WO2014119617A1 - Composé amidine et sel de celui-ci - Google Patents

Composé amidine et sel de celui-ci Download PDF

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Publication number
WO2014119617A1
WO2014119617A1 PCT/JP2014/051966 JP2014051966W WO2014119617A1 WO 2014119617 A1 WO2014119617 A1 WO 2014119617A1 JP 2014051966 W JP2014051966 W JP 2014051966W WO 2014119617 A1 WO2014119617 A1 WO 2014119617A1
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group
optionally substituted
substituted
methyl
added
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PCT/JP2014/051966
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Japanese (ja)
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正弘 竹林
康裕 筒井
歩夢 森
加藤　智也
宣知 藤野
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富山化学工業株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to a novel amidine compound having an antifungal activity or a salt thereof, and an antifungal agent containing them.
  • Non-patent Document 1 Serious deep mycosis such as invasive candidiasis is often a fatal disease.
  • the main defense mechanism on the host organism side against fungi such as Candida is considered to be due to non-specific immunity by neutrophils. If this defense mechanism is functioning normally, there is little risk of infection with fungi.
  • the number of patients with underlying diseases such as malignant tumors and AIDS that cause a decline in the immune function of this living body, frequent use of anticancer drugs and immunosuppressants, heavy use of antibacterial antibiotics and steroid hormones, and long-term focus
  • amphotericin B has a very strong bactericidal action, but has side-effects such as nephrotoxicity and is limited in clinical use. Since flucytosine has problems such as resistance, it is rarely used alone at present. Caspofungin and Micafungin are weakly active against the genus Cryptococcus.
  • Non-Patent Document 2 All other drugs are collectively referred to as azole antifungal agents, and their bactericidal action tends to be generally inferior to that of amphotericin B, but is currently most frequently used due to the balance between efficacy and safety.
  • Non-patent Document 3 The problem of resistance has a serious impact on the management of patients with deep mycosis, which is steadily increasing (Non-patent Document 3).
  • onychomycosis caused by ringworm is a kind of superficial mycosis and is an intractable disease that requires 3 to 6 months for its treatment.
  • itraconazole and terbinafine are used for the treatment.
  • both drugs cannot be said to have a sufficient cure rate, and recurrence has been observed (Non-patent Documents 4 and 5).
  • Terbinafine must be taken every day for 6 months, and it has been pointed out that medication compliance is poor due to long-term administration (Non-patent Document 6).
  • side effects were observed in approximately 10% or more of both drugs, and abnormal laboratory values such as liver function test values were confirmed in about 5% of patients.
  • Itraconazole is known to show drug interactions with many other drugs.
  • amidine compounds of the present invention or salts thereof having antifungal activity against pathogenic fungi, and antifungal agents containing them have never been known so far.
  • An object of the present invention is to provide a novel compound that exhibits excellent antifungal activity against pathogenic fungi including Candida, Aspergillus, and ringworm, and is useful as a pharmaceutical.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2- 6 alkenyl group, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, optionally substituted A C 1-6 alkylamino group, an optionally substituted di (C 1-6 alkyl) amino group, an optionally substituted C 1-6 alkylthio group, an optionally substituted aryloxy group, a substituted Arylthio group which may be substituted, aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic heterocyclic group which may be substituted, protected Good amino group, An optionally
  • Z 1 and Z 2 are the same or different and are each a nitrogen atom or a general formula CR c wherein R c is a hydrogen atom, a halogen atom, a cyano group, a nitro group, or an optionally substituted C 1-6 alkyl.
  • R 1 and R 2 are the same or different and are each a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a substituted An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkylamino group , An optionally substituted di (C 1-6 alkyl) amino group, an optionally substituted C 1-6 alkylthio group, an optionally substituted aryloxy group, an optionally substituted arylthio group, Aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic heterocyclic group which may be substituted, amino group which may be protected, protected May A hydroxyl group or an
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2 ⁇ A 6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted monocyclic heterocyclic group; or An optionally substituted cyclic amino group formed by R 4 and R 5 together with the nitrogen atom to which they are attached;
  • X 1 is a sulfur atom, a methylene group, or a group represented by the general formula NR a , wherein R a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group or an imino protecting group.
  • Z 1 and Z 2 are the same or different and are a nitrogen atom or a group represented by the formula CH;
  • the compound represented by the general formula [1] or a salt thereof has excellent antifungal activity and is useful as an antifungal agent.
  • the compound represented by the general formula [1] or a salt thereof is excellent in safety and is useful as an antifungal agent against Candida, Aspergillus, and Trichophyton.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl group means, for example, linear or branched C 1 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups.
  • -6 means an alkyl group.
  • the C 1-6 alkylene group means a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups.
  • C 2-6 alkenyl group means, for example, linear or branched C 2-6 alkenyl such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups Means a group.
  • C 2-6 alkynyl group for example, ethynyl, propynyl, butynyl, straight or branched C 2-6 alkynyl group such as pentynyl and hexynyl groups.
  • C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • An aryl group means, for example, a phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl, benzocycloheptyl, dihydro-5H-benzocycloheptenyl or 5H-benzocycloheptenyl group.
  • the Al C 1-6 alkyl group for example, refers to a benzyl, diphenylmethyl, trityl, Al C 1-6 alkyl groups such as phenethyl and naphthylmethyl groups.
  • C 1-6 alkoxy group means, for example, linear or branched C groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups Means a 1-6 alkyloxy group;
  • the al C 1-6 alkoxy group means an al C 1-6 alkyloxy group such as benzyloxy, phenethyloxy and naphthylmethyloxy groups.
  • An aryloxy group means, for example, a phenoxy or naphthyloxy group.
  • the C 1-6 alkoxy C 1-6 alkyl group means, for example, a C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
  • the ar C 1-6 alkoxy C 1-6 alkyl group means an ar C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl groups.
  • the C 2-12 alkanoyl group for example, means acetyl, propionyl, valeryl, a linear or branched C 2-12 alkanoyl group such as isovaleryl and pivaloyl groups.
  • An aroyl group means, for example, a benzoyl or naphthoyl group.
  • the heterocyclic carbonyl group means, for example, nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
  • the ( ⁇ -substituted) aminoacetyl group is, for example, an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine. , Phenylalanine, tyrosine, tryptophan, proline and hydroxyproline and the like.)
  • the N-terminus derived from ( ⁇ -substituted) aminoacetyl group may be protected.
  • Acyl group means, for example, formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C 2-12 alkanoyl group, aroyl group, heterocyclic carbonyl group or ( ⁇ -substituted) aminoacetyl group.
  • Acyl C 1-6 alkyl group for example, means an acyl C 1-6 alkyl group such as acetyl, methyl, benzoyl methyl and 1-benzoyl ethyl.
  • acyloxy C 1-6 alkyl group for example, means acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, a benzoyloxy methyl and 1- acyloxy C 1-6 alkyl group such as (benzoyloxy) ethyl.
  • C 1-6 alkoxycarbonyl group means, for example, linear or branched C 1-6 such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl groups.
  • the al C 1-6 alkoxycarbonyl group means an al C 1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.
  • An aryloxycarbonyl group means, for example, a phenyloxycarbonyl or naphthyloxycarbonyl group.
  • the C 1-6 alkylamino group is, for example, a linear or branched group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino groups. It means a branched C 1-6 alkylamino group.
  • di (C 1-6 alkyl) amino group examples include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl)
  • linear or branched di (C 1-6 alkyl) amino groups such as amino and (methyl) (propyl) amino groups are meant.
  • the C 1-6 alkylthio group means, for example, a C 1-6 alkylthio group such as methylthio, ethylthio and propylthio groups.
  • An arylthio group means, for example, a phenylthio or naphthylthio group.
  • the C 1-6 alkylsulfonyl group means, for example, a C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.
  • An arylsulfonyl group means, for example, a benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
  • the C 1-6 alkylsulfonyloxy group means a C 1-6 alkylsulfonyloxy group such as methylsulfonyloxy, trifluoromethylsulfonyloxy and ethylsulfonyloxy groups.
  • the arylsulfonyloxy group means, for example, benzenesulfonyloxy or p-toluenesulfonyloxy group.
  • a silyl group means, for example, a trimethylsilyl, triethylsilyl or tributylsilyl group.
  • Monocyclic nitrogen-containing heterocyclic groups include, for example, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, dihydropyrrolyl, piperidyl, tetrahydropyridyl, pyridyl, homopiperidinyl, octahydroazosinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, It means a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring, such as pyrazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazinyl, triazolyl and tetrazolyl groups.
  • the monocyclic oxygen-containing heterocyclic group means, for example, a tetrahydrofuranyl, furanyl, tetrahydropyranyl or pyranyl group.
  • the monocyclic sulfur-containing heterocyclic group means, for example, a thienyl group.
  • the monocyclic nitrogen-containing / oxygen heterocyclic group is, for example, a monocyclic nitrogen-containing / oxygen containing only a nitrogen atom and an oxygen atom as hetero atoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl and morpholinyl groups. Means a heterocyclic group.
  • a monocyclic nitrogen-containing / sulfur heterocyclic group forms the ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups
  • the monocyclic heterocyclic group is a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, or a monocyclic nitrogen-containing / oxygen heterocyclic group. It means a group or a monocyclic nitrogen-containing / sulfur heterocyclic group.
  • Bicyclic nitrogen-containing heterocyclic groups include, for example, indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, Bicyclic nitrogen-containing heterocyclic groups containing only a nitrogen atom as a hetero atom forming the ring, such as quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups Means.
  • bicyclic oxygen-containing heterocyclic group examples include 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3- It means a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a hetero atom forming the ring, such as benzodioxanyl and 1,4-benzodioxanyl groups.
  • the bicyclic sulfur-containing heterocyclic group is, for example, a bicyclic sulfur-containing heterocyclic ring containing only a sulfur atom as a hetero atom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups.
  • Bicyclic nitrogen-containing / oxygen heterocyclic groups include, for example, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl and dihydropyridyl.
  • Bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as a dooxazinyl group.
  • Bicyclic nitrogen-containing / sulfur heterocyclic groups are, for example, bicyclic compounds containing nitrogen and sulfur atoms as hetero atoms forming the ring such as benzothiazolyl, benzisothiazolyl and benzothiadiazolyl groups. This means a nitrogen-containing / sulfur heterocyclic group.
  • a bicyclic heterocyclic group is a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, or a bicyclic nitrogen-containing group. -An oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group.
  • the heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.
  • Cyclic amino groups include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, thiazolinyl, thiazolidinyl, dihydrothiadiazyl, Including one or more nitrogen atoms as a hetero atom forming the ring, such as homomorpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzomorpholinyl, dihydropyridoxazinyl and quinuclidinyl, Means a 3-, 4-, 5-, 6- or 7-membered, fused or bridged cyclic amino group which may contain one or more oxygen or sulfur
  • Amino protecting groups and imino protecting groups include all groups that can be used as protecting groups for conventional amino and imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.
  • Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-299, 2007, John Wiley & Sons (John Wiley & Sons, INC.).
  • a C 1-6 alkyl group a C 2-6 alkenyl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an ar C 1-6 alkoxy C 1- 1 6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, al C 1-6 alkoxycarbonyl group, C 1-6 alkylsulfonyl group, arylsulfonyl group, silyl group, tetrahydrofuranyl group or tetrahydropyranyl group .
  • the carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-643, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an ar C 1-6 alkoxy C 1 Examples include a -6 alkyl group, an acyl C 1-6 alkyl group, an acyloxy C 1-6 alkyl group, and a silyl group.
  • Examples of the leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group or an arylsulfonyloxy group.
  • Examples of the aliphatic hydrocarbons include pentane, hexane, cyclohexane, and decahydronaphthalene.
  • Examples of halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.
  • Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol, and 2-methyl-2-propanol.
  • Examples of ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.
  • ketones include acetone, 2-butanone, and 4-methyl-2-pentanone.
  • esters include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate.
  • amides include N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
  • aromatic hydrocarbons include benzene, toluene, and xylene.
  • Substituent group A1 Halogen atom, a cyano group, a nitro group, one or more C 1-6 alkyl carbamoyl group which may be substituted with a group, optionally substituted with one or more groups selected from Substituent Group A2 C 1 A -6 alkoxy group, a C 1-6 alkylamino group optionally substituted with one or more groups selected from Substituent Group A2, and a substituent substituted with one or more groups selected from Substituent Group A2 A good di (C 1-6 alkyl) amino group, an aryl group which may be substituted with one or more groups selected from Substituent Group B1, and one or more groups selected from Substituent Group B1 A monocyclic heterocyclic group which may be substituted, a bicyclic heterocyclic group which may be substituted with one or more groups selected from substituent group B1, an amino group which may be protected, a protected group Optionally imino groups, optionally protected hydro A xyl
  • Substituent group A2 A halogen atom, a cyano group, a carbamoyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, an optionally protected amino group, an optionally protected hydroxyl group, and an optionally protected carboxyl group;
  • Substituent group B1 A halogen atom, a cyano group, a nitro group, an oxo group, a carbamoyl group that may be substituted with one or more C 1-6 alkyl groups, and a substituent that is substituted with one or more groups selected from Substituent Group A2.
  • Substituent group C1 A halogen atom, a cyano group, a nitro group, an oxo group, a carbamoyl group that may be substituted with one or more C 1-6 alkyl groups, and a substituent that is substituted with one or more groups selected from Substituent Group A2.
  • a C 1-6 alkylamino group which may be substituted, a di (C 1-6 alkyl) amino group which may be substituted with one or more groups selected from the substituent group A2, and a substituent group A2.
  • C optionally substituted with one or more groups 1-6 alkylthio group
  • C 3-8 cycloalkyl group optionally substituted with one or more groups selected from substituent group C2, substituted with one or more groups selected from substituent group C2 Or an aroyl group, an al C 1-6 alkyl group which may be substituted with one or more groups selected from substituent group C2, and one or more groups selected from substituent group C2.
  • Substituent group C2 Substituted with one or more groups selected from a halogen atom, a cyano group, a nitro group, an oxo group, an adamantyl group, a carbamoyl group optionally substituted with one or more C 1-6 alkyl groups, and substituent group A2.
  • a C 1-6 alkyl group which may be substituted with one or more, a C 2-6 alkenyl group which may be substituted with one or more groups selected from substituent group A2, and one or more selected from substituent group A2
  • a C 2-6 alkynyl group which may be substituted with one group, a C 1-6 alkoxy group which may be substituted with one or more groups selected from substituent group A2, and a group selected from substituent group A2
  • Substituted with two or more groups A C 1-6 alkylamino group which may be optionally substituted with one or more groups selected from substituent group A2, and a di (C 1-6 alkyl) amino group which may be substituted with 1 or more groups selected from substituent group A2.
  • Substituent group D1 A halogen atom, a cyano group, a nitro group, an oxo group, a carbamoyl group that may be substituted with one or more C 1-6 alkyl groups, and a substituent that is substituted with one or more groups selected from Substituent Group A2.
  • a C 1-6 alkylamino group which may be substituted a di (C 1-6 alkyl) amino group which may be substituted with one or more groups selected from substituent group A2, and a substituent group B1 C optionally substituted with one or more groups 3-8 cycloalkyl group, amino group which may be protected, imino group which may be protected, hydroxyl group which may be protected, carboxyl group which may be protected.
  • the amino group and the C 1-6 alkylthio group may be substituted with one or more groups selected from the substituent group A1.
  • the C 3-8 cycloalkyl group, aryloxy group, arylthio group, aryl group, monocyclic heterocyclic group and bicyclic heterocyclic group represented by R 1 and R 2 are selected from the substituent group B1. It may be substituted with more than one group.
  • R 3 dihydrobenzocyclobutenyl, indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl, benzocycloheptyl, dihydro-5H-benzocycloheptenyl, 5H-benzocycloheptenyl, hexahydrobenzo
  • the cyclooctenyl group, tetrahydrobenzocyclooctenyl group, dihydrobenzocyclooctenyl group, tetrahydromethanonaphthyl group and tetrahydroethanonaphthyl group may be substituted with one or more groups selected from the substituent group C1.
  • the C 1-6 alkyl group, C 2-6 alkenyl group and C 2-6 alkynyl group of R 4 and R 5 may be substituted with one or more groups selected from the substituent group A1.
  • the C 3-8 cycloalkyl group, aryl group and monocyclic heterocyclic group of R 4 and R 5 may be substituted with one or more groups selected from substituent group B1.
  • the cyclic amino group of R 4 and R 5 may be substituted with one or more groups selected from the substituent group D1.
  • the C 1-6 alkyl group of R a may be substituted with one or more groups selected from Substituent Group A1.
  • the C 1-6 alkyl group of R b may be substituted with one or more groups selected from Substituent Group A1.
  • the C 1-6 alkylthio group may be substituted with one or more groups selected from Substituent Group A1.
  • the C 3-8 cycloalkyl group, aryloxy group, arylthio group, aryl group, monocyclic heterocyclic group and bicyclic heterocyclic group of R c are one or more selected from the substituent group B1. It may be substituted with a group.
  • preferable compounds include the following compounds.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or a substituted
  • the compound is an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group or an optionally substituted aryl group.
  • Compounds are preferred.
  • R 1 and R 2 are the same or different and are each a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted
  • a compound that is a compound having a C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, or an optionally substituted C 1-6 alkoxy group is more preferable. More preferred is a compound wherein R 1 and R 2 are the same or different and each is a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group.
  • R 1 and R 2 may be the same or different and each may be a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted More preferred are compounds that are good C 1-6 alkoxy groups.
  • R 1 and R 2 are the same or different and each is a halogen atom, a C 1-6 alkyl group which may be substituted with one or more halogen atoms, or C 3 which may be substituted with one or more halogen atoms Even more preferred are compounds that are -8 cycloalkyl groups.
  • R 3 is an optionally substituted dihydrobenzocyclobutenyl group, an optionally substituted indanyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted benzocycloheptyl group, a substituted
  • a compound which is an optionally substituted hexahydrobenzocyclooctenyl group or an optionally substituted tetrahydromethanonaphthyl group is preferred.
  • a compound in which R 3 is an optionally substituted indanyl group, an optionally substituted tetrahydronaphthyl group or an optionally substituted benzocycloheptyl group is more preferable.
  • R 3 is represented by the general formula [X] "Wherein R 6 is the same or different and is a group selected from substituent group C1; R 7 is the same or different and is a group selected from substituent group C1; n is an integer of 2 to 6 M1 represents an integer of 0 to 10; m2 represents an integer of 0 to 3. ”is more preferable.
  • m 1 R 6 s are the same or different and each is a halogen atom, a C 1-6 alkyl group which may be substituted with one or more groups selected from Substituent Group A2, or one selected from Substituent Group A2
  • a compound which is a C 1-6 alkoxy group which may be substituted with the above groups is preferred.
  • a compound in which m1 R 6 s are the same or different and each is a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group is more preferable.
  • m1 pieces of R 6 are the same or different, compounds which are C 1-6 alkyl group is more preferred.
  • m2 R 7 s are the same or different and each is a halogen atom, a C 1-6 alkyl group which may be substituted with one or more groups selected from Substituent Group A2, or one selected from Substituent Group A2
  • a compound which is a C 1-6 alkoxy group which may be substituted with the above groups is preferred.
  • a compound in which m 2 R 7 s are the same or different and each is a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group is more preferable.
  • a compound in which m1 represents an integer of 0 to 4 is preferable.
  • a compound in which m1 represents an integer of 0 to 2 is more preferable.
  • a compound in which m2 is 0 or 1 is preferable.
  • a compound in which m2 is 0 is more preferable.
  • n 3, 4 or 5 are preferred.
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2 ⁇
  • a compound which is a 6 alkynyl group or an optionally substituted C 3-8 cycloalkyl group is preferred.
  • a compound in which R 4 and R 5 are the same or different and each is a C 1-6 alkyl group which may be substituted with a hydrogen atom or one or more groups selected from substituent group A1 is more preferable. More preferred are compounds in which R 4 and R 5 are the same or different and are a hydrogen atom or a C 1-6 alkyl group.
  • a compound in which X 1 is a C 1-6 alkylene group or a group represented by the general formula NR a , wherein R a has the same meaning as described above is preferable. More preferred is a compound in which X 1 is a methylene group or a group represented by the general formula NR a1 , wherein R a1 represents a hydrogen atom or an imino protecting group. A compound in which X 1 is a methylene group is more preferable.
  • Z 1 and Z 2 are the same or different and is a group represented by the general formula CR c "wherein R c has the same meaning as described above" is preferable.
  • Z 1 and Z 2 may be the same or different and have the general formula CR c1 , wherein R c1 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, a substituted An optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group or a substituted group
  • the aryl group which may be made is a group represented by "is more preferable.
  • Z 1 and Z 2 are the same or different and have the general formula CR c2 "wherein R c2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 1
  • R c2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 1
  • a compound represented by the formula “ 3-8 cycloalkyl group” is more preferred.
  • Z 1 and Z 2 are the same or different and have the general formula CR c3 , wherein R c3 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may be substituted with one or more halogen atoms, or A compound having a group represented by “denotes a C 3-8 cycloalkyl group which may be substituted with one or more halogen atoms” is even more preferable. Most preferred are compounds wherein Z 1 and Z 2 are groups represented by the formula CH.
  • a compound in which Z 3 is a group represented by the general formula CR b "wherein R b has the same meaning as described above" is preferable.
  • a compound in which Z 3 is a group represented by the formula CH is more preferable.
  • preferable compounds include the following compounds.
  • R 1, R 2, two of Z 1 of R c and Z 2 of R c are the same or different, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, optionally substituted
  • a compound having an optionally substituted C 3-8 cycloalkyl group or an optionally substituted C 1-6 alkoxy group, and the other two being a hydrogen atom is preferable.
  • R 1, R 2, two of Z 1 of R c and Z 2 of R c are the same or different, substituted is also C 1-6 alkyl group, the other two are hydrogen atom
  • R 1 and R 2 are the same or different, a C 1-6 alkyl group, R c and Z 2 of R c of Z 1 is, compounds and more preferably a hydrogen atom.
  • preferable compounds include the following compounds. N ′-(5-Bromo-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl)- N-ethyl-N-methylimidoformamide, N ′-(5-cyclopropyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3- Thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalene-2) -Yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide
  • An antifungal agent means a substance capable of acting on a pathogenic fungus and suppressing or sterilizing its growth. It may be something that suppresses fungal growth or kills some fungi to reduce their number.
  • pathogenic fungi examples include yeast-like fungi, filamentous fungi, and zygomycetes.
  • yeast-like fungi include Candida (Candida albicans, Candida glabrata, Candida giermondii, Candida crusei, Candida parapsilosis, Candida tropicalis, etc.), Cryptococcus genus (such as Cryptococcus neoformans), Examples include the genus Malassezia (such as Malassezia fullfur) and the genus Trichosporon (such as Trichosporon and Asahi).
  • Aspergillus Aspergillus fumigatus, Aspergillus tereus, Aspergillus niger, Aspergillus flavus, etc.
  • Genus Fusarium such as Fusarium solani
  • genus Schedosporum such as skedosporum apiospermum
  • Microsporium such as Microsporum canis
  • Examples of the zygomycete include the genus Mucor (Mucor plum plumus, etc.), the genus Rhizopus (such as Rhizopus oryzae), and the genus Absidia (such as Absidia cholinebifera).
  • the antifungal agent of the present invention exhibits an excellent antifungal action against bacterial species such as Candida, Aspergillus and ringworm, and more excellent antifungal action against ringworm .
  • the antifungal agent of the present invention is a bacterial species such as Candida albicans, Aspergillus fumigatus, Trichophyton rubulum, Trichophyton mentagrophytes, Malassezia furfur, and Cryptococcus neoformans. Excellent antifungal activity.
  • the compound represented by the general formula [1] or a salt thereof exhibits excellent safety.
  • Safety is evaluated by various tests, for example, cytotoxicity test, hERG test, repeated dose toxicity test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, in vivo mouse micronucleus It can be evaluated by various safety tests selected from a test and an in vivo rat liver UDS test.
  • Examples of the salt of the compound represented by the general formula [1] include a salt of a commonly known basic group such as amino group or acidic group such as hydroxyl or carboxyl group.
  • salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid , Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid Is mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
  • Salts with organic carboxylic acids
  • Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
  • preferred salts include pharmacologically acceptable salts.
  • the present invention when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist, the present invention includes those isomers, It includes solvates, hydrates and crystals of various shapes.
  • the compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.
  • N-ethyl-N-methylformamide, N-methylformamide, and the like are known as compounds of the general formula [3].
  • the compound of the general formula [1] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [3] in the presence of an activator.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons and water, and these may be used as a mixture.
  • Preferable solvents include halogenated hydrocarbons.
  • Examples of the activator used in this reaction include oxalyl chloride, phosphoryl chloride and p-toluenesulfonyl chloride.
  • the amount of the activator used may be 1 to 20 times mol, preferably 1 to 5 times mol, of the compound of the general formula [2].
  • the amount of the compound of the general formula [3] used may be 1 to 20 times mol, preferably 1 to 5 times mol for the compound of the general formula [2].
  • This reaction may be carried out at ⁇ 50 to 200 ° C., preferably 0 to 50 ° C., for 10 minutes to 48 hours.
  • Compounds of general formula [5] include 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and 2-bromo-1- (2,3-dihydro-1H-indene- 5-yl) ethanone is known.
  • the compound of the general formula [1a] can be produced by reacting the compound of the general formula [4] with the compound of the general formula [5]. This reaction may be carried out by the method described in International Publication No. 05/115382 pamphlet and US Patent No. 20060052420 or a method based thereon.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons and water, and these may be used as a mixture.
  • Preferred solvents include alcohols.
  • the amount of the compound of the general formula [5] used may be 1 to 20 times mol, preferably 1 to 5 times mol for the compound of the general formula [4]. This reaction may be carried out at ⁇ 50 to 200 ° C., preferably 0 to 150 ° C., for 10 minutes to 48 hours.
  • the compound of the general formula [Ab] can be produced by reacting the compound of the general formula [Aa] with dithiophosphoric acid O, O′-diethyl or the like in the presence of an acid.
  • This reaction is the method described in WO 06/137658 and the Journal of Medicinal Chemistry, 1990, Vol. 33, p.2715-2720, or a similar method. Just do it.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons and water, and these may be used as a mixture.
  • Preferable solvents include esters.
  • acids used in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen chloride and hydrogen bromide; organic carboxylic acids such as acetic acid, trichloroacetic acid and trifluoroacetic acid; and methanesulfonic acid and Examples thereof include organic sulfonic acids such as p-toluenesulfonic acid.
  • a preferred acid is hydrogen chloride.
  • the amount of the acid used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [Aa].
  • the amount of dithiophosphoric acid O, O′-diethyl used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [Aa]. This reaction may be carried out at ⁇ 50 to 200 ° C., preferably 0 to 50 ° C., for 10 minutes to 48 hours.
  • the compound of the general formula [2a] can be produced by reducing the compound of the general formula [Ac]. This reaction was performed by Richard C. Richard C. Larock et al., Comprehensive Organic Transformations, 2nd edition, pages 823-827, 1999, John Wiley & Sons , INC.) Or a method similar thereto. Specific examples include a catalytic hydrogenation reaction using a metal catalyst and a reduction reaction using a metal such as iron or zinc.
  • the solvent used is not particularly limited as long as it does not adversely affect the reaction.
  • the metal catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metal such as Raney nickel; and platinum salts such as platinum oxide.
  • the amount of the metal catalyst used may be 0.001 to 5 times (w / w), preferably 0.01 to 1 times (w / w) of the compound of the general formula [Ac].
  • the hydrogen source include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene; and cyclohexadiene.
  • the amount of the hydrogen source used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [Ac]. This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.
  • the solvent used is not particularly limited as long as it does not adversely affect the reaction, but water, halogenated hydrocarbons, alcohols, Examples include ethers, ketones, esters, amides, aromatic hydrocarbons, nitriles such as acetonitrile, and water, and these may be used as a mixture.
  • the metal used in this reaction include iron, zinc, tin, and tin (II) chloride.
  • the amount of the metal used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [Ac].
  • Examples of the acid that is optionally used in this reaction include hydrogen chloride, hydrogen bromide, acetic acid, and ammonium chloride.
  • the amount of the acid used may be 0.001 to 100 times (v / w), preferably 0.01 to 20 times (v / w) of the compound of the general formula [Ac]. This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.
  • R d is a protected amino group
  • the compound of the general formula [2a] can be produced by deprotecting the amino protecting group of the compound of the general formula [Cc].
  • Deprotection of amino protecting groups is described, for example, in W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-868, 2007, John Wiley & Sons (John Wiley & Sons, INC.).
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons, sulfoxides such as dimethyl sulfoxide and water, and these may be used as a mixture.
  • a preferred solvent is dimethyl sulfoxide.
  • Examples of the base used in this reaction include organic bases such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, pyridine, dimethylaminopyridine and triethylamine; sodium hydride, sodium hydroxide, potassium hydroxide, Examples thereof include inorganic bases such as sodium hydrogen carbonate, potassium carbonate and sodium carbonate. Preferred bases include sodium hydroxide and potassium hydroxide.
  • the amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [Da].
  • the amount of the compound of the general formula [Db] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [Da]. This reaction may be carried out at ⁇ 50 to 200 ° C., preferably 0 to 50 ° C., for 10 minutes to 48 hours.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, aromatic hydrocarbons. Nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, and water, and these may be used as a mixture.
  • the amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [Ea].
  • the ligands optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphine such as triphenylphosphine and tritolylphosphine Trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1,3- Imidazolium salts such as bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetylacetate Diketones such as trimethylamine, triethylamine, trip
  • the palladium catalyst used in this reaction examples include metal palladium such as palladium-carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Bis (tri-tert-butylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, (E) -di ( ⁇ -Acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) and tris (dibenzylideneacetone) dipalladium (0) (II And polymer supported di (acetato) such as a polymer immobilized organopalladium complex such as dicyclohex
  • the amount of acrylonitrile used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [Ea]. This reaction is preferably carried out at 40 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, nitrogen, argon) atmosphere.
  • an inert gas eg, nitrogen, argon
  • the compound of the general formula [Caa] can be produced by reducing the compound of the general formula [Eb].
  • Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, aromatic hydrocarbons. , Nitriles such as acetonitrile, carboxylic acids such as acetic acid, heteroaromatics such as pyridine and water, and these may be used as a mixture.
  • Examples of the metal catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metals such as Raney nickel and platinum salts such as platinum oxide. It is done.
  • the amount of the metal catalyst used may be 0.001 to 5 times (w / w), preferably 0.01 to 1 times (w / w) of the compound of the general formula [Eb].
  • Examples of the reducing agent include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene and cyclohexadiene.
  • the amount of the reducing agent used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [Eb]. This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.
  • (F-1) As a compound of the general formula [Fa], ethyl cyanoacetate or methyl cyanoacetate is known.
  • the compound of the general formula [Fb] is produced by reacting the compound of the general formula [Ea] with the compound of the general formula [Fa] in the presence of a base, in the presence or absence of a ligand, and in the presence of a palladium catalyst. can do.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, aromatic hydrocarbons. Nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, and water, and these may be used as a mixture.
  • Examples of the base used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; organic bases such as triethylamine and diisopropylethylamine.
  • the amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [Ea].
  • the ligands optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphine such as triphenylphosphine and tritolylphosphine Trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1,3- Imidazolium salts such as bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetylacetate Diketones such as trimethylamine, triethylamine, trip
  • Examples of the palladium catalyst used in this reaction include metal palladium such as palladium-carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Bis (tri-tert-butylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride and tris (dibenzylideneacetone)
  • Organopalladium complexes such as dipalladium (0) and polymer-supported bis (acetate) triphenylphosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II)
  • the amount of the compound of the general formula [Fa] used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [Ea]. This reaction is preferably carried out at 40 to 170 ° C. for 1 minute to 96 hours in an inert gas (eg, nitrogen, argon) atmosphere.
  • an inert gas eg, nitrogen, argon
  • the compound of the general formula [Cab] can be produced by subjecting the compound of the general formula [Fb] to a decarboxylation reaction.
  • This reaction is carried out by a method known per se, for example, the method described in New Experimental Chemistry Course, Vol. 15, [II], edited by The Chemical Society of Japan, pages 808-811 (1977, Maruzen) or a method analogous thereto. Just do it.
  • a compound that can take the form of a salt can also be used as a salt.
  • examples of such salts include the same salts as the salts of the compound of the general formula [1].
  • a compound having a substituent that can be protected such as an amino group, a hydroxyl group, or a carboxyl group, is previously protected with a normal protecting group.
  • these protecting groups can be removed by a method known per se.
  • formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed.
  • excipients such as excipients, carriers and diluents usually used for formulation
  • these are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection.
  • 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, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg daily may be divided into 1 to several doses. Good.
  • Test Example The susceptibility test of fungi to the test substance was performed by a micro liquid dilution method according to the Clinical and Laboratory Standards Institute method.
  • the microplate was prepared by the following method.
  • the medium used for the sensitivity test was RPMI1640 (RPMI / MOPS) adjusted to pH 7.0 with 0.165 mol / L morpholinepropanesulfonic acid (MOPS) and 50% sodium hydroxide.
  • the test substance was dissolved in DMSO, diluted 2-fold serially with DMSO on a 96-well microplate, and then dispensed at 1 ⁇ L into a 96-well microplate.
  • Trichophyton rubrum NBRC 5467 stored at ⁇ 80 ° C. was diluted with RPMI / MOPS to prepare an inoculum (about 2 ⁇ 10 3 CFU / mL). 199 ⁇ L of the inoculum solution was dispensed into each well to prepare a microplate containing a predetermined concentration of the test substance, medium and cells. C. albicans and A. fumigatus were cultured at 35 ° C. for 2 days. T. rubrum was cultured at 35 ° C for 4 days. After completion of the culture, the MIC was visually determined. The MIC of C. albicans and A. fumigatus was the lowest concentration at which about 50% growth inhibition was observed compared to the growth control without addition of the test substance. The MIC of T. rubrum was set to the lowest concentration at which about 80% growth inhibition was observed compared to the growth control with no test substance added. The results are shown in Tables 1 to 3.
  • the carrier in silica gel column chromatography is Kanto Chemical Co., Inc., silica gel 60 (spherical, 63-210 ⁇ m);
  • the carrier in DIOL type silica gel chromatography is Chromatrex DIOL MB 100- manufactured by Fuji Silysia Chemical Ltd. 75/200;
  • the carrier in DNH silica gel chromatography is Chromatrex DNHDMB 100-75 / 200 (110 ⁇ m) manufactured by Fuji Silysia Chemical Ltd.
  • the mixing ratio in the eluent is a volume ratio.
  • DMSO dimethyl sulfoxide
  • DMSO-d 6 heavy dimethyl sulfoxide s: singlet d: doublet dd: double doublet m: multiplet
  • Reference example 2 A mixture of 2.5 g of (2-bromo-5-methyl-4-nitrophenyl) acetonitrile, 2.3 mL of dithiophosphoric acid O, O′-diethyl and 7.5 mL of a 4.9 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 1 day. . The solid was collected by filtration to obtain 2.1 g of 2- (2-bromo-5-methyl-4-nitrophenyl) ethanethioamide as a yellow solid.
  • Reference example 4 (2-Bromo-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 200 mg, ethanol 2.0 mL and water 2.0 mL To the mixture, 76 mg of iron powder and 72 mg of ammonium chloride were added and heated to reflux for 30 minutes. Ethanol 2.0mL was added to the reaction mixture, and it heated and refluxed for 30 minutes. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration.
  • reaction mixture is cooled to room temperature, toluene is added, the solid is collected by filtration, and the dark brown solid 2- (2,5-dimethyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydro 0.29 g of naphthalen-2-yl) -1,3-thiazole was obtained.
  • reaction mixture was cooled to room temperature, ethyl acetate, methanol and water were added, and insoluble materials were removed by filtration.
  • organic layer of the filtrate was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 19 A mixture of 1.72 g of 4-chloro-1-methyl-2-nitrobenzene, 1.68 g of potassium hydroxide, 2.89 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 5 mL of dimethyl sulfoxide was stirred at room temperature for 2 hours. To the reaction mixture, 1.68 g of potassium hydroxide was added and stirred for 2 hours and 30 minutes. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture.
  • Reference Example 24 A mixture of 0.40 g of (2-fluoro-5-methyl-4-nitrophenyl) acetonitrile, 0.49 mL of dithiophosphoric acid O, O′-diethyl and 2 mL of 5 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 12 hours and 30 minutes. did. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 28 A mixture of 5.5 g of sodium hydroxide, 3.2 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 18 mL of dimethyl sulfoxide was stirred at 30 ° C. for 5 minutes. To the reaction mixture was added 2.8 g of 4- (difluoromethoxy) -1-methyl-2-nitrobenzene in 10 mL of dimethyl sulfoxide, and the mixture was stirred at 30 ° C. for 1 hour. Ice water, toluene and ethyl acetate were added to the reaction mixture, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated and the aqueous layer was extracted with toluene.
  • Reference Example 31 A mixture of 0.84 g of 4-methoxy-1-methyl-2-nitrobenzene, 1.20 g of sodium hydroxide, 1.45 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 5 mL of dimethyl sulfoxide was stirred at room temperature for 6 hours. Water and toluene were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 38 A mixture of 0.50 g of (5-methyl-4-nitro-2- (propan-2-yloxy) phenyl) acetonitrile, 0.51 mL of dithiophosphoric acid O, O′-diethyl and 5.0 mL of 5 mol / L hydrogen chloride-ethyl acetate solution The mixture was stirred at room temperature for 1 hour and 15 minutes and allowed to stand for 14 hours. The reaction mixture was evaporated under reduced pressure. A mixture of the obtained brown oily substance, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone (0.65 g) and ethanol (5.0 mL) was heated to reflux for 2 hours and 30 minutes.
  • the reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure.
  • a mixture of 0.40 g of the obtained yellow oil, 30 mg of ammonium chloride, 0.16 g of iron powder, 8.0 mL of ethanol and 2.0 mL of water was heated to reflux for 3 hours.
  • To the reaction mixture were added 0.33 g of the obtained yellow oil, 30 mg of ammonium chloride and 0.16 g of iron powder, and the mixture was heated to reflux for 1 hour.
  • Reference Example 40 4-Bromo-2-methyl-5- (propan-2-yl) aniline 0.50 g, ethyl cyanoacetate 0.70 mL, bis (tri-tert-butylphosphine) palladium (0) 56 mg, tripotassium phosphate 1.40 g and toluene 10 mL of the mixture was heated to reflux under a nitrogen atmosphere for 3 hours 30 minutes. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 42 A mixture of 150 mg of hydrochloride of (4-amino-5-methyl-2- (propan-2-yl) phenyl) acetonitrile, 158 ⁇ L of dithiophosphoric acid O, O′-diethyl and 3 mL of 5 mol / L hydrogen chloride-ethyl acetate solution, The mixture was stirred at room temperature for 5 hours and then allowed to stand for 14 hours. To the reaction mixture, 84 ⁇ L of dithiophosphoric acid O, O′-diethyl was added and stirred for 3 hours. To the reaction mixture, 84 ⁇ L of dithiophosphoric acid O, O′-diethyl was added and stirred for 2 hours.
  • Reference Example 45 4-bromo-5- (tert-butyl) -2-methylaniline 0.50 g, ethyl cyanoacetate 0.66 mL, bis (tri-tert-butylphosphine) palladium (0) 53 mg, tripotassium phosphate 1.31 g and toluene 10 mL The mixture was heated to reflux under a nitrogen atmosphere for 3 hours 30 minutes. To the reaction mixture, 0.66 mL of ethyl cyanoacetate, 53 mg of bis (tri-tert-butylphosphine) palladium (0), 10 mL of toluene and 3 mL of dioxane were added, and the mixture was heated to reflux for 6 hours under a nitrogen atmosphere.
  • Reaction B To a suspension of 0.11 g of sodium hydroxide in 0.30 mL of dimethylsulfoxide was added 53 ⁇ L of (phenylthio) acetonitrile and 0.20 mL of dimethylsulfoxide in 50 mg of 4- (difluoromethyl) -1-methyl-2-nitrobenzene at room temperature. After stirring for 20 minutes, toluene and water were added to obtain reaction mixture B. Reaction mixture A and reaction mixture B were added to ice water. 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.
  • Reference Example 51 0.10 g 2- (2- (difluoromethyl) -5-methyl-4-nitrophenyl) ethanethioamide, 0.15 g 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and A mixture of 2.0 mL of ethanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, iron powder (64 mg), ammonium chloride (12 mg) and water (0.50 mL) were added, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate, methanol and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration.
  • Reference Example 56 A mixture of 6.48 g of sodium hydroxide, 10 g of 1-bromo-4-methyl-2-nitrobenzene, 11.6 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 50 mL of dimethyl sulfoxide was stirred at room temperature for 88 hours. To the reaction mixture, 13 g of potassium tert-butoxide was added under ice cooling, and the mixture was stirred for 2 hours under ice cooling. Water and ethyl acetate were added to the reaction mixture.
  • Reference Example 70 A mixture of 0.60 g of (2-methyl-4-nitro-5- (propan-2-yloxy) phenyl) acetonitrile, 0.61 mL of dithiophosphoric acid O, O′-diethyl and 6.0 mL of 5 mol / L hydrogen chloride-ethyl acetate solution The mixture was stirred at room temperature for 1 hour and 15 minutes and allowed to stand for 12 hours. The solvent of the reaction mixture was distilled off under reduced pressure to obtain a yellow solid. A mixture of the obtained yellow solid, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone 0.78 g and ethanol 6.0 mL was heated to reflux for 2 hours 30 minutes.
  • Reference Example 72 A mixture of 2.54 g of 1- (difluoromethoxy) -4-methyl-2-nitrobenzene, 5.00 g of sodium hydroxide, 2.90 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 25 mL of dimethyl sulfoxide is stirred at 30 to 40 ° C. for 2 hours. Stir. The reaction mixture was ice-cooled, water and ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 75 4-bromo-5-methyl-2- (propan-2-yl) aniline 500 mg, ethyl cyanoacetate 702 ⁇ L, bis (tri-tert-butylphosphine) palladium (0) 56 mg, tripotassium phosphate 1.40 g and toluene 10 mL The mixture was heated to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 80 A mixture of N- (2- (tert-butyl) -5-methylphenyl) -1,1-diphenylmethanimine (3.0 g), 2 mol / L hydrochloric acid (2.5 mL) and tetrahydrofuran (30 mL) was stirred at room temperature for 4 hours and 30 minutes. To the reaction mixture, 2 mL of 6 mol / L hydrochloric acid was added and stirred for 9 hours. To the reaction mixture was added 2 mL of 6 mol / L hydrochloric acid, and the mixture was allowed to stand for 15 hours. Toluene and water were added to the reaction mixture.
  • the aqueous layer was separated, and the organic layer was extracted with 1 mol / L hydrochloric acid.
  • the aqueous layer and the extract were combined, and 10% aqueous potassium carbonate solution and ethyl acetate were added.
  • the organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.78 g of 2- (tert-butyl) -5-methylaniline as a pale red oil.
  • a mixture of the obtained black oily substance, 0.47 mL of dithiophosphoric acid O, O′-diethyl and 4 mL of 5 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 19 hours.
  • To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution.
  • the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 91 In the same manner as in Reference Example 10, from 90 mg of 2- (2,5-dichloro-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole, 72 mg of 2,5-dichloro-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained.
  • Reference Example 93 1.40 g of N ′-(4- (cyanomethyl) -2,6-dimethylphenyl) -N-ethyl-N-methylimidoformamide hydrochloride, 40 mL of 5 mol / L hydrogen chloride-ethyl acetate solution and dithiophosphoric acid O, O ′ -A mixture of 1.25 mL of diethyl was stirred at room temperature for 5 hours and allowed to stand for 14 hours. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform.
  • Reference Example 94 4-bromo-2,3-dimethylaniline 2.00 g, ethyl cyanoacetate 3.20 mL, tris (dibenzylideneacetone) dipalladium (0) 275 mg, tri-tert-butylphosphonium tetrafluoroborate 348 mg, tripotassium phosphate 6.37 g
  • the mixture of toluene and 40 mL was heated to reflux for 4 hours and 10 minutes under a nitrogen atmosphere.
  • To the reaction mixture was added 260 mg of bis (tri-tert-butylphosphine) palladium (0), and the mixture was heated to reflux for 3 hours.
  • the reaction mixture was cooled to room temperature and ice water and ethyl acetate were added.
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • the organic layer and the extract were combined, washed successively with 1 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Reference Example 96 A mixture of 150 mg of (4-amino-2,3-dimethylphenyl) acetonitrile hydrochloride, 181 ⁇ L of dithiophosphoric acid O, O′-diethyl and 3 mL of 5 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 5 hours, and 12 hours Left to stand. To the reaction mixture, 97 ⁇ L of dithiophosphoric acid O, O′-diethyl was added and stirred for 3 hours, and 97 ⁇ L of dithiophosphoric acid O, O′-diethyl was added and stirred for 2 hours.
  • the mixture was stirred at 90-100 ° C. for 1 hour.
  • To the reaction mixture was added 0.12 mL of 2,2,7,7-tetramethyl-4-((trimethylsilyl) oxy) -3,6-dioxa-2,7-disilaoct-4-ene, and the mixture was stirred at 90-100 ° C. for 3 hours. Stir for 30 minutes.
  • To the reaction mixture 1.6 mL of dioxane and 0.80 mL of 1 mol / L hydrochloric acid were added, and the mixture was stirred at 70 to 80 ° C. for 1 hour.
  • the reaction mixture was cooled to room temperature, adjusted to pH 2 with a 1 mol / L aqueous sodium hydroxide solution, and ethyl acetate was added to the reaction mixture.
  • 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.
  • Reaction B 1- (5,6,7,8,9,10-hexahydrobenzo [8] annulen-2-yl) -2-hydroxyethanone in a suspension of 170 mg of acetonitrile in 1.4 mL of acetonitrile under ice cooling Then, 0.23 g of triphenylphosphine and 0.28 g of carbon tetrabromide were added, and the mixture was stirred for 20 minutes under ice-cooling and for 15 minutes at room temperature, and then ethyl acetate and water were added to obtain a reaction mixture B. Reaction mixture A and reaction mixture B were combined.
  • Example 1 Under a nitrogen atmosphere, 54 ⁇ L of oxalyl chloride was added to a solution of N-ethyl-N-methylformamide 55 mg in chloroform 1.0 mL, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 131 mg of 5-bromo-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. A chloroform 1.0 mL solution was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture.
  • the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 2 In the same manner as in Example 1, 5-cyclopropyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl ) Methyl) aniline from 90 mg, N ′-(5-cyclopropyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole-2) 70 mg of hydrochloride of -yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
  • Example 3 2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 0.13 g and N-methylformamide 2.6
  • 0.11 g of p-toluenesulfonyl chloride was added and stirred at room temperature for 16 hours.
  • Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture.
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • Example 4 In the same manner as in Example 3, 2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) From 114 mg of aniline to N ′-(2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl as a white solid 66 mg of phenyl) -N-ethylimidoformamide hydrochloride was obtained.
  • Example 5 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 200 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalene A mixture of -2-yl) ethanone 186 mg and methanol 2 mL was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the pH was adjusted to 9.5 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 6 According to the same procedure as in Example 5, 0.36 g of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- ( From 0.48 g of 5,6,7,8-tetrahydronaphthalen-2-yl) propan-1-one to N ′-(2,5-dimethyl-4-((5-methyl-4- (5,6 , 7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide hydrochloride 0.25 g was obtained.
  • Example 7 In the same manner as in Example 5, 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 100 mg, 2-bromo-1- (5 , 5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ethanone from 108 mg of white solid N ′-(2,5-dimethyl-4-((4- (5 Of 5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide 142 mg of hydrochloride was obtained.
  • Example 8 In the same manner as in Example 5, 200 mg of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- (indane -5-yl) ethanone to 175 mg of light yellow solid N ′-(4-((4- (indan-5-yl) -1,3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) 245 mg of hydrochloride salt of -N-ethyl-N-methylimidoformamide was obtained.
  • Example 9 In the same manner as in Example 5, 100 mg of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- (benzo From 94 mg of cycloheptan-2-yl) ethanone to N ′-(2,5-dimethyl-4-((4- (benzocycloheptan-2-yl) -1,3-thiazol-2-yl) methyl as a white solid 124 mg of phenyl) -N-ethyl-N-methylimidoformamide hydrochloride was obtained.
  • Example 10 0.12 mL of oxalyl chloride was added to a 2.4 mL chloroform solution of 0.14 g N-isopropyl-N-methylformamide and stirred at room temperature for 20 minutes. To the reaction mixture, 2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 0.24 g of chloroform was added. 2.4 mL solution was added and stirred at room temperature for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. Ethanol was added to the obtained residue, and the solvent was distilled off under reduced pressure.
  • Example 11 In the same manner as in Example 1, 2,5-dimethyl-4- (2- (4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) N '-(2,5-dimethyl-4- (2- (4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole-2) from 82 mg of ethyl) aniline 87 mg of hydrochloride of -yl) ethyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
  • Example 12 To a solution of N-ethyl-N-methylformamide 48 mg in chloroform 1.0 mL was added oxalyl chloride 48 ⁇ L, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 5-amino-4-methyl-2-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) benzonitrile 0.10. A solution of g in chloroform (3.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 13 To a solution of 33 mg of N-ethyl-N-methylformamide in 1 mL of chloroform was added 32 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 92 mg of 5-chloro-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 15 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 14 30 ⁇ L of oxalyl chloride was added to 1 mL of chloroform in 30 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 82 mg of 5-fluoro-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 10 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 15 To a solution of 36 mg of N-ethyl-N-methylformamide in 5 mL of methylene chloride was added 36 ⁇ L of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 85 mg of 4-methyl-6-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) biphenyl-3-amine. Methylene chloride (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. Ice water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture.
  • Example 16 34 ⁇ L of oxalyl chloride was added to 1 mL of chloroform in 34 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 30 minutes.
  • a solution of 79 mg of aniline in 1 mL of chloroform was added, and the mixture was stirred at room temperature for 30 minutes.
  • the solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 17 To a solution of 27 mg of N-ethyl-N-methylformamide in 1 mL of chloroform was added 26 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 75 mg of 5-methoxy-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. Chloroform 2mL solution was added and stirred at room temperature for 5 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 18 2- (5-Methyl-4-nitro-2- (trifluoromethyl) phenyl) ethanethioamide 0.12 g, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone 0.16 g
  • a mixture of ethanol and 2.0 mL was heated to reflux for 1 hour.
  • the reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain a light brown solid.
  • a mixture of the obtained light brown solid, water 0.6 mL, ethanol 2.4 mL, iron powder 58 mg and ammonium chloride 11 mg was heated to reflux for 1 hour.
  • the reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration.
  • the organic layer of the filtrate was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and activated carbon was added.
  • the insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give a yellow oil.
  • 17 ⁇ L of oxalyl chloride was added to a 1.0 mL chloroform solution of 18 mg N-ethyl-N-methylformamide and stirred at room temperature for 10 minutes.
  • Example 19 To a solution of 107 mg of N-ethyl-N-methylformamide in 1.5 mL of chloroform was added 105 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 2-methyl-5- (propan-2-yloxy) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl. ) Methyl) aniline (240 mg) in chloroform (1.5 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 20 To a solution of N-ethyl-N-methylformamide 27 mg in 1 mL of chloroform was added 27 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 56 mg of 5-ethynyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline Chloroform 1mL solution was added and stirred at room temperature for 30 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 21 To a solution of 42 mg of N-ethyl-N-methylformamide in 1 mL of methylene chloride was added 42 ⁇ L of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 2-methyl-5- (propan-2-yl) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3- under ice cooling. A solution of thiazol-2-yl) methyl) aniline hydrochloride (100 mg) in methylene chloride (10 mL) was added, and the mixture was stirred at room temperature for 50 minutes.
  • Example 22 Reaction A: To 1 mL of methylene chloride in 41 mg of N-ethyl-N-methylformamide was added 40 ⁇ L of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was stirred under ice cooling with 5- (tert-butyl) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole- 2-yl) methyl) aniline hydrochloride (100 mg) in methylene chloride (10 mL) was added, and the mixture was stirred at room temperature for 50 minutes.
  • reaction B 40 ⁇ L of oxalyl chloride was added to 2 mL of methylene chloride in 41 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 20 minutes to obtain a reaction mixture B. Under ice-cooling, reaction mixture B was added to reaction mixture A and stirred at room temperature for 10 minutes. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 23 To a 1.0 mL chloroform solution of 26 mg N-ethyl-N-methylformamide was added 26 ⁇ L oxalyl chloride, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture, 5- (difluoromethyl) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) A solution of aniline (58 mg) in chloroform (1.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 24 To a solution of N-ethyl-N-methylformamide 32 mg in 1 mL of chloroform was added 31 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 85 mg of 2-fluoro-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 10 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 25 To a solution of N-ethyl-N-methylformamide 25 mg in 1 mL of chloroform was added 25 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was charged with 2-amino-4-methyl-5-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) benzonitrile 52 mg. In chloroform (2 mL) and stirred at room temperature for 2 hours. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added.
  • Example 26 To a solution of N-ethyl-N-methylformamide 13 mg in 1 mL of chloroform was added 13 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 37 mg of 2-chloro-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. Chloroform 2mL solution was added and stirred at room temperature for 5 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 27 27 ⁇ L of oxalyl chloride was added to 1 mL of chloroform in 28 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture, 77 mg of 2-methoxy-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 10 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 28 To a 2.0 mL solution of 84 mg of N-ethyl-N-methylformamide in chloroform was added 82 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 5-methyl-2- (propan-2-yloxy) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl. ) 206 mg of methyl) aniline hydrochloride was added and stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 29 To a 1.5 mL chloroform solution of 101 mg N-ethyl-N-methylformamide was added 100 ⁇ L oxalyl chloride, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 2- (difluoromethoxy) -5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) A solution of aniline 233 mg in chloroform 1.5 mL was added, and the mixture was stirred at room temperature for 40 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue.
  • Reaction B 70 ⁇ L of oxalyl chloride was added to 2 mL of methylene chloride in 71 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 1 hour.
  • 2 mL of a methylene chloride solution of light yellow solid obtained in Reaction A and 28 ⁇ L of triethylamine were added under ice cooling, and the mixture was stirred for 25 minutes under ice cooling. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture.
  • reaction B To 1 mL of methylene chloride in 12 mg of N-ethyl-N-methylformamide was added 12 ⁇ L of oxalyl chloride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a mixture of the pale yellow solid obtained in reaction A, 12 ⁇ L of triethylamine and 1 mL of methylene chloride, and stirred at room temperature for 30 minutes to obtain reaction mixture B.
  • Reaction C 12 ⁇ L of oxalyl chloride was added to 1 mL of methylene chloride in 12 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 15 minutes to obtain a reaction mixture C.
  • Reaction mixture C was added to reaction mixture B and stirred at room temperature for 30 minutes.
  • a 10% aqueous potassium carbonate solution was added to the reaction mixture.
  • the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 32 15 ⁇ L of oxalyl chloride was added to a solution of N-ethyl-N-methylformamide 15 mg in 1 mL of chloroform and stirred at room temperature for 10 minutes. To the reaction mixture, 2,5-difluoro-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 41 mg chloroform 2 mL The solution was added and stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 33 24 ⁇ L of oxalyl chloride was added to 1 mL of chloroform in 24 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 10 minutes.
  • 2,5-dichloro-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 72 mg chloroform 2 mL
  • the solution was added and stirred at room temperature for 15 minutes.
  • the solvent of the reaction mixture was distilled off under reduced pressure.
  • Example 34 2- (4-((((Ethyl (methyl) amino) methylene) amino) -3,5-dimethylphenyl) ethanethioamide 100 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalene-2- Yl) A mixture of 98 mg of ethanone and 5 mL of methanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. To the obtained residue, ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • Example 35 To a solution of 42 mg of N-ethyl-N-methylformamide in 5 mL of methylene chloride was added 42 ⁇ L of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture was added 2,3-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) under ice cooling. A solution of 85 mg of aniline in 5 mL of methylene chloride was added, and the mixture was stirred for 1 hour and 30 minutes under ice cooling. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture.
  • Example 36 0.10 g of hydrochloride of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide, 2-bromo-1- (1,2,3,4-tetrahydro
  • a mixture of 0.11, 4-methanonaphthalen-6-yl) ethanone and 2.0 mL of methanol was heated to reflux for 2 hours.
  • the reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added.
  • the organic layer was separated, dried over anhydrous magnesium sulfate, and activated carbon was added. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure.
  • Example 37 0.12 g of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- (2-methyl-2,3-dihydro
  • Example 38 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 67 mg, 2-bromo-1- (2,2-dimethyl-2,3- A mixture of 53 mg of dihydro-1H-inden-5-yl) ethanone and 2.0 mL of methanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added. 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.
  • Example 39 2- (4-(((Ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 0.29 g, 1- (bicyclo [4.2.0] octa-1,3 , 5-trien-3-yl) -2-bromoethanone and 4.4 mL of methanol were heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 40 2- (4-((((Ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 0.14 g, 2-bromo-1- (5,6,7,8,9 , 10-hexahydrobenzo [8] annulen-2-yl) ethanone and a mixture of methanol 2.0 mL were heated to reflux for 1 hour 35 minutes. The reaction mixture is cooled to room temperature, 0.13 g of 2-bromo-1- (5,6,7,8,9,10-hexahydrobenzo [8] annulen-2-yl) ethanone and 2.0 mL of methanol are added, and 1 Heated to reflux for hours.
  • the reaction mixture was cooled to room temperature, and saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution and ethyl acetate were added.
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • the organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the solvent was distilled off.
  • the compound represented by the general formula [1] or a salt thereof has excellent antifungal activity and is useful as an antifungal agent.
  • the compound represented by the general formula [1] or a salt thereof is excellent in safety and is useful as an antifungal agent against Candida, Aspergillus, and Trichophyton.

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Abstract

Composé qui peut être représenté par la formule générale ou sel de celui-ci utile à titre d'agent antifongique. (Dans la formule, R1 et R2 peuvent être identiques ou différents l'un de l'autre et chacun représente un atome d'halogène, un groupe alkyle C1-6 qui peut être substitué, ou autre; R3 représente un groupe indanyle qui peut être substitué, un groupe indényle qui peut être substitué, un groupe dihydronaphtyle qui peut être substitué, un groupe tétrahydronaphtyle qui peut être substitué, ou autre; R4 et R5 peuvent être identiques ou différents l'un de l'autre et chacun représente un atome d'hydrogène, un groupe alkyle C1-6 qui peut être substitué, ou autre; X1 représente un groupe alkylène C1-6 ou autre; Z1 et Z2 peuvent être identiques ou différents l'un de l'autre et chacun représente un atome d'azote, le groupe représenté par la formule CH, ou autre; et Z3 représente un atome d'azote, le groupe représenté par la formule CH, ou autre).
PCT/JP2014/051966 2013-01-30 2014-01-29 Composé amidine et sel de celui-ci WO2014119617A1 (fr)

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WO2015025962A1 (fr) * 2013-08-23 2015-02-26 富山化学工業株式会社 Composé amidine ou sel associé
WO2016043260A1 (fr) * 2014-09-19 2016-03-24 塩野義製薬株式会社 Composé d'amidine ou de guanidine cyclique
WO2016095870A1 (fr) * 2014-12-19 2016-06-23 中国科学院上海有机化学研究所 Motif structural de benzocyclobutène contenant du bisphénol et une diamine et sa préparation et son application
WO2018069841A1 (fr) * 2016-10-14 2018-04-19 Pi Industries Ltd Dérivés de phénylamine 4-substitués et leur utilisation pour protéger des cultures par lutte contre des micro-organismes phytopathogènes indésirables
WO2018193385A1 (fr) 2017-04-20 2018-10-25 Pi Industries Ltd. Nouveaux composés de phénylamine
WO2018211442A1 (fr) 2017-05-18 2018-11-22 Pi Industries Ltd. Composés de formimidamidine utiles contre des micro-organismes phytopathogènes
WO2019202459A1 (fr) 2018-04-16 2019-10-24 Pi Industries Ltd. Utilisation de composés de phénylamidine substitués en 4 pour lutter contre les maladies dues à la rouille chez les plantes
CN113387842A (zh) * 2021-07-08 2021-09-14 成都泰和伟业生物科技有限公司 一种通过OTf胺化合成芳香伯胺的方法
RU2796397C2 (ru) * 2016-10-14 2023-05-23 Пи Индастриз Лтд Производные 4-замещенного фениламина и их применение для защиты культур от нежелательных фитопатогенных микроорганизмов

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015025962A1 (fr) * 2013-08-23 2015-02-26 富山化学工業株式会社 Composé amidine ou sel associé
WO2016043260A1 (fr) * 2014-09-19 2016-03-24 塩野義製薬株式会社 Composé d'amidine ou de guanidine cyclique
WO2016095870A1 (fr) * 2014-12-19 2016-06-23 中国科学院上海有机化学研究所 Motif structural de benzocyclobutène contenant du bisphénol et une diamine et sa préparation et son application
CN105777519A (zh) * 2014-12-19 2016-07-20 中国科学院上海有机化学研究所 一类含苯并环丁烯结构单元的双酚、双胺及其制备和应用
CN105777519B (zh) * 2014-12-19 2019-05-17 中国科学院上海有机化学研究所 一类含苯并环丁烯结构单元的双酚、双胺及其制备和应用
WO2018069841A1 (fr) * 2016-10-14 2018-04-19 Pi Industries Ltd Dérivés de phénylamine 4-substitués et leur utilisation pour protéger des cultures par lutte contre des micro-organismes phytopathogènes indésirables
CN109843056A (zh) * 2016-10-14 2019-06-04 印度商皮埃企业有限公司 4-经取代之苯基胺衍生物及其通过对抗不要的植物病原性微生物而保护作物之用途
RU2796397C9 (ru) * 2016-10-14 2024-03-26 Пи Индастриз Лтд Производные 4-замещенного фениламина и их применение для защиты культур от нежелательных фитопатогенных микроорганизмов
RU2796397C2 (ru) * 2016-10-14 2023-05-23 Пи Индастриз Лтд Производные 4-замещенного фениламина и их применение для защиты культур от нежелательных фитопатогенных микроорганизмов
US11155517B2 (en) 2016-10-14 2021-10-26 Pi Industries Ltd. 4-substituted phenylamine derivatives and their use to protect crops by fighting undesired phytopathogenic micoorganisms
US11524934B2 (en) 2017-04-20 2022-12-13 Pi Industries Ltd Phenylamine compounds
WO2018193385A1 (fr) 2017-04-20 2018-10-25 Pi Industries Ltd. Nouveaux composés de phénylamine
WO2018211442A1 (fr) 2017-05-18 2018-11-22 Pi Industries Ltd. Composés de formimidamidine utiles contre des micro-organismes phytopathogènes
WO2019202459A1 (fr) 2018-04-16 2019-10-24 Pi Industries Ltd. Utilisation de composés de phénylamidine substitués en 4 pour lutter contre les maladies dues à la rouille chez les plantes
CN113387842A (zh) * 2021-07-08 2021-09-14 成都泰和伟业生物科技有限公司 一种通过OTf胺化合成芳香伯胺的方法

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