mol / L morpholine propanesulfonic acid (MOPS) and 1.0 mol / L sodium hydroxide was used as the medium for the sensitivity test.
  • Test substances were dissolved in sterile water and diluted 2-fold serially with 100 L RPMI / MOPS on 96-well round bottom plates.
  • Candida albicans TIMM1623 cultured in Sabouraud agar at 35 ° C overnight was suspended in sterile physiological saline.
  • Example 6 The compound of Example 6 was stronger than the comparative compound and showed antifungal activity.
  • Example 6 The compound of Example 6 was selected as the compound of the present invention.
  • a comparative compound the compound described in the example of WO03 / 074476, which has the most similar structure to the compound of the present invention, was selected. Their chemical structural formulas are shown below.
  • Red blood cell count 2-angle laser flow cytometry
  • Reticulocyte flow cytometry by RNA staining
  • Example 6 had higher safety than the comparative compound that did not reduce the reticulocyte count.
  • Example 3 The compound of Example 3 was selected as the compound of the present invention.
  • a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 074476. Their chemical structural formulas are shown below.
  • Red blood cell count 2-angle laser flow cytometry
  • Reticulocyte flow cytometry by RNA staining
  • the comparative compound decreased the reticulocyte count at the dose of 3.13 mg / kg.
  • the compound of Example 3 was much safer than the comparative compound that did not decrease the reticulocyte count even at the dose of 6.25 mg / kg.
  • Example 6 The compound of Example 6 was selected as the compound of the present invention.
  • a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 074476. Their chemical structural formulas are shown below.
  • Vero cells Compound cytotoxicity was assessed using Vero cells. Each test substance was dissolved in dimethyl sulfoxide (DMSO), serially diluted with E'MEM containing 10% FBS, and added to a 96-well plate. The cells were suspended in E'MEM supplemented with 10% FBS, inoculated with 3000 cells / well (96 well plate), and cultured in a CO incubator at 37 ° C for 3 days. The degree of growth of Vero cells
  • Example 10 The compound of Example 10 was selected as the compound of the present invention.
  • a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 0 74476. Their chemical structural formulas are shown below.
  • Example 10 The compound of Example 10 and the comparative compound were stored for one week under conditions of room temperature and relative humidity of 75%. As a result, the compound of Example 10 was a powder with no change in appearance. On the other hand, the comparative compound changed into a paste.
  • the compound of Example 10 had higher stability than the comparative compound.
  • Example 10 The compound of Example 10 was selected as the compound of the present invention.
  • a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 0 74476. Their chemical structural formulas are shown below.
  • HCI salt The compound of Example 10 and the comparative compound were stored for 10 days under conditions of room temperature and 75% relative humidity, and the weight was measured. The results are shown in Table 5.
  • Example 10 did not absorb moisture at all, and had higher stability than the comparative compound.
  • the antiprotozoal activity of the compound of Example 6 was measured.
  • Trichomonas vaginalis CDC337 is cultured with Diamond's trypticase-yeast-maltose medium (pH6.8) containing 8% fetal Bovine Serum (FBS). It was. 3 Centrifuge the worms cultured at 7 ° C for 2 days (1500 rpm, 10 minutes), change the medium with fresh medium, adjust to 2 X 10 4 worms / mL, and add 100 ⁇ L / well to the microplate (96 Dispensing into holes, flat bottom). The test substance was dissolved in sterilized distilled water, diluted to a predetermined concentration in the medium, and 100 L / well was dispensed onto a microplate. After culturing at 37 ° C under anaerobic conditions for 2 days, the minimum test substance concentration at which no insect movement was observed was defined as MIC.
  • the MIC of the compound of Example 6 was g / mL.
  • Example 37 The compound of Example 37 was selected as the compound of the present invention. Its chemical structural formula is shown below.
  • Candida albicans TIMM1 623 on an SDA plate cultured overnight at 35 ° C was suspended in sterile physiological saline and diluted to prepare an inoculum.
  • cyclophosphamide 200 mg / kg 4 days before infection and cyclophosphamide 100 mg / kg intraperitoneally the day after infection Administered.
  • Suspend the test substance in 0.5% methylcellulose Mice were orally administered at 0.57 mol / kg. Treatment began 7 hours after infection and lasted for 7 days. The number of surviving mice was observed and recorded for 8 days after infection.
  • the compound of Example 37 showed an excellent therapeutic effect even after oral administration.
  • the compounds of the present invention had much superior antifungal activity than the comparative compounds.
  • the compound of the present invention did not decrease the reticulocyte count and had higher safety than the comparative compound.
  • the comparative compound was hygroscopic and difficult to control the quality, but the compound of the present invention was not hygroscopic and was far superior to the comparative compound as an active pharmaceutical ingredient. . Further, the compound of the present invention showed an excellent effect against protozoa.
  • the mixing ratios in the eluent are all volume ratios, and B.W.silica gel and BW-127ZH (Fuji Silicon Chemical Co., Ltd.) were used as the carriers in column chromatography unless otherwise specified.
  • tert-Butyl 4 (Bromomethyl) 1-piperidinecarboxylate 0.75 g of 2-butanone in 7.5 mL was charged with 0.56 g of potassium carbonate and 0.32 g of 4 cyanophenol at room temperature and heated to reflux for 4 hours. After adding 3.0 mL of 2-butanone, the mixture was further heated under reflux for 1.5 hours. After cooling to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue It was dissolved in ethyl acetate, washed successively with 10% aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • tert butyl 4 [(4-cyanophenoxy) methyl] 1-piperidinecarboxylate 0.45 g of Kuroguchi form in 4.5 mL solution was prepared at room temperature with 1 mL of trifluoroacetic acid. The mixture was stirred at the same temperature for 2 hours, and the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue and the solvent was distilled off under reduced pressure, and then the same operation was repeated. To the obtained residue, black mouth form and water were added, and the pH was adjusted to 13.0 with a 5.0 mol / L aqueous sodium hydroxide solution.
  • tert Butyl 4 (Bromomethyl) 1-piperidinecarboxylate 6.40 g of dimethyl sulfoxide in 52 mL solution was charged with 4.77 g of potassium carbonate and 3.15 g of 2 fluoro-4-hydroxybenzo-tolyl at room temperature, and stirred at 40 ° C for 18 hours. did.
  • the reaction mixture was added to a mixture of ethyl acetate and ice water. Separate the organic layer, add water, and adjust to pHll.O with potassium carbonate. It was adjusted. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by reversed-phase silica gel column chromatography [silica gel; YDS ODS-A, eluent; water], and the resulting white solid was dissolved in water to give 5.0 mol / L hydroxy acid.
  • the pH was adjusted to 12.5 with sodium hydroxide aqueous solution.
  • the solid product was collected by filtration to obtain 0.16 g of 4-solid solid (4- ⁇ [1— (3— ⁇ 4— [amino (imino) methyl] phenoxy ⁇ pill) -4-piberidyl] methoxy ⁇ benzamidine. It was.
  • the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by reversed-phase silica gel column chromatography [silica gel; YDS ODS-A, eluent: water]. .
  • the obtained white solid was dissolved in water and adjusted to pH 3.0 with a 5.0 mol / L aqueous sodium hydroxide solution. The solid was collected by filtration, and the white solid 4— ⁇ 3— [4— ( ⁇ 4— [amino-imino] methyl] phenoxy ⁇ methyl) — 1-piveridyl-propoxy ⁇ — 2-fluorbenzenes 0.12 g of amidine was obtained.
  • the obtained residue was dissolved in water and adjusted to PH13.0 with a 3.0 mol / L aqueous sodium hydroxide solution.
  • the solid was collected by filtration to obtain 3.80 g of 4 ⁇ [1— (3— ⁇ 4— [amino (imino) methyl] phenoxy ⁇ propyl) 4 piberidyl] methoxy ⁇ 2 fluoro oral benzamidine as a pale yellow solid. .
  • 2-Fluorobenzamide O Acetyloxime 2.78 g of 2 propanol and 8 mL To a suspension of 8 mL of water, 0.30 g of 5% palladium carbon and 3 mL of formic acid were added at room temperature, followed by stirring at 25 to 35 ° C. for 3 hours and 50 minutes. Acetic anhydride at 25 ° C 0.3 mL and 1 mL of formic acid were added, and the mixture was stirred at 20 to 25 ° C. for 1 hour and 15 minutes.
  • the solvent was distilled off under reduced pressure, and black residue was added to the resulting residue to obtain a 1.0 mol / L aqueous sodium hydroxide solution.
  • the solution was adjusted to pHIO.
  • the organic layer was separated, washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the solvent was distilled off under reduced pressure, and chloroform was added to the obtained residue, and the pH was adjusted to 1.0 with 1.0 mol / L sodium hydroxide aqueous solution.
  • the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the solvent was distilled off under reduced pressure, and chloroform, formaldehyde, 2-propanol and saturated aqueous sodium hydrogen carbonate solution were added to the resulting residue under ice cooling.
  • the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the organic layer was separated, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • H9'S f'P'HS) 06'S '(ra'HS) S6 — S8' C "'HS) — 8S' ( ⁇ ' ⁇ ) 86 ⁇ ⁇ — ⁇ 8 ⁇ ⁇ '( ⁇ ' ⁇ ) 08 ⁇ ⁇ —
  • Example 4 500 mg of the compound obtained in Example 4, 350 mg of lactose, 250 mg of corn starch, and 400 mg of crystalline cellulose [Product name: Cerath PH101: Asahi Kasei Chemicals] were mixed and kneaded with 0.6 mL of 5% hydroxypropylcellulose aqueous solution and water. Combined. The obtained mixture was dried at 60 ° C. and then mixed with 100 mg of crospovidone [trade name: Kollidon CL: BASF], 10 mg of light anhydrous silicic acid lOO mg and 20 mg of magnesium stearate. 175 mg of the mixture was tableted as a round tablet with a diameter of 8 mm to obtain a tablet.
  • crospovidone trade name: Kollidon CL: BASF
  • Example 4 The compound obtained in Example 4 (500 mg), lactose (200 mg) and corn starch (530 mg) were mixed, and kneaded with 0.6% 5% hydroxypropylcellulose aqueous solution and water. After the resulting mixture was dried at 60 ° C, 70 mg of crospovidone [trade name: Kollidon CL: BASF], 180 mg of crystalline cellulose [trade name: Cerath PH302: Asahi Kasei Chemicals] and 20 mg of magnesium stearate were collected. Mixed. 150 mg of the mixture was filled into a No. 3 gelatin capsule to obtain a capsule.
  • Example 10 0.89 g of the compound obtained in Example 10 and 31.5 g of sodium chloride salt were dissolved in water for injection to make the total volume 3.5L. The solution is filtered through a 0.22 m membrane filter and the resulting drug solution 1 An ampule was filled with OmL and sealed, and then steam sterilized to obtain an injection.
  • the compound of the present invention has a strong activity against fungi including azole drug-resistant fungi, and further has high safety and excellent physical properties in repeated dose toxicity tests, so it is useful as an excellent antifungal agent. .

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Abstract

Cette invention a trait à un dérivé d’arylamidine représenté par la formule générale (R1 représentant facultativement l’amidino protégé ou substitué ; et R2 et R3 sont égaux ou différents et chacun représente un hydrogène ou un halogène) ou un sel du dérivé. Le dérivé et le sel possèdent une excellente activité contre les champignons y compris ceux affichant une tolérance aux médicaments à base d’azole et présentent également un degré élevé de sécurité et d’excellentes propriétés dans un test de toxicité à doses répétées. Ils sont donc extrêmement utiles en tant qu’antifongiques. En outre, ils présentent une activité excellente contre les protozoaires et sont donc également utiles en tant qu’agents anti-protozoaires.
PCT/JP2005/013702 2004-07-28 2005-07-27 Nouveau dérivé d’arylamidine, sel de celui-ci et antifongique contenant celui-ci WO2006011499A1 (fr)

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EP2070536A1 (fr) * 2006-10-06 2009-06-17 Toyama Chemical Co., Ltd. Composition pharmaceutique contenant un dérivé de phénylamidine et procédé d'utilisation de la composition pharmaceutique combinée à un agent antifongique
WO2012043701A1 (fr) * 2010-09-30 2012-04-05 富山化学工業株式会社 Préparation pour absorption transdermique
WO2015087857A1 (fr) * 2013-12-10 2015-06-18 日本曹達株式会社 Composé d'arylamidine et agent bactéricide
AU2009209564B2 (en) * 2008-02-01 2015-07-02 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Amino acid derivatives used as pharmaceutical substances
WO2016047550A1 (fr) * 2014-09-24 2016-03-31 日本曹達株式会社 Fongicide agricole et horticole contenant un composé d'arylamidine
JPWO2016195077A1 (ja) * 2015-06-03 2018-02-01 日本曹達株式会社 グアニジン化合物および殺菌剤
CN108299239A (zh) * 2018-02-23 2018-07-20 广州同隽医药科技有限公司 一种1，6-（对脒基苯基）己二醚新的合成方法

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JPH04295470A (ja) * 1991-03-22 1992-10-20 Wakamoto Pharmaceut Co Ltd モノアミンオキシダーゼ−ｂ酵素阻害活性を有する１，２，４−オキサジアゾール誘導体及びその製造法
WO2003074476A1 (fr) * 2002-03-06 2003-09-12 Toyama Chemical Co., Ltd. Nouveau derive d'arylamidine ou sel de celui-ci
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GB868552A (en) * 1957-12-03 1961-05-17 Wellcome Found Improvements in or relating to novel amidines and the preparation thereof
JPS4936650A (fr) * 1972-08-09 1974-04-05
JPH04295470A (ja) * 1991-03-22 1992-10-20 Wakamoto Pharmaceut Co Ltd モノアミンオキシダーゼ−ｂ酵素阻害活性を有する１，２，４−オキサジアゾール誘導体及びその製造法
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TIDWELL R.R. ET AL: "Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia", J. MED. CHEM., vol. 33, no. 4, 1990, pages 1252 - 1257, XP000644781 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2070536A1 (fr) * 2006-10-06 2009-06-17 Toyama Chemical Co., Ltd. Composition pharmaceutique contenant un dérivé de phénylamidine et procédé d'utilisation de la composition pharmaceutique combinée à un agent antifongique
EP2070536A4 (fr) * 2006-10-06 2010-02-10 Toyama Chemical Co Ltd Composition pharmaceutique contenant un dérivé de phénylamidine et procédé d'utilisation de la composition pharmaceutique combinée à un agent antifongique
US8173157B2 (en) 2006-10-06 2012-05-08 Toyama Chemical Co., Ltd. Pharmaceutical composition comprising phenylamidine derivative and method of using the pharmaceutical composition in combination with antifungal agent
AU2009209564B2 (en) * 2008-02-01 2015-07-02 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Amino acid derivatives used as pharmaceutical substances
WO2012043701A1 (fr) * 2010-09-30 2012-04-05 富山化学工業株式会社 Préparation pour absorption transdermique
WO2015087857A1 (fr) * 2013-12-10 2015-06-18 日本曹達株式会社 Composé d'arylamidine et agent bactéricide
JPWO2015087857A1 (ja) * 2013-12-10 2017-03-16 日本曹達株式会社 アリールアミジン化合物および殺菌剤
WO2016047550A1 (fr) * 2014-09-24 2016-03-31 日本曹達株式会社 Fongicide agricole et horticole contenant un composé d'arylamidine
JPWO2016195077A1 (ja) * 2015-06-03 2018-02-01 日本曹達株式会社 グアニジン化合物および殺菌剤
US10111437B2 (en) 2015-06-03 2018-10-30 Nippon Soda Co., Ltd. Substituted guanidines as fungicides
CN108299239A (zh) * 2018-02-23 2018-07-20 广州同隽医药科技有限公司 一种1，6-（对脒基苯基）己二醚新的合成方法
WO2019161705A1 (fr) * 2018-02-23 2019-08-29 广州同隽医药科技有限公司 Nouveau procédé de synthèse de diéther de 1,6-(p-amidinophényl)hexyle

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