WO1998058905A1 - Novel amidrazone derivatives having antifungal activity - Google Patents

Novel amidrazone derivatives having antifungal activity Download PDF

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Publication number
WO1998058905A1
WO1998058905A1 PCT/JP1998/002817 JP9802817W WO9858905A1 WO 1998058905 A1 WO1998058905 A1 WO 1998058905A1 JP 9802817 W JP9802817 W JP 9802817W WO 9858905 A1 WO9858905 A1 WO 9858905A1
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Prior art keywords
optionally substituted
bond
monocyclic
substituted
mycosis
Prior art date
Application number
PCT/JP1998/002817
Other languages
French (fr)
Japanese (ja)
Inventor
Shunji Kageyama
Toru Kontani
Masahiro Fujii
Kiyoshi Igarashi
Osamu Yamamoto
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU79330/98A priority Critical patent/AU7933098A/en
Publication of WO1998058905A1 publication Critical patent/WO1998058905A1/en

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/22—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having nitrogen atoms of amidino groups further bound to nitrogen atoms, e.g. hydrazidines
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    • 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
    • C07D277/32—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/32—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
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    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel amidrazone derivative or a pharmaceutically acceptable salt thereof having a medicament, particularly an antifungal activity, particularly an activity against causative bacteria of deep mycosis.
  • the present invention also provides a pharmaceutical composition comprising the amidrazone derivative or a salt thereof and a pharmaceutically acceptable carrier, particularly a pharmaceutical composition useful as a prophylactic or therapeutic agent for mycosis, especially for mycosis profound.
  • a pharmaceutical composition useful as a prophylactic or therapeutic agent for mycosis, especially for mycosis profound.
  • Pathogenic fungi are known to cause various infectious diseases (mycosis).
  • mycosis fungi represented by Candida, Aspergillus, and Cryptococcus have recently been the causative agents of deep-seated mycosis that affects deep organs and often leads to fatal outcomes.
  • chemotherapy area 11 (6), 1135-1144 (1995) has been elucidated.
  • Farmaco, 44 (9), 819-829 (1989) reports that compounds represented by the following formula have activity against Candida albicans, Aspergillus niger, and the like.
  • X represents a 2, 3, or 4-pyridyl group
  • ⁇ represents any group represented by the following formula.
  • US2758050 also reports amidrazone derivatives for pesticide use that protect plants from parasitic pathogens such as fungi and bacteria.
  • R represents aryl or aralkyl
  • R ′ represents acyl or cyano having less than 5 carbon atoms.
  • the present inventors have conducted intensive studies on compounds having activity against the causative bacteria of deep mycosis, and as a result, have found that the amidrazone derivative exhibits excellent antifungal activity. Completed the invention.
  • fungal diseases containing an amidrazone derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient, particularly fungi such as Candida, Aspergillus, and Cryptococcus, are included.
  • the present invention provides an agent for preventing or treating deep mycosis.
  • R a (1) optionally substituted monocyclic to tricyclic aryl, (2) optionally substituted monocyclic having at least one heteroatom selected from N, 0 and S To tricyclic saturated or unsaturated heterocyclic ring, (3) optionally substituted and crosslinked cycloalkyl or (4) optionally substituted and crosslinked cycloalkenyl ,
  • R b (1) optionally substituted monocyclic to tricyclic aryl or (2) optionally substituted, having one or more hetero atoms selected from N, 0 and S Monocyclic to tricyclic saturated or unsaturated heterocyclic ring,
  • R e and R d one is H and the other is absent,
  • R e -H or-0H
  • R f -H, -lower alkyl or -YR al ,
  • n 1 to 8
  • A a lower alkylene which may be substituted with a bond or -lower alkyl
  • R g -H, -lower alkyl or -YR a2 ,
  • Rg l to Rg ll the same groups as Rg,
  • R al and R a2 the same groups as R a
  • R b is phenyl which is unsubstituted or substituted with -CH 3 , -NO 2 or -S 0 3 H
  • R a -AX- is benzoimidazole-2-ylsulfa
  • the compounds that are benzyl and benzothiazolyl-2-ylsulfanyl are described in Rentogenol. Radiol., 10, 11-16 (1971) and 8, 230-236 (1969). Compounds that are ylsulfanyl are described in Stud.
  • phenyl (the phenyl may be substituted by -Cl, -C3 ⁇ 4 or -OCH 3 )-hydroxymethyl is a compound which is described in J. Chem. Soc, Perkin Trans. 1, 1977 (6 ), 646-651 and 1975 (22), 2280-2284. However, all of these compounds have been used as radioprotective effects or as intermediates in the synthesis of other compounds. No antifungal activity is disclosed.
  • R b is an unsubstituted or - CH 3, -N0 2 also is properly - S0
  • phenyl substituted with 3 H is, 1H-Benzoimidazo 2-ylsulfanylmethyl, 1H-benzimidazole-2-ylsulfanylethyl, benzothiazole-2-ylsulfanylmethyl, benzothiazol-2-ylsulfanylethyl, 1H-indole-2 -Ylsulfanylmethyl, 1H-indole-2-ylsulfanylethyl, 1H-indole-3-ylmethyl, 2-pyridylmethylsulfanylethyl, benzyloxycarbonylaminomethyl, 4,5-dihydro-1H-imidazo Lumpur 2 Irumechiru, (said phenyl - Cl, -CH 3 or - Yo Le be substitution
  • the present invention further includes a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • lower means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms.
  • the “lower alkyl” is preferably an alkyl having 1 to 4 carbon atoms.
  • the “lower alkylene” is preferably an alkylene having 1 to 3 carbon atoms.
  • Cycle mouth alkyl is preferably cycloalkyl having 3 to 10 carbon atoms.
  • Cycloalkenyl is preferably cycloalkenyl having 3 to 10 carbon atoms.
  • Preferred examples of the "monocyclic to tricyclic aryl" include benzene, indane, naphthylene, azulene and fluorene.
  • “Monocyclic to tricyclic saturated or unsaturated heterocyclic ring having one or more heteroatoms selected from N, 0 and S” means that the heteroatom selected from N, 0 and S is 1 to Four- to eight-membered, preferably five- to seven-membered monocyclic heterocyclic compounds, or these monocyclic heterocyclic compounds are other heterocycles or four- to eight-membered hydrocarbon rings And bicyclic or tricyclic heterocyclic compounds.
  • the monocyclic heterocyclic compound preferably, furan, tetrahydrofuran, tetrahydropyran, pyrrole, thiophene, thiazol, pyrazole, triazole, tetrazole, dihydroimidazole, imidazolidine, thiadiazole, oxazol, pyridine, Dihydropyridine, piperidine, morpholine, pyrimidine, dihydropyrimidine, tetrahydropyrimidine, pyrazine, azepane.
  • bicyclic or tricyclic heterocyclic compound preferably, indole, dihydroindole, benzofuran, chromene, benzoimidazole, benzothiazole, dihydrobenzothiazolyl, imidazopyridine, tetrahydrofurodixol, purine, Benzoxazine, benzodioxin, quinoline, tetrahydroquinoline, naphthyridine, quinoxaline, benzazepine, carbazole, acridine, phenothiazine.
  • the expression "may be cross-linked” means that it may be cross-linked by a bond or lower alkylene.
  • Optionally bridged cycloalkyl is preferably cyclopropyl, cyclohexyl, decalyl, norpinanyl, adamantyl.
  • the “optionally crosslinked cycloalkenyl” is preferably cyclohexenyl, bicyclo [2.2.1] heptenyl and norpolenyl.
  • Halogen is F, Cl, Br and I.
  • Optionally substituted monocyclic to tricyclic aryl "optionally substituted monocyclic to tricyclic saturated having one or more heteroatoms selected from N, 0 and S” Is an unsaturated heterocyclic ring, a optionally substituted and optionally crosslinked cycloalkyl, or an optionally substituted and optionally crosslinked cycloalkenyl group. Any group may be used as long as it can be substituted on these ring groups.
  • R 1 and R 2 are the same or different and are -H or- lower alkyl, R 3 is - select amino-protecting group such as benzyl, R 4 is from may be substituted by R 6, N, 0 and S - C (Ph) 3, -C0 2 A 5- to 8-membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms, wherein R 5 is -halogen, -lower alkylene-OH and -halogen which may be substituted with -halogen.
  • R 6 is - OH, -NR l R - lower alkyl, - lower alkylene - OH, - lower alkylene - 0- lower ⁇ alkyl or - lower alkylene -. Shown NRi-CO-R 2 each hereinafter the same).
  • the “lower alkyl optionally substituted with halogen” is preferably chloroethyl, trifluoromethyl or trifluoroethyl.
  • the compound of the present invention may have optical isomers or Although a number of isomers and tautomers may exist, the present invention includes a separated form or a mixture of these isomers.
  • the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent.
  • Such salts are pharmaceutically acceptable salts, and specifically include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propionate.
  • Acid addition with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, cunic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and dalluminic acid
  • organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, cunic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and dalluminic acid
  • examples thereof include salts, inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ordithine; and ammonium salts.
  • the present invention also includes various hydrates, solvates, and polymorphic substances of the compound of
  • the compounds of the present invention and salts thereof can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or types of substituents.
  • DG Neilson et al. Chem. Rev., 70 (1 ), 151-170 (1970), KM Doyle et al. Synthesis, 583-584 (1974) or S. Patai ed.The Chemistry of Functional Groups "The chemistry of amidines and imidates", Vol. 1, 491-545. It can be manufactured by applying the method.
  • it is effective in production technology to replace the functional group with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group that can be easily converted to the functional group. It may be.
  • the desired compound can be obtained by removing the protecting group as necessary.
  • a functional group include a hydroxyl group, a hydroxyl group, an amino group, and the like.
  • Examples of such a protecting group are described in Greene et al., "Protective Groups in Organic Synthesis” (Second Edition) (1991). The protecting groups described above can be mentioned. These can be used according to the reaction conditions.
  • the present production method is a method for obtaining the compound (I) of the present invention by reacting the intermediate (IV) obtained from the nitrile form (II) with the compound (V).
  • Intermediates (IV) may not react with alcohols such as methanol and ethanol, ethers such as getyl ether and dioxane, ketones such as acetone and 2-butanone, ethyl acetate and dimethylformamide (DMF).
  • the compound of the present invention (I) is obtained by reacting the hydrazine derivative (V) in an active solvent. This reaction is carried out under cooling to heating, preferably at a temperature of -20 ° C to 50 ° C.
  • the compound (V) is commercially available, or can be produced by applying the method described in “The 4th Edition Experimental Chemistry Course” edited by The Chemical Society of Japan, 20, 338-342 or a modification thereof.
  • Intermediate (IV) is inactive in the reaction of halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and ethers in the presence of one or more equivalents of alcohol (III) (preferably ethanol). It is obtained by reacting hydrogen chloride in a suitable solvent. This reaction is carried out under cooling to heating, preferably at a temperature of from 170 to 30 ° C.
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform
  • alcohol (III) preferably ethanol
  • Hal means octogen. The same applies hereinafter.
  • This production method is a method for obtaining the compound (I) of the present invention by reacting the intermediate (VII) obtained from the thioamide (VI) with the compound (V).
  • reaction for obtaining the compound (I) of the present invention from the intermediate (VII) can be carried out under almost the same conditions as in the method for preparing the intermediate (IV) described in the first method.
  • Intermediate (VII) can be obtained by reacting thioamide (VI) with a methylating agent such as methyl halide or Miyabaine reagent such as methyl iodide in a suitable solvent such as ketones or DM.F. This reaction is carried out under cooling to heating, preferably at a temperature of 0 ° C to: 120 ° C.
  • a methylating agent such as methyl halide or Miyabaine reagent
  • methyl iodide such as methyl iodide
  • a suitable solvent such as ketones or DM.F.
  • the raw material compound (II) is commercially available, or a known nitrile production method, for example, Kameya et al., “Synthetic Organic Chemistry” 6, 203-252, and the Chemical Society of Japan, “New Experimental Chemistry Course” 14 It can be manufactured by applying the method described in (3), 1428-1484, or a modification thereof. Further, it can also be produced by condensing a compound having a desired Ra group and a compound having a nitrile group by the following acylation, sulfonylation, alkylation, ureaization, or cationization.
  • Rt is - a OS0 2 R v, is R u - - halogen or OH, -SH or -.
  • the NHR g, R v represents lower ⁇ alkyl or substituted or unsubstituted good phenyl respectively forth )
  • the carboxylic acid compound is cooled or heated in an inert solvent such as halogenated hydrocarbons, ethers, DMF, etc., preferably at ⁇ 20 ° (: to 60 ° C., acid halide method, mixing or Are symmetric acid anhydride method, active ester method, condensing agent (1,3-dicyclohexylcarpimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carpimide (WSC), carbonyldiimidazole ( CDI), etc.) by condensation with an amino compound or alcohol compound by a method, etc.
  • an inert solvent such as halogenated hydrocarbons, ethers, DMF, etc.
  • an organic base preferably, triethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine
  • an organic base preferably, triethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine
  • the alkylation reaction is incompatible with the reaction of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons, ethers, ketones, DMF, dimethylacetamide (DMA) and N-methylpyrrolidone.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as benzene, toluene and xylene
  • ethers ketones
  • DMF dimethylacetamide
  • DMA dimethylacetamide
  • N-methylpyrrolidone N-methylpyrrolidone.
  • an alkylating agent such as an organic halide or an organic sulfonic acid ester such as methanesulfonyloxy or P-toluenesulfonyloxy and an alcohol, a thiol or an amino compound are used in an equivalent amount or an excess amount of one. It is performed under cooling to heating.
  • the reaction is carried out in the presence of the above-mentioned organic base, inorganic base (preferably, sodium hydroxide, potassium carbonate) or metal salt base (preferably, sodium hydride, potassium tert-butoxy, butyllithium, lithium diisopropylamide).
  • organic base preferably, sodium hydroxide, potassium carbonate
  • metal salt base preferably, sodium hydride, potassium tert-butoxy, butyllithium, lithium diisopropylamide.
  • the ureation can be obtained by reacting a desired isocyanate with the desired rubamic acid ester, and the desired chloroformate can be reacted with an amino compound.
  • the reaction is carried out under almost the same conditions as in the above amidation.
  • X is - SO- or - S0 2 - starting compound is (Ila) is, X is - are synthesized by oxidizing the S-, compound with a peroxide such as m- black port perbenzoate You.
  • a peroxide such as m- black port perbenzoate You.
  • For the reaction apply the method described in “New Experimental Chemistry Course” edited by the Chemical Society of Japan, 15 (1-1), 60 or “New Experimental Chemistry Course” edited by the Chemical Society of Japan, 15 (1-2), 664-727, etc. Done.
  • X is - S0 2 - Compounds that are also synthesized cowpea in subjecting a scan luffin salt and an organic halide to the conditions of alkylation of the.
  • the starting compound (VI) can be produced by applying the thioamide production method described in “New Experimental Chemistry Course” edited by The Chemical Society of Japan, 14 (3), 1827-1832 or a modification thereof.
  • it can be synthesized by reacting an amide compound with diphosphorus pentasulfide or a Lawesson reagent in an inert solvent such as aromatic hydrocarbons and ethers.
  • the compound of the present invention thus produced is isolated and purified as a free compound, salt or hydrate, and various solvates.
  • the salt can be obtained by subjecting the salt to a usual salt-forming treatment. Isolation and purification include extraction, concentration, solvent evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the compound of the present invention exhibits strong antifungal activity, especially activity against causative bacteria of deep mycosis, and is useful for prevention or treatment of various deep mycoses such as fungal diseases, especially opportunistic infections. It is.
  • the antifungal activity was measured by a microfluidic dilution method using a synthetic liquid medium (0.5% glucose-added yeast nitrogen base in phosphate buf fer). That is, 200 ⁇ l of a liquid medium adjusted to a final bacterial concentration of l ⁇ 10 4 cells / ml was added to 2 ⁇ l of the drug solution in a 2-fold serial dilution series. After the culture, the absorbance at 595 nm was measured, and the minimum concentration of the test compound that showed a growth inhibition rate of 80% or more was defined as the antifungal activity value ⁇ g / ml).
  • Candida albican (Candida albican ⁇ 1768: 37 ° C; l: Cliffcoc Js nonophoremanos ix ⁇ ryptococcus neoformans) T ⁇ 0362: 2 days at 27 ° C; Aspergillus fumigatus fumigatu # 1776 was 3 days at 27 ° C.
  • Farmaco, 44 as a control agent (9), 819-829 The compound according to (1989) Da (N 2 - (5- Nitorofu Rufuriden) -2-pyridinecarboxamide amidrazone) (in Table 1, Ref 1) and Fluconazole (Ref 2 in Table 1) was used.
  • Table 1 shows the antifungal activity ( ⁇ / ⁇ 1) of the compound of the present invention and the control drug.
  • Example compound number CA: Candida albicans ⁇ 1768;
  • the growth inhibitory concentration for HeLa S3 was measured. That is, 2 ⁇ l of a two-fold serial dilution of the drug solution was added to 200 ⁇ l of a medium (MEM containing 10% FBS) containing 5 ⁇ 10 4 cells / ml of HeLa S 3 cells prepared at 5 ⁇ 10 4 cells / ml and cultured for 3 days. After washing the cells, using the Cell Counting Kit, the inhibition rate was calculated, to calculate the concentration (IC 50 value) that inhibits 50%, the compound of the present invention was confirmed to be less cytotoxic.
  • MEM containing 10% FBS containing 5 ⁇ 10 4 cells / ml of HeLa S 3 cells prepared at 5 ⁇ 10 4 cells / ml and cultured for 3 days.
  • compositions containing one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as carriers, excipients, and other ingredients commonly used in pharmaceutical preparations. Prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, vaginals, ointments, patches, etc. using additives, and orally or parenterally Is administered.
  • the clinical dose of the compound of the present invention for humans is appropriately determined depending on the individual case in consideration of the symptoms of the patient to be applied, the age, sex, administration route, and the like of the administration subject. Or 0 per day! ⁇ 200 mg kg range per force or an adult is orally administered several times from one in the range of 1 day diary 0.001 01 3 ⁇ 4 1 3 ⁇ 4, it is given intravenously throw divided into one to several times Or continuous intravenous administration for 1 to 24 hours per day.
  • a smaller dose than the above dose may be sufficient.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, Metasilicate Silicate is mixed with magnesium aluminate.
  • inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, Metasilicate Silicate is mixed with magnesium aluminate.
  • the composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose dalycholate, a stabilizer such as lactose, A solubilizing agent such as glutamic acid or aspartic acid may be contained.
  • a lubricant such as magnesium stearate
  • a disintegrant such as calcium cellulose dalycholate
  • a stabilizer such as lactose
  • a solubilizing agent such as glutamic acid or aspartic acid may be contained.
  • tablets or pills may be coated with a sugar such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose sulfate or a gastric or enteric film.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as e.g. Includes water production and ethanol.
  • the composition may contain, besides the inert diluent, solubilizing or solubilizing agents, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline.
  • Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (trade name).
  • Such compositions may also contain additional carotenoids, such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or dissolving aids. .
  • Table 2 shows the production method for the starting compound ( ⁇ ).
  • the starting compound (II) is produced by reacting any of the R a -groups shown in Table 2 with any of the R e -groups.
  • combinations of these groups will be described after the reference example numbers as synthesis routes for the reference example compounds.
  • 1-a is 1 and R e of R a -group - shows the route by reacting g roup of a, synthesized starting compounds (II).
  • N-Benzylethanolamine is reacted with 4-bromobut-2-eneethyl ester in the presence of diisopropylethylamine in dichloroethane, and then in toluene with 1,8-diazabicycle [5.4.0]-
  • the compound obtained by treating with 7-pentadecene is hydrolyzed with a 1N aqueous hydrochloric acid solution, and then reacted with 3-methylaminopropane nitrile in dichloroethane in the presence of 1-hydroxybenzotriazole (HOBT) and WSC, (4-Benzylmorpholin-2-yl) -N- (2-cyanoethyl) -N-methylacetoamide was obtained.
  • HOBT 1-hydroxybenzotriazole
  • WSC 4-Benzylmorpholin-2-yl) -N- (2-cyanoethyl) -N-methylacetoamide
  • Isonicotinol chloride monohydrochloride was reacted with 3-aminopropane nitrile in methylene chloride in the presence of triditylamine to obtain N- (2-cyanoethyl) isonicotinamide.
  • N-Cyanomethyl-N- (4-methoxyphenyl) nicotinamide was obtained in the same manner as in Reference Example 8, except that nicotinyl chloride monohydrochloride was used instead of acetyl chloride.
  • Reference Example 10 (5-b)
  • N- (2-Cyanoethyl) -N-methylbenzenesulfonamide was obtained in the same manner as in Reference Example 7, except that benzenesulfonyl chloride was used instead of isonicotinoyl chloride monohydrochloride.
  • N- (cyanomethyl) -4-methylbenzenesulfonamide was obtained in the same manner as in Reference Example 7, except that 4-methylbenzenesulfonyl chloride was used instead of isonicotinoyl chloride monohydrochloride.
  • Reference Example 2 1 (Other manufacturing method (Oth-1))
  • Reference Example 2 2 (Other manufacturing method (Oth-2))
  • 2- [4- (5-Hydroxymethyl-2-oxoxazolidin-3-yl) phenyl] acetonitrile is reacted with methanesulfonyl chloride in methylene chloride in the presence of triethylamine, then azide in DMF React with sodium, then treat with triphenylphosphine, and further react with acetyl chloride in methylene chloride in the presence of tritylamine.
  • 2- [4- (5-acetamidomethyl-2-oxoxazolidin-3-yl) phenyl] acetonitrile was obtained.
  • N-Cyanomethyl-N- (4-hydroxyphenyl) acetamide is reacted with 1- (2-chloroethyl) piperidine monohydrochloride in DMF in the presence of lime carbonate to give N-cyanomethyl-N- [ 4- (2-Pyridinoethoxy) phenyl] acetoamide was obtained.
  • Reference Example 2 5 (Other manufacturing method (Oth-5))
  • Reference Example 2 7 (Other manufacturing method (Oth-7))
  • 3-oxo-3,4-dihydro-2H-1,4-benzoxazine is treated with lithium hydride in THF in THF, and reacted with ethyl bromoacetate in THF in the presence of sodium hydride.
  • the mixture was treated with a solution, and further reacted with a Lawesson reagent in THF to obtain 2- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) thioacetamide.
  • Table 3 The compounds of Reference Examples 32 to 105 shown in Table 3 were produced in the same manner as in the above Reference Examples, using commercially available compounds or compounds known in the literature. Tables 3 and 4 show the structures, synthesis routes, and physicochemical data of the compounds of Reference Examples 1 to 105.
  • Hydrogen chloride gas was blown into a 50 ml solution of 1.8 g of 2- (2-oxo-1,2-dihydro-1-pyridyl) acetonitrile and 1.1 ml of ethanol in 50 ml of ice-cold form under ice-cooling for 30 minutes, and 5 ° C
  • the reaction was performed before and after for 2 days.
  • the reaction solution was poured into an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 2.4 g of a crude imidate.
  • Example 2 In the same manner as in Example 1, the compounds of Examples 6 to 23 shown in Tables 5 to 8 were synthesized, and in the same manner as in Example 2, the compounds of Examples 23 and 23 shown in Table 7 were synthesized. did. Tables 5 to 8 show the structures, production methods, and physicochemical data of Examples 1 to 39.
  • Table 9 shows the structure of another compound of the present invention. These can be easily synthesized by using the methods described in the above-mentioned production methods and Examples and methods obvious to those skilled in the art, or modified methods thereof.
  • Ad 1-adamantyl
  • Boa Benzoxazole-2-yl
  • Bta benzothiazol-2-yl
  • DAM dimethylaminomethylideneamino
  • DB2 2,3-dihydro-1,4-benzodioxin-2-yl
  • DDP1 2,6-dioxo-2,3,6,7-tetrahydrido-1H-purine-1-yl;
  • DDP7 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-7yl
  • F4P 4-fluorophenyl
  • Imp imidazo [1,2-a] pyrazine-2-yl
  • IPY imidazo [l, 2-a] pyridine-3-yl
  • Mor4 Morpholino
  • Mor2 Morpholine-2-yl
  • Mpe 4-methylpiperazine-1-yl
  • ODB 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl
  • ODP 2-oxo-1,2-dihydro-1-pyridyl
  • OTP 2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl
  • OXA 2-oxosoxazolidine-3-yl
  • OXT 2-thioxoxazolidine-3-yl
  • Ppe Pyrazine-1-yl
  • Prr pyrrol-2-yl
  • Pyro pyrrolidine-1-yl
  • Pyz pyrazine-2-yl
  • Tbp 3a, 5a, 8a, 8b-tetrahydropene-5H-bis [1,3] dioxolo [4,5-b: 4 ', 5'-d] pyran-5-yl
  • Tfo tetrahydrofuro [2, 3-d] -l, 3-dioxole-6-yl;
  • Thp tetrahydropyran-2-yl
  • TrN triphenylmethylamino

Abstract

Amidrazone derivatives of formula (I) useful for prevention or treatment of lupus mycosis attributable to fungi, such as Candida, Aspergillus, and Cryptococcus, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein Ra represents: (1) an optionally substituted monocyclic to tricyclic aromatic hydrocarbon, (2) an optionally substituted monocyclic to tricyclic saturated or unsaturated hetero ring containing one or more hetero atoms selected from N, O and S, (3) an optionally substituted and optionally cross-linked cycloalkyl, or (4) an optionally substituted and optionally cross-linked cycloalkenyl; Rb represents (1) an optionally substituted monocyclic to tricyclic aromatic hydrocarbon or (2) an optionally substituted monocyclic to tricyclic saturated or unsaturated hetero ring containing one or more hetero atoms selected from N, O and S; ... represents a single bond or a double bond; n is 1 to 8; A represents a bond or a lower alkylene optionally substituted by a lower alkyl; and X represents a bond, -CO-, -CO¿2?-, -CONR?g¿-, -COCONRg1, -CH=CHCONR?g2-, -NRg3, -NRg4¿CO-, -NRg5CO2-, -NR?g6CONRg7¿-, -O-, -OCO-, -OCONRg8-, -OCH¿2CONR?g9-, -S-, -SO-, -SO¿2?-, -SO2NR?g10¿-, or -SO¿2NR?g11CO-.

Description

明 細 書 抗真菌活性を有する新規アミドラゾン誘導体 技術分野  Description New amidrazone derivatives with antifungal activity
本発明は、 医薬、 特に抗真菌活性、 殊に深在性真菌症の起因菌に対する活性を有 する新規なアミドラゾン誘導体又はその製薬学的に許容される塩に関する。また、 本発明は該アミドラゾン誘導体又はその塩と、製薬学的に許容される担体とからな る医薬組成物、 特に真菌症、 殊に深在性真菌症の予防又は治療剤として有用な医薬 組成物に関する。 背景技術  The present invention relates to a novel amidrazone derivative or a pharmaceutically acceptable salt thereof having a medicament, particularly an antifungal activity, particularly an activity against causative bacteria of deep mycosis. The present invention also provides a pharmaceutical composition comprising the amidrazone derivative or a salt thereof and a pharmaceutically acceptable carrier, particularly a pharmaceutical composition useful as a prophylactic or therapeutic agent for mycosis, especially for mycosis profound. About things. Background art
病原性の真菌は、 種々の感染症 （真菌症） の原因となることが知られている。 中 でも、 カンジダ （Candida) 、 ァスペルギルス （Aspergillus) 、 クリプトコッカス (Cryptococcus) に代表される真菌は、 深部諸臓器を冒してしばしば致死的転帰を 迪る深在性真菌症の原因菌であることが近年明らかにされてきた（化学療法の領域 11 (6)， 1135-1144 (1995)) 。  Pathogenic fungi are known to cause various infectious diseases (mycosis). In particular, fungi represented by Candida, Aspergillus, and Cryptococcus have recently been the causative agents of deep-seated mycosis that affects deep organs and often leads to fatal outcomes. Has been elucidated (chemotherapy area 11 (6), 1135-1144 (1995)).
深在性真菌症の大半の例は、様々な基礎疾患又は侵襲的医療処置によって生体防 御能の低下した患者に発生する。現在、 深在性真菌症に対してはフルコナゾ一ルゃ イトラコナゾールが使用されているが、 抗真菌スペクトル、 体内動態、 耐性化等の 点で臨床の現場に於いて十分満足できる状態とは言い難い。 また、 この領域におい て主に研究されてきたァゾール系薬剤は、 重篤化した患者への有効性、 同一系薬剤 の長期使用による耐性化が問題となっていることから、従来の化合物とは構造が異 なり、 深在性真菌症の起因菌に対して優れた抗真菌活性を有し、 医薬品として十分 に満足できる化合物の開発が切望されている。  Most examples of deep mycosis occur in patients with reduced host defense due to various underlying diseases or invasive medical procedures. Currently, fluconazoyl itraconazole is used for deep-seated mycosis, but it cannot be said that the antifungal spectrum, pharmacokinetics, tolerance, etc. are sufficiently satisfactory in clinical practice. . In addition, azoles, which have been mainly studied in this area, have problems in terms of their efficacy in severely ill patients and resistance due to long-term use of the same drugs. There is an urgent need to develop compounds that differ in structure, have excellent antifungal activity against the causative bacteria of deep mycosis, and are sufficiently satisfactory as pharmaceuticals.
Farmaco, 44 (9)， 819-829 (1989)に、 下式で示される化合物が、 Candida albicansや Aspergillus niger等に対する活性を有することが報告されている。
Figure imgf000004_0001
Farmaco, 44 (9), 819-829 (1989) reports that compounds represented by the following formula have activity against Candida albicans, Aspergillus niger, and the like.
Figure imgf000004_0001
(式中、 Xは 2、 3又は 4-ピリジル基を意味し、 Υは下式で示されるいずれかの基 を意味する。  (In the formula, X represents a 2, 3, or 4-pyridyl group, and Υ represents any group represented by the following formula.
Figure imgf000004_0002
Figure imgf000004_0002
また、 US2758050には、 真菌や細菌などの寄生病原体から植物を保護する農薬用 途のアミドラゾン誘導体が報告されている。  US2758050 also reports amidrazone derivatives for pesticide use that protect plants from parasitic pathogens such as fungi and bacteria.
H H
RN— N=C-R' RN— N = C-R '
NH2 NH 2
(式中、 Rはァリール又はァラルキルを、 R'は炭素数 5未満のァシル又はシァノを 意味する。 ） 発明の開示 (In the formula, R represents aryl or aralkyl, and R ′ represents acyl or cyano having less than 5 carbon atoms.)
本発明者等は、深在性真菌症の起因菌に対して活性を有する化合物について鋭意 研究を行った結果、 アミドラゾン誘導体が、 優れた抗真菌活性を示すことを見出し、 この知見に基づいて本発明を完成した。  The present inventors have conducted intensive studies on compounds having activity against the causative bacteria of deep mycosis, and as a result, have found that the amidrazone derivative exhibits excellent antifungal activity. Completed the invention.
即ち、 本発明によれば下記一般式 （Γ ) で示されるアミドラゾン誘導体又はそ の製薬学的に許容される塩を有効成分とする真菌症、 殊にカンジダ、 ァスペルギル ス、 クリプトコッカス等の真菌に起因する深在性真菌症の予防又は治療剤が提供さ れる。  That is, according to the present invention, fungal diseases containing an amidrazone derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient, particularly fungi such as Candida, Aspergillus, and Cryptococcus, are included. The present invention provides an agent for preventing or treating deep mycosis.
Figure imgf000004_0003
Figure imgf000004_0003
[式中、 記号は以下の意味を有する。 Ra： (1)置換されていてもよい単環乃至三環式ァリール、 （2)置換されていてもよ く、 N、 0及び Sから選択されるへテロ原子を 1個以上有する単環乃至三環式飽 和もしくは不飽和へテロ環、（3)置換されていてもよく、架橋されていてもよい シクロアルキル又は（4)置換されていてもよく、 架橋されていてもよいシクロ アルケニル、 [Wherein the symbols have the following meanings. R a : (1) optionally substituted monocyclic to tricyclic aryl, (2) optionally substituted monocyclic having at least one heteroatom selected from N, 0 and S To tricyclic saturated or unsaturated heterocyclic ring, (3) optionally substituted and crosslinked cycloalkyl or (4) optionally substituted and crosslinked cycloalkenyl ,
Rb： (1)置換されていてもよい単環乃至三環式ァリ一ル又は（2)置換されていても よく、 N、 0および Sから選択されるへテロ原子を 1個以上有する単環乃至三環 式飽和もしくは不飽和へテロ環、 R b : (1) optionally substituted monocyclic to tricyclic aryl or (2) optionally substituted, having one or more hetero atoms selected from N, 0 and S Monocyclic to tricyclic saturated or unsaturated heterocyclic ring,
Re及び Rd：一方は Hであり他方は存在しない、 R e and R d : one is H and the other is absent,
Re： -H又は- 0H、 R e : -H or-0H,
Rf ： -H、 -低級アルキル又は- Y-Ral、 R f : -H, -lower alkyl or -YR al ,
― ：単結合又は二重結合、 -: Single bond or double bond,
n： 1〜 8、 n: 1 to 8,
A：結合又は-低級アルキルで置換されていてもよい低級アルキレン、  A: a lower alkylene which may be substituted with a bond or -lower alkyl,
X：結合、 -C0-、 -C02-、 -CONRg -、 -COCONRg〗-、 -CH=CHCONRg2-、 -NRg3-、 -NRg4CO-、X: bond, -C0-, -C0 2 -, -CONR g -, -COCONR g 〗 -, -CH = CHCONR g2 -, -NR g3 -, -NR g4 CO-,
-NRg5C02-、 -NRg6CONRg7-、 -O-、 -OCO-、 -OCONRg8-、 -OC¾CONRg9-、 -S -、 -SO-、 -NR g5 C0 2 -, -NR g6 CONR g7 -, -O-, -OCO-, -OCONR g8 -, -OC¾CONR g9 -, -S -, -SO-,
-S02-、 -S02NRglC)-又は- S02NRgllCO-、 -S0 2- , -S0 2 NR glC) -or- S0 2 NR gll CO-,
Rg： -H、 -低級アルキル又は- Y-Ra2、 R g : -H, -lower alkyl or -YR a2 ,
Rgl〜Rgll： Rgと同様の基、 Rg l to Rg ll: the same groups as Rg,
Ral及び Ra2： Raと同様の基、 R al and R a2 : the same groups as R a
Y：結合、 -CH2-又は- CO-。 以下同様。 ] Y: bond, —CH 2 — or —CO—. The same applies hereinafter. ]
該一般式 （Γ ) で示される化合物中、 Rbが無置換あるいは- CH3、 -NO2もしくは -S03Hで置換されたフエニルで、 Ra-A-X-がべンゾイミダゾ一ル -2-ィルスルファ二 ル及びべンゾチアゾ一ル -2-ィルスルファニルである化合物は Rentogenol. Radiol., 10, 11-16 (1971)及び同 8， 230-236 (1969)に、 1H-ィンド一ル -2-ィルスルファニルであ る化合物は Stud. Biophys., 29, 169-175 (1971)に、 また、 が 2-ピリジ
Figure imgf000005_0001
ルメチルスルファニルェチルである化合物は US4252819 に、 ベンジルォキシカル ポニルァミノメチルである化合物は Chem. Ber" 99, 1111-1117 (1966)に、 1H-ィンド ール -3-ィルメチルである化合物は Khim. Geterotsikl. Soedin., 1993 (2), 189-196に、 4,5-ジヒドロ- 1H-イミダゾール -2-ィルメチルである化合物は Justus Liebigs Ann. Chem., 1978 (9), 1491-1504に、ベンジルである化合物は Acta Pol. Pharai., 37， 293-300 (1980)に、 フエニル (該フエニルは- Cl、 -C¾又は- OCH3で置換されていてもよい) - ヒドロキシメチルである化合物は J. Chem. Soc, Perkin Trans. 1, 1977 (6), 646-651及 び同 1975 (22)， 2280-2284にそれぞれ記載されている。 しかしながら、 これらの化合 物はいずれも放射線防御 （radioprotective effect) あるいは他の化合物の合成中間体 として用いられており、 抗真菌活性については何等開示されていない。 In the compound represented by the general formula (Γ), R b is phenyl which is unsubstituted or substituted with -CH 3 , -NO 2 or -S 0 3 H, and R a -AX- is benzoimidazole-2-ylsulfa The compounds that are benzyl and benzothiazolyl-2-ylsulfanyl are described in Rentogenol. Radiol., 10, 11-16 (1971) and 8, 230-236 (1969). Compounds that are ylsulfanyl are described in Stud. Biophys., 29, 169-175 (1971), and
Figure imgf000005_0001
The compound that is methylsulfanylethyl is described in US4252819 Compounds that are ponylaminomethyl are described in Chem. Ber "99, 1111-1117 (1966), and compounds that are 1H-indole-3-ylmethyl are described in Khim. Geterotsikl. Soedin., 1993 (2), 189-196. The compound which is 4,5-dihydro-1H-imidazole-2-ylmethyl is described in Justus Liebigs Ann. Chem., 1978 (9), 1491-1504, and the compound which is benzyl is described in Acta Pol. Pharai., 37, 293. -300 (1980), phenyl (the phenyl may be substituted by -Cl, -C¾ or -OCH 3 )-hydroxymethyl is a compound which is described in J. Chem. Soc, Perkin Trans. 1, 1977 (6 ), 646-651 and 1975 (22), 2280-2284. However, all of these compounds have been used as radioprotective effects or as intermediates in the synthesis of other compounds. No antifungal activity is disclosed.
また、 本発明によれば真菌に対して優れた活性を有する下記一般式 （I ) で示さ れる新規なアミドラゾン誘導体又はその製薬学的に許容される塩が提供される。  Further, according to the present invention, there is provided a novel amidrazone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, which has excellent activity against fungi.
Figure imgf000006_0001
Figure imgf000006_0001
[式中の記号は前記と同じ意味を示す。 但し、 Rbが無置換あるいは- CH3、 -N02も しくは- S03Hで置換されたフエニルの時、 は、 1H-ベンゾィミダゾ
Figure imgf000006_0002
ール -2-ィルスルファニルメチル、 1H-ベンゾイミダゾ一ル -2-ィルスルファ二ルェチ ル、 ベンゾチアゾール -2-ィルスルファニルメチル、 ベンゾチアゾ一ル -2-ィルスル ファニルェチル、 1H-インド一ル -2-ィルスルファニルメチル、 1H-インドール- 2-ィ ルスルファニルェチル、 1H-インドール- 3-ィルメチル、 2-ピリジルメチルスルファ ニルェチル、 ベンジルォキシカルポニルアミノメチル、 4，5-ジヒドロ- 1H-イミダゾ ール -2-ィルメチル、 ベンジル又はフエニル (該フエニルは- Cl、 -CH3又は- 0C¾で置 換されていてもょレ )ヒドロキシメチルであることはない。 ] [The symbols in the formula have the same meaning as described above. However, R b is an unsubstituted or - CH 3, -N0 2 also is properly - S0 When been phenyl substituted with 3 H, is, 1H-Benzoimidazo
Figure imgf000006_0002
2-ylsulfanylmethyl, 1H-benzimidazole-2-ylsulfanylethyl, benzothiazole-2-ylsulfanylmethyl, benzothiazol-2-ylsulfanylethyl, 1H-indole-2 -Ylsulfanylmethyl, 1H-indole-2-ylsulfanylethyl, 1H-indole-3-ylmethyl, 2-pyridylmethylsulfanylethyl, benzyloxycarbonylaminomethyl, 4,5-dihydro-1H-imidazo Lumpur 2 Irumechiru, (said phenyl - Cl, -CH 3 or - Yo Le be substitution in 0C¾) benzyl or phenyl is not hydroxymethyl. ]
化合物 （I ) において好ましい化合物としては、 （1 ) nが、 1〜6である化合物、 X力^ 結合、 -C0-、 -C0NRg -、 -COCONRgl-、 -CH=CHC0NRg2-、 - NRg3-、 -NRg4C0-、 -NRg6CONRg7-、 -0-、 -OCONRg8-、 -OCH2CONRg9-、 -S-又は- S02NRgl()-である化合物、 ( 3 ) Rbが、ハロゲン及びハロゲンで置換されていてもよい低級アルキルから選択 される置換基で置換されていてもよいフエニルである化合物又は （4 ) Re及び Rf が、 Hである化合物である。 Preferred compounds in the compound (I), (1) n is, compounds which are 1 to 6, X force ^ bond, -C0-, -C0NR g -, -COCONR gl -, -CH = CHC0NR g2 -, - NR g3 -, -NR g4 C0-, -NR g6 CONR g7 -, -0-, -OCONR g8 -, -OCH 2 CONR g9 -, -S- or - S0 2 NR gl () - compounds wherein, (3) a compound in which R b is phenyl optionally substituted with a substituent selected from halogen and lower alkyl optionally substituted with halogen, or (4) R e and R f are H Compound.
本発明には、 更に、 化合物 （I ) 又はその製薬学的に許容される塩と製薬学的に 許容される担体とからなる医薬組成物が包含される。  The present invention further includes a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
以下に、 本発明化合物を更に詳細に説明する。  Hereinafter, the compound of the present invention will be described in more detail.
本明細書において特に断らない限り、 「低級」 なる語は、 炭素数 1乃至 6個の直 鎖状又は分枝状の炭化水素鎖を意味する。  In this specification, unless stated otherwise, the term "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms.
「低級アルキル」 としては、 好ましくは炭素数 1〜4個のアルキルである。 「低 級アルキレン」 としては、 好ましくは炭素数 1〜3個のアルキレンである。 「シク 口アルキル」 は、 好ましくは炭素数 3〜： 10個のシクロアルキルである。 「シクロア ルケニル」 は、 好ましくは炭素数 3〜10個のシクロアルケニルである。  The “lower alkyl” is preferably an alkyl having 1 to 4 carbon atoms. The “lower alkylene” is preferably an alkylene having 1 to 3 carbon atoms. “Cycle mouth alkyl” is preferably cycloalkyl having 3 to 10 carbon atoms. “Cycloalkenyl” is preferably cycloalkenyl having 3 to 10 carbon atoms.
「単環乃至三環式ァリール」 としては、 好ましくは、 ベンゼン、 インダン、 ナフ 夕レン、 ァズレン、 フルオレンが挙げられる。  Preferred examples of the "monocyclic to tricyclic aryl" include benzene, indane, naphthylene, azulene and fluorene.
「N、 0及び Sから選択されるへテロ原子を 1個以上有する単環乃至三環式飽和 もしくは不飽和へテロ環」 とは、 N、 0及び Sから選択されるへテロ原子を 1〜4 個有する 4〜8員、 好ましくは、 5〜7員の単環式へテロ環化合物、 もしくはこれら の単環式へテロ環化合物が、 他のへテロ環あるいは 4〜8員の炭化水素環と縮合し た二乃至三環式へテロ環化合物である。 単環式へテロ環化合物としては、 好ましく は、 フラン、 テトラヒドロフラン、 テトラヒドロピラン、 ピロ一ル、 チォフェン、 チアゾ一ル、 ピラゾール、 トリァゾール、 テトラゾール、 ジヒドロイミダゾール、 イミダゾリジン、 チアジアゾール、 ォキサゾ一ル、 ピリジン、 ジヒドロピリジン、 ピぺリジン、 モルホリン、 ピリミジン、 ジヒドロピリミジン、 テトラヒドロピリミ ジン、 ピラジン、 ァゼパンが挙げられる。 二乃至三環式へテロ環化合物としては、 好ましくは、 インドール、 ジヒドロインドール、 ベンゾフラン、 クロメン、 ベンゾ イミダゾ一ル、 ベンゾチアゾール、 ジヒドロべンゾチアゾ一ル、 イミダゾピリジン、 テトラヒドロフロジォキソール、 プリン、 ベンゾォキサジン、 ベンゾジォキシン、 キノリン、 テトラヒドロキノリン、 ナフチリジン、 キノキサリン、 ベンゾァゼピン、 カルバゾール、 ァクリジン、 フエノチアジンが挙げられる。 「架橋されていてもよい」 とは、 結合もしくは低級アルキレンで架橋されていて もよいことをしめす。 「架橋されていてもよいシクロアルキル」 としては、 好まし くは、 シクロプロピル、 シクロへキシル、 デカリル、 ノルピナニル、 ァダマンチル である。 「架橋されていてもよいシクロアルケニル」 としては、 好ましくは、 シク 口へキセニル、 ビシクロ [2.2.1]ヘプテニル、 ノルポルネニルである。 "Monocyclic to tricyclic saturated or unsaturated heterocyclic ring having one or more heteroatoms selected from N, 0 and S" means that the heteroatom selected from N, 0 and S is 1 to Four- to eight-membered, preferably five- to seven-membered monocyclic heterocyclic compounds, or these monocyclic heterocyclic compounds are other heterocycles or four- to eight-membered hydrocarbon rings And bicyclic or tricyclic heterocyclic compounds. As the monocyclic heterocyclic compound, preferably, furan, tetrahydrofuran, tetrahydropyran, pyrrole, thiophene, thiazol, pyrazole, triazole, tetrazole, dihydroimidazole, imidazolidine, thiadiazole, oxazol, pyridine, Dihydropyridine, piperidine, morpholine, pyrimidine, dihydropyrimidine, tetrahydropyrimidine, pyrazine, azepane. As the bicyclic or tricyclic heterocyclic compound, preferably, indole, dihydroindole, benzofuran, chromene, benzoimidazole, benzothiazole, dihydrobenzothiazolyl, imidazopyridine, tetrahydrofurodixol, purine, Benzoxazine, benzodioxin, quinoline, tetrahydroquinoline, naphthyridine, quinoxaline, benzazepine, carbazole, acridine, phenothiazine. The expression "may be cross-linked" means that it may be cross-linked by a bond or lower alkylene. "Optionally bridged cycloalkyl" is preferably cyclopropyl, cyclohexyl, decalyl, norpinanyl, adamantyl. The “optionally crosslinked cycloalkenyl” is preferably cyclohexenyl, bicyclo [2.2.1] heptenyl and norpolenyl.
「ハロゲン」 とは、 F、 Cl、 Br及び Iである。  "Halogen" is F, Cl, Br and I.
「置換されていてもよい単環乃至三環式ァリール」 、 「置換されていてもよく、 N、 0及び Sから選択されるへテロ原子を 1個以上有する単環乃至三環式飽和もし くは不飽和へテロ環」 、 「置換されていてもよく、 架橋されていてもよいシクロア ルキル」 又は 「置換されていてもよく、 架橋されていてもよいシクロアルケニル」 の置換基としては、 通常これらの環基に置換しうる基であればいずれでもよい。好 ましくは、 -ハロゲン、 -ハロゲンで置換されていてもよい低級アルキル、 -0-低級ァ ルキル、 -S-低級アルキル、 -CO-低級アルキル、 -C02-低級アルキル、 -N02、 -CN、 -C02H、 -OH、 =0、 -SH、 -NRiR2 -NH-R3、 -N=CH-NR1R2, -CO-NR1!^ -R4、 -O- R4、 -低級アルキレン- R4、 -O-低級アルキレン- R4、 -R5、 -低級アルキレン- R5である (ここで、 R1及び R2は、 同一又は異なって- H又は-低級アルキルを、 R3は、 - C(Ph)3、 -C02-ベンジル等のアミノ基の保護基を、 R4は、 R6で置換されていてもよく、 N、 0 及び Sから選択されるへテロ原子を 1〜4個有する 4〜8員の飽和もしくは不飽和へ テロ環を、 R5は、 -ハロゲン、 -低級アルキレン- OH及び-ハロゲンで置換されていて もよい低級アルキルから選択される置換基で置換されていてもよいフエニルを、 R6 は- OH、 -NRlR -低級アルキル、 -低級アルキレン- OH、 -低級アルキレン- 0-低級ァ ルキル又は-低級アルキレン- NRi-CO-R2をそれぞれ示す。 以下同様。 ） 。 "Optionally substituted monocyclic to tricyclic aryl", "optionally substituted monocyclic to tricyclic saturated having one or more heteroatoms selected from N, 0 and S" Is an unsaturated heterocyclic ring, a optionally substituted and optionally crosslinked cycloalkyl, or an optionally substituted and optionally crosslinked cycloalkenyl group. Any group may be used as long as it can be substituted on these ring groups. Good Mashiku is - halogen, - halogen optionally substituted lower alkyl, -0- lower § alkyl, -S- lower alkyl, -CO- lower alkyl, -C0 2 - lower alkyl, -N0 2, -CN, -C0 2 H, -OH, = 0, -SH, -NRiR 2 -NH-R 3 , -N = CH-NR 1 R 2 , -CO-NR 1 ! ^ -R 4 , -O- R 4 , -lower alkylene-R 4 , -O-lower alkylene- R 4 , -R 5 , -lower alkylene-R 5 (wherein R 1 and R 2 are the same or different and are -H or- lower alkyl, R 3 is - select amino-protecting group such as benzyl, R 4 is from may be substituted by R 6, N, 0 and S - C (Ph) 3, -C0 2 A 5- to 8-membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms, wherein R 5 is -halogen, -lower alkylene-OH and -halogen which may be substituted with -halogen. Phenyl optionally substituted with a selected substituent, R 6 is - OH, -NR l R - lower alkyl, - lower alkylene - OH, - lower alkylene - 0- lower § alkyl or - lower alkylene -. Shown NRi-CO-R 2 each hereinafter the same)..
「ハロゲンで置換されていてもよい低級アルキル」 としては、 好ましくは、 クロ ロェチル、 トリフルォロメチル、 トリフルォロェチルである。  The “lower alkyl optionally substituted with halogen” is preferably chloroethyl, trifluoromethyl or trifluoroethyl.
一般式 （I ) において、 nが 2以上の時、 Re及び Rfは複数個存在するが、 これら の基は同一でも互いに異なっていてもよい。 In the general formula (I), when n is 2 or more, there are a plurality of R e and R f, but these groups may be the same or different from each other.
本発明化合物は、 一般式 （Γ ) 又は （I ) において、 RC=H又は Rd=Hの互変異 性体が存在する。 以下、 本明細書においては、 これらの互変異性体を代表して Re =Hで記載する。 また、 本発明化合物は、 置換基の種類によっては光学異性体、 幾 何異性体や互変異性体が存在する場合があるが、本発明にはこれらの異性体の分離 したもの、 あるいは混合物を包含する。 The compound of the present invention has a tautomer of R C = H or R d = H in the general formula (Γ) or (I). Hereinafter, in the present specification, these tautomers are represented by R e = H. In addition, the compound of the present invention may have optical isomers or Although a number of isomers and tautomers may exist, the present invention includes a separated form or a mixture of these isomers.
本発明化合物は、酸付加塩又は置換基の種類によっては塩基との塩を形成する場 合もある。 かかる塩としては、 製薬学的に許容される塩であり、 具体的には、 塩酸、 臭化水素酸、 ヨウ化水素酸、 硫酸、 硝酸、 リン酸等の無機酸、 ギ酸、 酢酸、 プロピ オン酸、 シユウ酸、 マロン酸、 コハク酸、 フマル酸、 マイレン酸、 乳酸、 リンゴ酸、 酒石酸、 クェン酸、 メタンスルホン酸、 エタンスルホン酸、 ァスパラギン酸、 ダル 夕ミン酸等の有機酸との酸付加塩、 ナトリウム、 カリウム、 マグネシウム、 カルシ ゥム、 アルミニウム等の無機塩基、 メチルァミン、 ェチルァミン、 エタノールアミ ン、 リジン、 オル二チン等の有機塩基との塩やアンモニゥム塩等が挙げられる。 さらに、 本発明は、 本発明化合物及びその塩の各種の水和物や溶媒和物及び結晶 多形の物質をも包含する。  The compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent. Such salts are pharmaceutically acceptable salts, and specifically include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propionate. Acid addition with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, cunic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and dalluminic acid Examples thereof include salts, inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ordithine; and ammonium salts. Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of the compound of the present invention and salts thereof.
(製造法）  (Manufacturing method)
本発明化合物及びその塩は、その基本骨格あるいは置換基の種類に基づく特徴を 利用し、種々の合成法を適用して製造することができ、例えば、 D. G. Neilsonら Chem. Rev., 70 (1), 151-170 (1970)、 K. M. Doyleら Synthesis, 583-584 (1974)又は S. Patai編 The Chemistry of Functional Groups "The chemistry of amidines and imidates", Vol. 1, 491-545に記載の各方法を適用して製造することができる。その際、官能基の種類に よっては、 当該官能基を原料ないし中間体の段階で適当な保護基、 即ち容易に当該官 能基に転化可能な基に置き換えておくことが製造技術上効果的な場合がある。 しかる のち、 必要に応じて保護基を除去し、 所望の化合物を得ることができる。 このような 官能基としては例えば水酸基、 力ルポキシル基、 アミノ基等を挙げることができ、 そ れらの保護基としては例えば Greeneら "Protective Groups in Organic Synthesis" (第二版） (1991)に記載の保護基を挙げることができ、これらを反応条件に応じて ¾!：用いればよ レ^ 以下にその代表的な製造法について説明する。 第 1製法 The compounds of the present invention and salts thereof can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or types of substituents. For example, DG Neilson et al., Chem. Rev., 70 (1 ), 151-170 (1970), KM Doyle et al. Synthesis, 583-584 (1974) or S. Patai ed.The Chemistry of Functional Groups "The chemistry of amidines and imidates", Vol. 1, 491-545. It can be manufactured by applying the method. At that time, depending on the type of the functional group, it is effective in production technology to replace the functional group with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group that can be easily converted to the functional group. It may be. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include a hydroxyl group, a hydroxyl group, an amino group, and the like. Examples of such a protecting group are described in Greene et al., "Protective Groups in Organic Synthesis" (Second Edition) (1991). The protecting groups described above can be mentioned. These can be used according to the reaction conditions. First manufacturing method
Figure imgf000010_0001
Figure imgf000010_0001
(I)  (I)
(式中、 Rsは低級アルキルを意味する。 以下同様。 ）  (In the formula, Rs represents lower alkyl. The same applies hereinafter.)
本製法は、 二トリル体 （II) より得られる中間体 （IV) を化合物 （V) と反応さ せることにより本発明化合物 （I ) を得る方法である。  The present production method is a method for obtaining the compound (I) of the present invention by reacting the intermediate (IV) obtained from the nitrile form (II) with the compound (V).
中間体 （IV) に、 メタノール、 エタノール等のアルコール類、 ジェチルエーテル、 ジォキサン等のエーテル類、 アセトン、 2-ブ夕ノン等のケトン類、 酢酸ェチル又は ジメチルホルムアミド （DMF) 等の反応に不活性な溶媒中、 ヒドラジン体 （V) を 反応させて、 本発明化合物 （I ) を得る。 本反応は冷却下乃至加熱下、 好ましくは、 ― 20°C〜50°Cの温度下で行うことが望ましい。  Intermediates (IV) may not react with alcohols such as methanol and ethanol, ethers such as getyl ether and dioxane, ketones such as acetone and 2-butanone, ethyl acetate and dimethylformamide (DMF). The compound of the present invention (I) is obtained by reacting the hydrazine derivative (V) in an active solvent. This reaction is carried out under cooling to heating, preferably at a temperature of -20 ° C to 50 ° C.
尚、 化合物 （V) は、 市販されているか、 あるいは、 日本化学会編 「第 4版 実験 化学講座」 20， 338-342に記載の方法やその変法を適用して製造可能である。  The compound (V) is commercially available, or can be produced by applying the method described in “The 4th Edition Experimental Chemistry Course” edited by The Chemical Society of Japan, 20, 338-342 or a modification thereof.
中間体 （IV) は、 1当量以上のアルコール類 （I I I) (好ましくは、 エタノール） の存在下、 ジクロロメタン、 ジクロロェタン、 クロ口ホルム等のハロゲン化炭化水 素類やエーテル類等の反応に不活性な溶媒中、 塩化水素を作用させて得られる。 本 反応は冷却下乃至加熱下、好ましくは一 70°C〜30°Cの温度下で行うことが望ましい。 Intermediate (IV) is inactive in the reaction of halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and ethers in the presence of one or more equivalents of alcohol (III) (preferably ethanol). It is obtained by reacting hydrogen chloride in a suitable solvent. This reaction is carried out under cooling to heating, preferably at a temperature of from 170 to 30 ° C.
第 2製法 Second manufacturing method
Figure imgf000011_0001
Solv.
Figure imgf000011_0001
Solv.
(I)  (I)
(式中、 Halは八ロゲンを意味する。 以下同様。 ）  (In the formula, Hal means octogen. The same applies hereinafter.)
本製法は、 チオアミド体 （VI) より得られる中間体 （VII) を化合物 （V) と反応 させることにより本発明化合物 （I ) を得る方法である。  This production method is a method for obtaining the compound (I) of the present invention by reacting the intermediate (VII) obtained from the thioamide (VI) with the compound (V).
中間体 （VII) より本発明化合物 （ I ) を得る反応は、 前記第 1製法に記載の中 間体 （IV) からの製法とほぼ同様の条件下で行うことができる。  The reaction for obtaining the compound (I) of the present invention from the intermediate (VII) can be carried out under almost the same conditions as in the method for preparing the intermediate (IV) described in the first method.
中間体 （VII) は、 チオアミド体 （VI) を、 ケトン類、 DM.F等適当な溶媒中、 ョ ゥ化メチル等のメチルハライドゃミヤバイン試薬等のメチル化剤を反応させて得 られる。 本反応は冷却下乃至加熱下、 好ましくは、 0°C〜： 120°Cの温度下で行うこと が望ましい。  Intermediate (VII) can be obtained by reacting thioamide (VI) with a methylating agent such as methyl halide or Miyabaine reagent such as methyl iodide in a suitable solvent such as ketones or DM.F. This reaction is carried out under cooling to heating, preferably at a temperature of 0 ° C to: 120 ° C.
原料化合物 （II) は、 市販されているか、 あるいは、 公知の二トリル体の製迨法、 例えば、亀谷ら「有機合成化学」 6， 203-252や日本化学会編「新実験化学講座」 14(3), 1428-1484等に記載の方法やその変法を適用して製造可能である。 また、 所望の Ra 基を有する化合物と二トリル基を含む化合物を、 下記ァシル化、 スルホニル化、 ァ ルキル化、 ウレァ化又は力ルバメート化で縮合することによつても製造可能である The raw material compound (II) is commercially available, or a known nitrile production method, for example, Kameya et al., “Synthetic Organic Chemistry” 6, 203-252, and the Chemical Society of Japan, “New Experimental Chemistry Course” 14 It can be manufactured by applying the method described in (3), 1428-1484, or a modification thereof. Further, it can also be produced by condensing a compound having a desired Ra group and a compound having a nitrile group by the following acylation, sulfonylation, alkylation, ureaization, or cationization.
Re R e
Ra+A— COOH + R" C-hCN Ra+A— S02CI + HN CN (1) L R n (2) (5) R9 L RfJn (2) R a + A- COOH + R " C-hCN R a + A- S0 2 CI + HN CN (1) LR n (2) (5) R 9 LR f Jn (2)
Figure imgf000012_0001
Figure imgf000012_0001
c Rl  c Rl
(表中、 Rtは-ハロゲン又は- OS02Rvを、 Ruは- OH、 -SH又は- NHRgを、 Rvは低級ァ ルキル又は置換されていてもよいフエニルをそれぞれ示す。 以下同様。 ） (In the table, Rt is - a OS0 2 R v, is R u - - halogen or OH, -SH or -. The NHR g, R v represents lower § alkyl or substituted or unsubstituted good phenyl respectively forth )
( 1 ) ァシル化  (1) Acylation
カルボン酸化合物を、 ハロゲン化炭化水素類、 エーテル類、 DMF等の不活性溶 媒中、 冷却下乃至加熱下、 好ましくは、 — 20° (：〜 60°Cで、 酸ハライド法、 混合ある いは対称酸無水物法、 活性エステル法、 縮合剤 （1,3-ジシクロへキシルカルポジィ ミド (DCC)、 1-ェチル -3-[3- (ジメチルァミノ）プロピル]カルポジイミド (WSC)、 カル ポニルジイミダゾ一ル (CDI)等） 法等により、 ァミノ化合物あるいはアルコール化 合物と縮合することにより行う。 有機塩基 （好ましくは、 トリェチルァミン、 N- メチルモルホリン、 ピリジン、 4-(N，N-ジメチルァミノ）ピリジン） の存在下に反応 させるのが、 反応を円滑に進行させる上で有利な場合がある。  The carboxylic acid compound is cooled or heated in an inert solvent such as halogenated hydrocarbons, ethers, DMF, etc., preferably at −20 ° (: to 60 ° C., acid halide method, mixing or Are symmetric acid anhydride method, active ester method, condensing agent (1,3-dicyclohexylcarpimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carpimide (WSC), carbonyldiimidazole ( CDI), etc.) by condensation with an amino compound or alcohol compound by a method, etc. The presence of an organic base (preferably, triethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine) In some cases, it is advantageous to make the reaction proceed smoothly in order for the reaction to proceed smoothly.
( 2 ) スルホニル化  (2) Sulfonylation
塩化スルホ二ル基を有する化合物を、 ァミノ化合物と縮合することにより行う。 反応は前記ァシル化とほぼ同様の条件下で行われる。 It is carried out by condensing a compound having a sulfonyl chloride group with an amino compound. The reaction is carried out under substantially the same conditions as in the above acylation.
( 3 ) アルキル化  (3) Alkylation
アルキル化反応は、 ベンゼン、 トルエン、 キシレン等の芳香族炭化水素類、 ハロ ゲン化炭化水素類、 エーテル類、 ケトン類、 DMF、 ジメチルァセトアミド (DMA) 及び N-メチルピロリドン等の反応に不活性な溶媒中、 有機ハロゲン化物や、 メタ ンスルホニルォキシ、 P-トルエンスルホニルォキシ等の有機スルホン酸エステル等 のアルキル化剤とアルコール、チオール又はアミノ化合物とを当量あるいは一方を 過剰量用いて、 冷却下〜加熱下に行われる。 前記の有機塩基、 無機塩基 （好ましく は、 水酸化ナトリウム、 炭酸カリウム） 又は金属塩塩基 （好ましくは、 水素化ナト リウム、 tert-ブトキシカリウム、 ブチルリチウム、 リチウムジイソプロピルアミド） の存在下に反応させるのが、 反応を円滑に進行させる上で有利な場合がある。 The alkylation reaction is incompatible with the reaction of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons, ethers, ketones, DMF, dimethylacetamide (DMA) and N-methylpyrrolidone. In an active solvent, an alkylating agent such as an organic halide or an organic sulfonic acid ester such as methanesulfonyloxy or P-toluenesulfonyloxy and an alcohol, a thiol or an amino compound are used in an equivalent amount or an excess amount of one. It is performed under cooling to heating. The reaction is carried out in the presence of the above-mentioned organic base, inorganic base (preferably, sodium hydroxide, potassium carbonate) or metal salt base (preferably, sodium hydride, potassium tert-butoxy, butyllithium, lithium diisopropylamide). However, there are cases where it is advantageous for the reaction to proceed smoothly.
( 4 ) ウレァ化、 力ルバメート化 (4) Urea, force bamate
ウレァ化は所望のイソシァネートを、力ルバミン酸エステル化は所望のクロロギ 酸エステルをそれぞれ用い、 ァミノ化合物と反応させることにより得られる。 反応 は前記アミド化とほぼ同様の条件下で行われる。  The ureation can be obtained by reacting a desired isocyanate with the desired rubamic acid ester, and the desired chloroformate can be reacted with an amino compound. The reaction is carried out under almost the same conditions as in the above amidation.
.また、 Xが- SO-又は- S02-である原料化合物 （Ila) は、 Xが- S-である化合物を m- クロ口過安息香酸等の過酸化物で酸化することにより合成される。 反応は、 日本化 学会編 「新実験化学講座」 15(1-1)， 60又は日本化学会編 「新実験化学講座」 15(1-2), 664-727等に記載の方法を適用して行われる。 また、 Xが- S02-である化合物は、 ス ルフィン酸塩と有機ハロゲン化物とを前記のアルキル化の条件に付すことによつ ても合成される。 . Further, X is - SO- or - S0 2 - starting compound is (Ila) is, X is - are synthesized by oxidizing the S-, compound with a peroxide such as m- black port perbenzoate You. For the reaction, apply the method described in “New Experimental Chemistry Course” edited by the Chemical Society of Japan, 15 (1-1), 60 or “New Experimental Chemistry Course” edited by the Chemical Society of Japan, 15 (1-2), 664-727, etc. Done. Further, X is - S0 2 - Compounds that are also synthesized cowpea in subjecting a scan luffin salt and an organic halide to the conditions of alkylation of the.
原料化合物 （VI) は、 日本化学会編 「新実験化学講座」 14(3), 1827-1832に記載の チォアミドの製造法やその変法を適用して製造可能である。 例えば、 アミド化合物 を芳香族炭化水素類、 エーテル類等の不活性溶媒中、 五硫化二リンあるいは Lawesson試薬等を反応させることにより合成できる。  The starting compound (VI) can be produced by applying the thioamide production method described in “New Experimental Chemistry Course” edited by The Chemical Society of Japan, 14 (3), 1827-1832 or a modification thereof. For example, it can be synthesized by reacting an amide compound with diphosphorus pentasulfide or a Lawesson reagent in an inert solvent such as aromatic hydrocarbons and ethers.
このようにして製造された本発明化合物は、 遊離の化合物、 塩あるいは水和物、 各種溶媒和物として単離 ·精製される。 塩は通常の造塩処理に付すことにより得ら れる。 単離 ·精製は抽出、 濃縮、 溶媒留去、 結晶化、 濾過、 再結晶、 各種クロマト  The compound of the present invention thus produced is isolated and purified as a free compound, salt or hydrate, and various solvates. The salt can be obtained by subjecting the salt to a usual salt-forming treatment. Isolation and purification include extraction, concentration, solvent evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
-等の通常の化学操作を適宜適用して行うことができる。各種異性体は異 性体間の物理化学的な差を利用して常法により単離できる。光学異性体は一般的な 光学分割法、 例えば分別結晶化又はクロマトグラフィー処理により分離できる。 あ るいは適当な光学活性な原料から又は各種不斉反応を利用することにより製造す ることもできる。 産業上の利用可能性 -Or the like can be performed by appropriately applying ordinary chemical operations. Different isomers are different It can be isolated by a conventional method utilizing the physicochemical difference between sexes. Optical isomers can be separated by common optical resolution methods, for example, fractional crystallization or chromatography. Alternatively, it can be produced from a suitable optically active raw material or by utilizing various asymmetric reactions. Industrial applicability
本発明化合物は、 強い抗真菌活性、 特に深在性真菌症の起因菌に対する活性を示す こと力ゝら、 真菌症、 特に日和見感染症等の各種の深在性真菌症の予防又は治療に有用 である。  The compound of the present invention exhibits strong antifungal activity, especially activity against causative bacteria of deep mycosis, and is useful for prevention or treatment of various deep mycoses such as fungal diseases, especially opportunistic infections. It is.
本発明化合物の真菌に対する有効性は以下の各実験により確認された。  The effectiveness of the compound of the present invention on fungi was confirmed by the following experiments.
1 . 抗真菌活性測定 1. Antifungal activity measurement
抗真菌活性は、 合成液体培地 （0.5%glucose添加 yeast nitrogen base in phosphate buf fer) を用いた微量液体希釈法により測定した。 即ち、 2倍段階希釈系列の薬液 2 μΐに 最終菌濃度 l X 104cells/mlに調整した液体培地 200μ1を加えた。 培養後、 595nmでの吸光 度を測定し、 80%以上の増殖阻害率を示した被験化合物の最小濃度をもって抗真菌活 性値 ^g/ml) とした。 培養条件は、 カンジダアルビカンス (Candida albican ΉΜΜ 1768は 37°C C、 l曰、 クリフ卜コッ Jス不オフォ レマノス ix^ryptococcus neoformans) T ΙΜΜ0362は 27°Cで 2日、 ァスペルギルスフミガタス (Aspergillus fumigatu ΉΜΜ177 6は 27°Cで 3日とした。 The antifungal activity was measured by a microfluidic dilution method using a synthetic liquid medium (0.5% glucose-added yeast nitrogen base in phosphate buf fer). That is, 200 μl of a liquid medium adjusted to a final bacterial concentration of l × 10 4 cells / ml was added to 2 μl of the drug solution in a 2-fold serial dilution series. After the culture, the absorbance at 595 nm was measured, and the minimum concentration of the test compound that showed a growth inhibition rate of 80% or more was defined as the antifungal activity value ^ g / ml). The culture conditions were as follows: Candida albican (Candida albican ΉΜΜ 1768: 37 ° C; l: Cliffcoc Js nonophoremanos ix ^ ryptococcus neoformans) T ΙΜΜ0362: 2 days at 27 ° C; Aspergillus fumigatus fumigatu # 1776 was 3 days at 27 ° C.
尚、対照薬として Farmaco, 44 (9), 819-829 (1989)に記載の化合物 Da (N2-(5-ニトロフ ルフリデン) -2-ピリジンカルボキシアミドラゾン） （表 1中、 Ref 1) 及びフルコナゾ ール （表 1中、 Ref 2) を使用した。 Incidentally, Farmaco, 44 as a control agent (9), 819-829 The compound according to (1989) Da (N 2 - (5- Nitorofu Rufuriden) -2-pyridinecarboxamide amidrazone) (in Table 1, Ref 1) and Fluconazole (Ref 2 in Table 1) was used.
表 1に本発明化合物及び対照薬の抗真菌活性 （μ§/ηα1) を示す。 Table 1 shows the antifungal activity ( μ§ / ηα1) of the compound of the present invention and the control drug.
Figure imgf000015_0001
Figure imgf000015_0001
表中の記号は以下に示す通りである。 The symbols in the table are as shown below.
Ex：実施例化合物番号； CA： Candida albicans ΉΜΜ1768； Ex: Example compound number; CA: Candida albicans ΉΜΜ1768;
Crv： Crvptococcus neoformans ΉΜΜ03οζ； Asp： Aspergillus fumigatus ΉΜΜ1776 表中の値から明らかなように、 本発明化合物は各深在性真菌症の起因菌に対し、 対 照薬と比較して数倍から数十倍の優れた抗菌活性を示すことが確認された。 Crv: Crvptococcus neoformans ΉΜΜ03οζ; Asp: Aspergillus fumigatus ΉΜΜ1776 As is clear from the values in the table, the compounds of the present invention showed several times to several tens times the bacterium of each deep mycosis compared with the control agent. It was confirmed to exhibit excellent antibacterial activity.
2 . 感染防御実験  2. Infection prevention experiment
( 1 ) カンジダアルビ力ンス ΉΜΜ1768株による感染モデルに対する治療効果  (1) Therapeutic effect of Candida albicans ΉΜΜ1768 strain on infection model
ICR系雄マウス （5週齢） の尾静脈内に 2 X 106cellsを投与し、 感染を惹起した。 治療 は、 感染直後または 2時間後より開始し、 1日 1回 4日間行った。 薬効は、 50%のマウス が生存した期間を MLD (median life days) としコントロールの MLDとの比を指標とし た。 尚、 対照薬としてフルコナゾール、 イトラコナゾ一ルを使用した。 2 × 10 6 cells were injected into the tail vein of ICR male mice (5 weeks old) to induce infection. Treatment was started immediately or 2 hours after infection and was performed once a day for 4 days. The drug efficacy was defined as the MLD (median life days) of the period in which 50% of the mice survived, and the ratio to the control MLD was used as an index. Fluconazole and itraconazole were used as control drugs.
( 2 ) ァスペルギルスフミガタス ΉΜΜ1776株による感染モデルに対する治療効果 ICR系雄マウス （5週齢） の尾静脈内に 5 X 105cellsを投与し、 感染を惹起した。 治療 は、 感染直後または 2時間後より開始し、 1日 1回 4日間行った。 薬効【お 0%のマウスが 生存した期間を MLDとしコントロールの MLDとの比を指標とした。 尚、 対照薬として イトラコナゾ一ルを使用した。 これらの試験の結果、 本発明化合物は、 各対照薬と比 較して良好な感染防御作用を示すことが確認された。 (2) Therapeutic effect of the Aspergillus fumigatus ΉΜΜ1776 strain on the infection model 5 × 10 5 cells were injected into the tail vein of male ICR mice (5 weeks old) to induce infection. Treatment was started immediately or 2 hours after infection and was performed once a day for 4 days. Efficacy [The period during which 0% of mice survived was defined as the MLD, and the ratio to the control MLD was used as an index. Itraconazole was used as a control. As a result of these tests, it was confirmed that the compound of the present invention exhibited a favorable infection protective effect as compared with each control drug.
3 . 細胞障害性試験  3. Cytotoxicity test
細胞障害性試験として、 ヒーラ S3に対する増殖阻害濃度を測定した。即ち、 ヒーラ S 3細胞を 5 X 104cells/ml〖こ調整した 20mM HEPESを含む培地（10%FBS添加 MEM) 200μ 1に 2倍段階希釈系列の薬液 2μ1を加え、 3日間培養した。 細胞を洗浄後、 Cell Counting Kitを用いて、 阻害率を計算し、 50%阻害する濃度 （IC50値） を算出し、 本発明化合物 は細胞障害性が低いことが確認された。 As a cytotoxicity test, the growth inhibitory concentration for HeLa S3 was measured. That is, 2 μl of a two-fold serial dilution of the drug solution was added to 200 μl of a medium (MEM containing 10% FBS) containing 5 × 10 4 cells / ml of HeLa S 3 cells prepared at 5 × 10 4 cells / ml and cultured for 3 days. After washing the cells, using the Cell Counting Kit, the inhibition rate was calculated, to calculate the concentration (IC 50 value) that inhibits 50%, the compound of the present invention was confirmed to be less cytotoxic.
本発明化合物 ( I ) 又はその製薬学的に許容される塩等の 1種又は 2種以上を有効成 分として含有する医薬組成物は、 通常製剤化に用いられる担体ゃ賦形剤、 その他の添 加剤を用いて、 錠剤、 散剤、 細粒剤、 顆粒剤、 カプセル剤、 丸剤、 液剤、 注射剤、 座 剤、 膣剤、 軟膏、 貼付剤等に調製され、 経口的又は非経口的に投与される。  Pharmaceutical compositions containing one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as carriers, excipients, and other ingredients commonly used in pharmaceutical preparations. Prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, vaginals, ointments, patches, etc. using additives, and orally or parenterally Is administered.
本発明化合物のヒトに対する臨床投与量は適用される患者の症状、投与対象の年齢、 性別、 投与経路等を考慮して個々の場合に応じて適宜決定されるが、 通常成人一人当 たり、 1日につき 0.；！〜 200 mg kgの範囲で 1回から数回に分け経口投与される力 又は 成人一人当たり、 1日にっき0.001〜25 01¾ 1¾の範囲で、 1回から数回に分け静脈内投 与されるか、 又は 1日 1〜24時間の範囲で静脈内持続投与される。 もちろん前記したよ うに、 投与量は種々の条件で変動するので、 上記投与量より少ない量で十分な場合も ある。 The clinical dose of the compound of the present invention for humans is appropriately determined depending on the individual case in consideration of the symptoms of the patient to be applied, the age, sex, administration route, and the like of the administration subject. Or 0 per day! ~ 200 mg kg range per force or an adult is orally administered several times from one in the range of 1 day diary 0.001 01 ¾ 1 ¾, it is given intravenously throw divided into one to several times Or continuous intravenous administration for 1 to 24 hours per day. Of course, as described above, since the dose varies under various conditions, a smaller dose than the above dose may be sufficient.
本発明による経口投与のための固体組成物としては、 錠剤、 散剤、 顆粒剤等が用い られる。 このような固体組成物においては、 一つ又はそれ以上の活性物質が、 少なく とも一つの不活性な希釈剤、 例えば乳糖、 マンニトール、 ブドウ糖、 ヒドロキシプロ ピルセルロース、 微結晶セルロース、 デンプン、 ポリビニルピロリドン、 メタケイ酸 アルミン酸マグネシウムと混合される。 組成物は、 常法に従って、 不活性な希釈剤以 外の添加剤、 例えばステアリン酸マグネシウムのような潤滑剤や繊維素ダリコール酸 カルシウムのような崩壊剤、 ラクト一スのような安定化剤、 グルタミン酸又はァスパ ラギン酸のような溶解補助剤を含有していても良い。 錠剤又は丸剤は必要によりショ 糖、 ゼラチン、 ヒドロキシプロピルセルロース、 ヒドロキシプロピルメチルセルロー スフ夕レート等の糖^^又は胃溶性あるいは腸溶性のフィルムで被膜しても良い。  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, Metasilicate Silicate is mixed with magnesium aluminate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose dalycholate, a stabilizer such as lactose, A solubilizing agent such as glutamic acid or aspartic acid may be contained. If necessary, tablets or pills may be coated with a sugar such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose sulfate or a gastric or enteric film.
経口投与のための液体組成物は、 製薬学的に許容される乳濁剤、 溶液剤、 懸濁剤、 シロップ剤、 エリキシル剤等を含み、 一般的に用いられる不活性な希釈剤、 例えば精 製水、 エタノールを含む。 この組成物は不活性な希釈剤以外に可溶化乃至溶解補助剤、 湿潤剤、 懸濁剤のような補助剤、 甘味剤、 風味剤、 芳香剤、 防腐剤を含有していても 良い。  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as e.g. Includes water production and ethanol. The composition may contain, besides the inert diluent, solubilizing or solubilizing agents, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances and preservatives.
非経口投与のための注射剤としては、 無菌の水性又は非水性の溶液剤、 懸濁剤、 乳 濁剤を包含する。 水性の溶液剤、 懸濁剤としては、 例えば注射剤用蒸留水及び生理食 塩水が含まれる。 非水性の溶液剤、 懸濁剤としては、 例えばプロピレングリコール、 ポリエチレングリコール、 オリ一ブ油のような植物油、 エタノールのようなアルコ一 ル類、 ポリソルべ一ト 80 (商品名） 等がある。 このような組成物は、 更に等張化剤、 防腐剤、 湿潤剤、 乳化剤、 分散剤、 安定化剤 （例えばラクト一ス） 、 可溶化乃至溶解 補助剤のような添カロ剤を含んでも良い。 これらは例えばバクテリア保留フィル夕一を 通す濾過、 殺菌剤の配合又は照射によって無菌化される。 又、 これらは無菌の固体組 成物を製造し、使用前に無菌水又は無菌の注射溶媒に溶解して使用することもできる。' 発明を実施するための最良の形態 Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (trade name). Such compositions may also contain additional carotenoids, such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or dissolving aids. . These can be sterilized by, for example, filtration through a bacterial retention filter, blending of a bactericide, or irradiation. In addition, these can be used by producing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use. ' BEST MODE FOR CARRYING OUT THE INVENTION
以下、 実施例によって本発明を具体的に説明するが、 これらは本発明の範囲を限 定するものではない。 また、 新規な原料化合物の製法を参考例に示す。  Hereinafter, the present invention will be described specifically with reference to Examples, but these do not limit the scope of the present invention. In addition, a method for producing a novel starting compound is shown in Reference Examples.
表 2に原料化合物 （Π) の製法を示す。 原料化合物 （II) は、 表 2に示す Ra-group のいずれかと Re-groupのいずれかとの反応により製造される。以下、 これらのダル ープの組み合わせを参考例化合物の合成ルートとして、参考例番号の後に掲記する。 例えば、 1-aは、 Ra-groupの 1と Re-groupの aを反応させ、 原料化合物 （II) を合成 するルートを示す。 Table 2 shows the production method for the starting compound (Π). The starting compound (II) is produced by reacting any of the R a -groups shown in Table 2 with any of the R e -groups. Hereinafter, combinations of these groups will be described after the reference example numbers as synthesis routes for the reference example compounds. For example, 1-a is 1 and R e of R a -group - shows the route by reacting g roup of a, synthesized starting compounds (II).
表 2 Table 2
Figure imgf000018_0001
Figure imgf000018_0002
また、 上記表 2の組み合わせ以外による原料化合物 （II) の製造法及びチォアミ ド体 （VI) の製造法を 「その他の製法 (Oth-:！〜 9)」 として同様に掲記する。
Figure imgf000018_0001
Figure imgf000018_0002
In addition, the method for producing the raw material compound (II) and the method for producing the thioamide derivative (VI) by a method other than the combination shown in Table 2 above are similarly described as “Other production methods (Oth- :! to 9)”.
参考例 1 (1-a) Reference example 1 (1-a)
ベンジルアルコールを DMF中、 水素化ナトリウム存在下、 3-クロ口プロパン二 トリルと反応させ、 3-ベンジルォキシプロパン二トリルを得た。  Benzyl alcohol was reacted with 3-chloropropane nitrile in DMF in the presence of sodium hydride to give 3-benzyloxypropane nitrile.
参考例 2 (2-b) Reference example 2 (2-b)
2,4-ジクロ口- 5-フルォロピリミジンをクロ口ホルム中、トリェチルァミン存在下、 3- (メチルァミノ、プロパン二トリルと反応させ、 3-[N-(2-ク口口- 5-フルォロピリミジ ン -4-ィル) -N-メチルァミノ]プロパン二トリルを得た。 Reaction of 2,4-dichro-5-fluoropyrimidine with 3- (methylamino, propanenitrile in the presence of triethylamine in chloroform form gives 3- [N- (2-c-mouth-5-fluoropyrimidine) N-4-yl) -N-methylamino] propane nitrile was obtained.
参考例 3 (2-d) Reference example 3 (2-d)
2—[(4-メチルベンゼンスルホニル)ォキシメチル] -2,3-ジヒドロ -1,4-ベンゾジォキ シンを DMSO中、 シアン化カリウムと反応させ、 2-(2，3-ジヒドロ- 1,4-ベンゾジォキ シン- 2-ィル)ァセトニトリルを得た。  2-[(4-Methylbenzenesulfonyl) oxymethyl] -2,3-dihydro-1,4-benzodioxin is reacted with potassium cyanide in DMSO to give 2- (2,3-dihydro-1,4-benzodioxin- 2-yl) acetonitrile was obtained.
参考例 4 (2-f) Reference example 4 (2-f)
4-クロ口- 2-メチルキノリンを、 2，2，-ァゾビスイソプチロニトリル （AIBN) 存在 下、 N-プロモスクシンイミド （NBS) で処理し、 2-ブロモメチル -4-クロ口キノリン を得、 該化合物をピストリメチルシリルアミドカリウム存在下、 3-ヒドロキシプロ パンニトリルと反応させ、 3-[(4-クロ口- 2-キノリル)メトキシ]プロパン二トリルを得 た。  4-Chloro-2-methylquinoline is treated with N-promosuccinimide (NBS) in the presence of 2,2, -azobisisobutyronitrile (AIBN) to give 2-bromomethyl-4-chloroquinoline The compound was reacted with 3-hydroxypropanenitrile in the presence of potassium pistrimethylsilylamide to give 3-[(4-chloro-2-quinolyl) methoxy] propanenitrile.
参考例 5 (3-a) Reference example 5 (3-a)
2-ブロモメチル -4-クロ口キノリンをチォゥレアと反応させ、 次いで、 水酸化ナト リウム存在下、 3-クロ口プロパン二トリルと反応させ、 3-[(4-クロ口- 2-キノリル)メ チルスルファニル]プロパン二トリルを得た。  Reaction of 2-bromomethyl-4-chloroquinoline with thioperia, followed by reaction with 3-chloropropanenitrile in the presence of sodium hydroxide to give 3-[(4-chloro-2-quinolyl) methyl [Sulfanyl] propane nitrile was obtained.
参考例 6 (4-b) Reference Example 6 (4-b)
N-ベンジルエタノールアミンをジクロロェ夕ン中、ジイソプロピルェチルァミン 存在下、 4-プロモブ夕- 2-ェンェチルエステルと反応後、 トルエン中、 1,8-ジァザビ シク口 [5.4.0]-7-ゥンデセンで処理して得た化合物を、 1N塩酸水溶液で加水分解後、 ジクロロェタン中、 1-ヒドロキシベンゾトリアゾール（HOBT) 及び WSC存在下、 3-メチルァミノプロパン二トリルと反応させ、 2-(4-ベンジルモルホリン -2-ィル) -N- (2-シァノエチル) -N-メチルァセトアミドを得た。  N-Benzylethanolamine is reacted with 4-bromobut-2-eneethyl ester in the presence of diisopropylethylamine in dichloroethane, and then in toluene with 1,8-diazabicycle [5.4.0]- The compound obtained by treating with 7-pentadecene is hydrolyzed with a 1N aqueous hydrochloric acid solution, and then reacted with 3-methylaminopropane nitrile in dichloroethane in the presence of 1-hydroxybenzotriazole (HOBT) and WSC, (4-Benzylmorpholin-2-yl) -N- (2-cyanoethyl) -N-methylacetoamide was obtained.
参考例 7 (4-c) Reference Example 7 (4-c)
イソニコチノィル クロリド 一塩酸塩を塩化メチレン中、 トリヱチルァミン存在 下、 3-ァミノプロパン二トリルと反応させ、 N-(2-シァノエチル)イソニコチンアミ ドを得た。  Isonicotinol chloride monohydrochloride was reacted with 3-aminopropane nitrile in methylene chloride in the presence of triditylamine to obtain N- (2-cyanoethyl) isonicotinamide.
参考例 8 (4-i) Reference Example 8 (4-i)
2-(4-メトキシァニリノ）ァセトニトリルを塩化メチレン中、 トリェチルアミン存 在下、 塩化ァセチルと反応して、 N-シァノメチル -N-(4-メトキシフエ二ル） ァセト アミドを得た。 2- (4-Methoxyanilino) acetonitrile reacts with acetyl chloride in methylene chloride in the presence of triethylamine to give N-cyanomethyl-N- (4-methoxyphenyl) acetate The amide was obtained.
参考例 9 (4-i) Reference Example 9 (4-i)
塩化ァセチルの代わりにニコチノィル クロリド 一塩酸塩を用いる以外は、参考 例 8と同様にして、 N-シァノメチル -N-(4-メトキシフエニル)ニコチンアミドを得た。 参考例 1 0 (5-b)  N-Cyanomethyl-N- (4-methoxyphenyl) nicotinamide was obtained in the same manner as in Reference Example 8, except that nicotinyl chloride monohydrochloride was used instead of acetyl chloride. Reference Example 10 (5-b)
イソニコチノィル クロリド 一塩酸塩の代わりにベンゼンスルホニル クロリド を用いる以外は、 参考例 7と同様にして、 N-(2-シァノエチル) -N-メチルベンゼンス ルホンアミドを得た。  N- (2-Cyanoethyl) -N-methylbenzenesulfonamide was obtained in the same manner as in Reference Example 7, except that benzenesulfonyl chloride was used instead of isonicotinoyl chloride monohydrochloride.
参考例 1 1 (5-c) Reference Example 1 1 (5-c)
イソニコチノィル クロリド 一塩酸塩の代わりに 4-メチルベンゼンスルホニル クロリドを用いる以外は、 参考例 7と同様にして、 N- (シァノメチル) -4-メチルベン ゼンスルホンアミドを得た。  N- (cyanomethyl) -4-methylbenzenesulfonamide was obtained in the same manner as in Reference Example 7, except that 4-methylbenzenesulfonyl chloride was used instead of isonicotinoyl chloride monohydrochloride.
参考例 1 2 (6-c) Reference Example 1 2 (6-c)
イソニコチノィル クロリ ド 一塩酸塩の代わりにフエ二ルイソシァネートを用 いる以外は、 実施例 7と同様にして、 1-(2-シァノエチル) -3-フエニルゥレアを得た。 参考例 1 3 (7-a)  1- (2-Cyanoethyl) -3-phenylperylene was obtained in the same manner as in Example 7, except that phenylisocyanate was used instead of isonicotinoyl chloride monohydrochloride. Reference Example 1 3 (7-a)
4-ァニシジンをァセトニトリル中、 炭酸カリウム存在下、 プロモアセトニトリル と反応させ、 2-(4-メトキシァニリノ）ァセトニトリルを得た。  4-Anisidine was reacted with bromoacetonitrile in acetonitrile in the presence of potassium carbonate to obtain 2- (4-methoxyanilino) acetonitrile.
参考例 1 4 (7-e) Reference example 1 4 (7-e)
2-ァミノチアゾール及びシァノ酢酸をピリジン中、 ォキシ塩化リン存在下反応し て、 2-シァノ -N- (チアゾール -2-ィル)ァセトアミドを得た。  2-Aminothiazole and cyanoacetic acid were reacted in pyridine in the presence of phosphorus oxychloride to give 2-cyano-N- (thiazol-2-yl) acetoamide.
参考例 1 5 (8-a) Reference Example 1 5 (8-a)
2-ヒドロキシピリジンをァセトニトリル中、 炭酸カリウム存在下、 クロロアセト 二トリルと反応して、 2-(2-ォキソ -1，2-ジヒドロ- 1-ピリジル)ァセトニトリリレを得た。 参考例 1 6 (8-a)  2-Hydroxypyridine was reacted with chloroacetonitrile in acetonitrile in the presence of potassium carbonate to give 2- (2-oxo-1,2-dihydro-1-pyridyl) acetonitrile. Reference Example 1 6 (8-a)
エトキシメチリデンマロン酸ジェチルをェ夕ノール中、ナトリウムエトキシド存 在下、 ァセトアミジン 一塩酸塩と反応し、 5-エトキシカルポニル -2-メチル -6-ォキ ソ -1，6-ジヒドロピリミジンを得、 更に、 以下、 参考例 1 5と同様にして、 2- (5-エト キシカルボニル -2-メチル -6-ォキソ -1，6-ジヒド口ピリミジン- 1-ィル)ァセトニトリル を得た。 The ethoxymethylidenemalonate getyl was reacted with acetamidine monohydrochloride in the presence of sodium ethoxide in ethanol to give 5-ethoxycarponyl-2-methyl-6-oxo-1,6-dihydropyrimidine, Further, hereinafter, in the same manner as in Reference Example 15, 2- (5-ethoxycarbonyl-2-methyl-6-oxo-1,6-dihydroxypyrimidin-1-yl) acetonitrile I got
参考例 1 7 (8-a) Reference Example 1 7 (8-a)
ァセトアミジン 一塩酸塩の代わりにベンズアミジン 一塩酸塩を用いる以外は、 参考例 1 6と同様にして、 2-[(5-エトキシカルポニル -2-フエエル-ピリミジン- 4-ィ ル)ォキシ]ァセトニトリルを得た。  2-[(5-ethoxycarponyl-2-phenyl-pyrimidine-4-yl) oxy] acetonitrile was obtained in the same manner as in Reference Example 16 except that benzamidine monohydrochloride was used instead of acetamidine monohydrochloride. Was.
参考例 1 8 (8-e) Reference Example 1 8 (8-e)
1- (2-クロ口フエニル）ピぺラジンを DMF中、 HOBT及び WSC存在下、 シァノ酢 酸と反応して 1-(2-クロ口フエニル) -4-(シァノアセチル)ピぺラジンを得た。  1- (2-Chlorophenyl) pirazine was reacted with cyanoacetic acid in DMF in the presence of HOBT and WSC to obtain 1- (2-chlorohlophenyl) -4- (cyanoacetyl) pirazine .
参考例 1 9 (9-g) Reference Example 1 9 (9-g)
(2-ァミノチアゾ一ル -4-ィル)酢酸ェチルエステルを、 メタノール中、 アンモニア と反応させ、 次いで、 DMF中ォキシ塩化リンで処理して、 N'-(4-シァノメチルチア ゾ一ル -2-ィル) -N，N-ジメチルメタンイミドアミドを得た。  Ethyl (2-aminothiazol-4-yl) acetate is reacted with ammonia in methanol and then treated with phosphorus oxychloride in DMF to give N '-(4-cyanomethylthiazol-2-yl). G) -N, N-dimethylmethanimidamide was obtained.
参考例 2 0 (9-g) Reference Example 2 0 (9-g)
2-ァミノ- 3-エトキシピリジンを 2-プロパノール中、 トリェチルァミン存在下、 メ チル 3-ブロモ -4-ォキソペン夕ノエ一卜と反応し、 次いで、 メタノール中、 28%ァ ンモニァ水で処理後、 以下、 参考例 1 9と同様にして、 2-(8-エトキシ -2-メチルイミ ダゾ [l，2-a]ピリジン- 3-ィル)ァセトニトリルを得た。  2-Amino-3-ethoxypyridine is reacted with methyl 3-bromo-4-oxopene in 2-propanol in the presence of triethylamine, and then treated with 28% aqueous ammonia in methanol. In the same manner as in Reference Example 19, 2- (8-ethoxy-2-methylimidazo [l, 2-a] pyridin-3-yl) acetonitrile was obtained.
参考例 2 1 (その他の製法 (Oth-1)) Reference Example 2 1 (Other manufacturing method (Oth-1))
2-(4-ァミノフエニル)ァセトニトリルと 2,3-0-ィソプロピリデングリセルアルデ ヒドをクロ口ホルム中、酢酸及び水素化トリァセトキシホウ素ナトリゥム存在下反 応させ、 次いで、 テトラヒドロフラン （THF) —水 （4:1) 中、 トリフルォロ酢酸で 処理し、 更に、 トルエン— THF (4:1) 中、 ナトリウムメトキシド存在下、 炭酸ジェ チルと反応することにより、 2-[4-(5-ヒドロキシメチル -2-ォキソォキサゾリジン -3- ィル)フエニル]ァセトニ卜リルを得た。  2- (4-Aminophenyl) acetonitrile and 2,3-0-isopropylidene glyceraldehyde were reacted in chloroform in the presence of acetic acid and hydrogenated triacetoxyboron sodium, followed by tetrahydrofuran (THF) —Treatment with trifluoroacetic acid in water (4: 1) followed by reaction with 2-ethyl-4-carbonate in the presence of sodium methoxide in toluene-THF (4: 1) to give 2- [4- (5- Hydroxymethyl-2-oxoxazolidine-3-yl) phenyl] acetonitrile was obtained.
参考例 2 2 (その他の製法 (Oth-2)) Reference Example 2 2 (Other manufacturing method (Oth-2))
2-[4-(5-ヒドロキシメチル -2-ォキソォキサゾリジン- 3-ィル)フエニル]ァセトニト リルを塩化メチレン中、 トリェチルァミン存在下、 メタンスルホニル クロリドと 反応後、 DMF 中、 アジ化ナトリウムと反応し、 次いで、 トリフエエルホスフィン で処理し、 更に塩化メチレン中、 トリヱチルァミン存在下、 塩化ァセチルと反応し て、 2-[4-(5-ァセトアミドメチル -2-ォキソォキサゾリジン- 3-ィル)フエニル]ァセトニ トリルを得た。 2- [4- (5-Hydroxymethyl-2-oxoxazolidin-3-yl) phenyl] acetonitrile is reacted with methanesulfonyl chloride in methylene chloride in the presence of triethylamine, then azide in DMF React with sodium, then treat with triphenylphosphine, and further react with acetyl chloride in methylene chloride in the presence of tritylamine. Thus, 2- [4- (5-acetamidomethyl-2-oxoxazolidin-3-yl) phenyl] acetonitrile was obtained.
参考例 2 3 (その他の製法 (Oth-3)) Reference Example 2 3 (Other manufacturing method (Oth-3))
8-ァセトキシ -2-メチルキノリンを四塩化炭素中、 AIBN存在下、 NBSと反応し、 次いで、 ァセトニトリル中、 炭酸カリウム存在下、 N-シァノメチル -N-(4-ヒドロキ シフエニル)ベンズアミドと反応して、 N-{4-[(8-ァセトキシ -2-キノリル)メトキシ] フエ二ル}-?^-シァノメチルベンズアミドを得た。  8-Acetoxy-2-methylquinoline reacts with NBS in carbon tetrachloride in the presence of AIBN, and then reacts with N-cyanomethyl-N- (4-hydroxyphenyl) benzamide in acetonitrile in the presence of potassium carbonate. N- {4-[(8-acetoxy-2-quinolyl) methoxy] phenyl}-? ^-Cyanomethylbenzamide was obtained.
参考例 2 4 (その他の製法 (Oth-4)) Reference Example 2 4 (Other manufacturing method (Oth-4))
N-シァノメチル -N-(4-ヒドロキシフエニル)ァセトアミドを DMF中、 炭酸力リウ ム存在下、 1-(2-クロロェチル)ピぺリジン 一塩酸塩と反応させて、 N-シァノメチル -N-[4-(2-ピぺリジノエトキシ)フエニル]ァセトアミドを得た。  N-Cyanomethyl-N- (4-hydroxyphenyl) acetamide is reacted with 1- (2-chloroethyl) piperidine monohydrochloride in DMF in the presence of lime carbonate to give N-cyanomethyl-N- [ 4- (2-Pyridinoethoxy) phenyl] acetoamide was obtained.
参考例 2 5 (その他の製法 (Oth-5)) Reference Example 2 5 (Other manufacturing method (Oth-5))
4-ピコリンを THF 中、 n-ブチルリチウム、 次いで、 2，4-ジフルォ口- N-メトキシ- N-メチルベンズアミドで処理し、 更に、 リチウムジイソプロピルアミドで処理した ァセトニトリルと反応して、 3-(2，4-ジフルオロフェニル )-3-ヒドロキシ -4-(4-ピリジ ル)ブタン二トリルを得た。  4-Picoline was treated with n-butyllithium in THF, then with 2,4-difluoro-N-methoxy-N-methylbenzamide, and further reacted with acetonitrile treated with lithium diisopropylamide to give 3- ( 2,4-Difluorophenyl) -3-hydroxy-4- (4-pyridyl) butanenitrile was obtained.
参考例 2 6 (その他の製法 (Oth-6)) Reference Example 2 6 (Other manufacturing method (Oth-6))
1— [2-(4-クロ口フエニル) -2-ォキソェチル ]-1,2-ジヒドロピリジン- 2-オンを DMSO 中、 水素化ナトリウム及びヨウ化トリメチルスルホキソニゥムで処理し、 次いで、 ァセトニトリル中、 シアン化カリウム及び過塩素酸リチウムで反応して、 3-(4-クロ 口フエニル) -3-ヒドロキシ -4-(2-ォキソ -1,2-ジヒドロ- 1-ピリジル)ブタン二トリルを 得た。  1- [2- (4-Chlorophenyl) -2-oxoethyl] -1,2-dihydropyridin-2-one is treated with sodium hydride and trimethylsulfoxonium iodide in DMSO, and then in acetonitrile. , Potassium cyanide and lithium perchlorate to give 3- (4-chlorophenyl) -3-hydroxy-4- (2-oxo-1,2-dihydro-1-pyridyl) butanenitrile.
参考例 2 7 (その他の製法 (Oth-7)) Reference Example 2 7 (Other manufacturing method (Oth-7))
2-アミノアセトニトリル 一塩酸塩をエタノール—クロ口ホルム （7:3) 中、 トリ ェチルァミン存在下、 2-クロ口ェチルクロ口ホルメートと反応後、 THF中、 水素化 ナトリゥムで処理して、 2-(2-ォキソォキサゾリジン- 3-ィル)ァセトニトリルを得た。 参考例 2 8 (その他の製法 (Oth-8))  After reacting 2-aminoacetonitrile monohydrochloride with 2-chloroethyl chloroformate in ethanol-chloroform form (7: 3) in the presence of triethylamine, treat with sodium hydride in THF to give 2- ( 2-Oxooxazolidine-3-yl) acetonitrile was obtained. Reference Example 2 8 (Other manufacturing method (Oth-8))
2-(2-ク口口- 5-フルォ口- 6-ォキソ -1,6-ジヒド口ピリミジン小ィル)ァセトニトリル を過剰量のピロリジンで処理して、 2-[5-フルォ口- 6-ォキソ -2イビロリジン- 1-ィル) - 1,6-ジヒドロピリミジン- 1-ィル]ァセトニトリルを得た。 2- (2-c-mouth-5-fluoro-6-oxo-1,6-dihydropyrimidine small yl) acetonitrile is treated with an excess amount of pyrrolidine to give 2- [5-fluor-6- (Oxo-2 -Ibirrolidine-1-yl)- 1,6-Dihydropyrimidine-1-yl] acetonitrile was obtained.
参考例 2 9 (その他の製法 (Oth-9)) Reference Example 2 9 (Other manufacturing method (Oth-9))
3-ォキソ -3,4-ジヒドロ- 2H-1, 4-ベンゾォキサジンを THF中、 水素化リチウムアル ミニゥムで処理し、 THF中、 水素化ナトリウム存在下、 ブロモ酢酸ェチルと反応後、 飽和アンモニア一メタノール溶液で処理し、 更に、 THF 中、 Lawesson試薬で反応 して、 2-(3,4-ジヒドロ- 2H-1, 4-ベンゾォキサジン- 4-ィル)チオアセトアミドを得た。 参考例 3 0  3-oxo-3,4-dihydro-2H-1,4-benzoxazine is treated with lithium hydride in THF in THF, and reacted with ethyl bromoacetate in THF in the presence of sodium hydride. The mixture was treated with a solution, and further reacted with a Lawesson reagent in THF to obtain 2- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) thioacetamide. Reference example 30
Macro Chiniら Tetrahedron Lett., 32, 4775-4788 (1991)に記載の方法を用いて、 3-ヒ ドロキシ -4-フエノキシブ夕ンニトリルを得た。  Using the method described in Macro Chini et al., Tetrahedron Lett., 32, 4775-4788 (1991), 3-hydroxy-4-phenoxybunitnitrile was obtained.
参考例 3 1 Reference example 3 1
P. G. Gassmanら Tetrahedron Lett., 40, 3773-3776 (1978)に記載の方法を用いて、 2- (2,4-ジフルオロフェニル) -2-ヒドロキシプロパン二トリルを得た。  2- (2,4-difluorophenyl) -2-hydroxypropane nitrile was obtained using the method described in P. G. Gassman et al., Tetrahedron Lett., 40, 3773-3776 (1978).
以下、 市販の化合物あるいは文献等で公知の化合物を用い、 上記の参考例の方法 と同様にして、 表 3に示す参考例 3 2〜1 0 5の化合物を製造した。 参考例 1〜1 0 5の化合物の構造、 合成ルート及び物理化学的データを表 3及び 4に示す。  The compounds of Reference Examples 32 to 105 shown in Table 3 were produced in the same manner as in the above Reference Examples, using commercially available compounds or compounds known in the literature. Tables 3 and 4 show the structures, synthesis routes, and physicochemical data of the compounds of Reference Examples 1 to 105.
実施例 1 Example 1
2-(2-ォキソ -1,2-ジヒドロ- 1-ピリジル)ァセトニトリル 1.8 g及びエタノ一ル 1.1 ml のクロ口ホルム 50 ml溶液に、 氷冷下、 塩化水素ガスを 30分間吹き込み、 5°C前後 で 2日間反応させた。反応液を氷冷した飽和炭酸水素ナトリウム水溶液に注加し、 有機層を無水硫酸マグネシウムで脱水後、 濃縮して粗イミデート体 2.4 gを得た。 次いで、 4-クロ口フエニルヒドラジン 一塩酸塩 1.2 g及びエタノール 20 ml混合物 に、 氷冷下、 ナトリウムエトキシド 260 mgを、 10分間後に、 先の粗イミデート体 1.2 gを順次加えた後、徐々に室温まで昇温し終夜攪拌した。反応混合液中の沈殿物 を濾過後、 濾液を濃縮し、 残渣をシリカゲルカラムクロマトグラフィーで精製し、 得られた淡黄色固体 1.4 gをェタノールから再結晶して、 N-(4-ク口口フエニル) -2-(2- ォキソ -1,2-ジヒド口- 1-ピリジル)ァセトアミドラゾン 1.0 gを白色結晶として得た。 1H NMR (DMSO-d6) δ: 4.56 (2Η, s)， 5.87 (2H, brs), 6.25 (1H， dt, J=7, 1.6 Hz), 6.41 (1H， d-like, J=9 Hz), 6.75 (2H， d, J=8 Hz), 7.08 (2H, d, J=8 Hz), 7.45 (1H， ddd, J=9, 7， 2 Hz), 7.63 (1H， dd, J=7, 2 Hz), 8.07 (IH, brs). 実施例 2 Hydrogen chloride gas was blown into a 50 ml solution of 1.8 g of 2- (2-oxo-1,2-dihydro-1-pyridyl) acetonitrile and 1.1 ml of ethanol in 50 ml of ice-cold form under ice-cooling for 30 minutes, and 5 ° C The reaction was performed before and after for 2 days. The reaction solution was poured into an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 2.4 g of a crude imidate. Then, to a mixture of 1.2 g of 4-chlorophenylphenylhydrazine monohydrochloride and 20 ml of ethanol, 260 mg of sodium ethoxide was added under ice-cooling, and after 10 minutes, 1.2 g of the crude imidate was added in order. And the mixture was stirred overnight. The precipitate in the reaction mixture was filtered, the filtrate was concentrated, the residue was purified by silica gel column chromatography, and 1.4 g of the obtained pale yellow solid was recrystallized from ethanol to give N- (4- 1.0 g of phenyl) -2- (2-oxo-1,2-dihydrido-1-pyridyl) acetoamidrazone was obtained as white crystals. 1H NMR (DMSO-d 6 ) δ: 4.56 (2Η, s), 5.87 (2H, brs), 6.25 (1H, dt, J = 7, 1.6 Hz), 6.41 (1H, d-like, J = 9 Hz ), 6.75 (2H, d, J = 8 Hz), 7.08 (2H, d, J = 8 Hz), 7.45 (1H, ddd, J = 9, 7, 2 Hz), 7.63 (1H, dd, J = 7, 2 Hz), 8.07 (IH, brs). Example 2
2-(3，4-ジヒドロ- 2H-1，4-ベンゾォキサジン- 4-ィル)チオアセトアミド 300 mg及び ヨウ化メチル 0.90 mlのアセトン 6 ml溶液を、 2時間還流下加熱した。 反応液を濃 縮後、 残渣をエタノール 6 mlに溶解し、 フエニルヒドラジン 0.17 gを加え、 室温 で 80分間攪拌した。 反応液を濃縮後、 エタノールージェチルエーテル混合溶媒か ら結晶化し、 無定結晶 170 mgを得た。 得られた結晶にクロ口ホルム及び 5%炭酸 カリウム水溶液を加え、 有機層を無水硫酸ナトリウムで脱水後、 濃縮して、 無色油 状物 95 mgを得た。 得られた油状物をエタノ―ル 3 mlに溶解し、 氷冷下、 4N HC1- 酢酸ェチル溶液 1.5 mlを加えた。 1時間後、 析出した結晶を濾取して、 2-(3，4-ジヒ ドロ- 2H-1,4-ベンゾォキサジン- 4-ィル) -N-フエニルァセトアミドラゾン 一塩酸塩 75 mgを無色無定結晶として得た。  A solution of 300 mg of 2- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) thioacetamide and 0.90 ml of methyl iodide in 6 ml of acetone was heated under reflux for 2 hours. After concentrating the reaction solution, the residue was dissolved in ethanol (6 ml), phenylhydrazine (0.17 g) was added, and the mixture was stirred at room temperature for 80 minutes. After concentrating the reaction solution, it was crystallized from a mixed solvent of ethanol-ethyl ether to obtain 170 mg of amorphous crystals. To the obtained crystals were added chloroform and a 5% aqueous solution of potassium carbonate, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give 95 mg of a colorless oil. The obtained oil was dissolved in 3 ml of ethanol, and 1.5 ml of a 4N HC1-ethyl acetate solution was added under ice-cooling. After 1 hour, the precipitated crystals are collected by filtration, and 2- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -N-phenylacetamidourazone monohydrochloride 75 mg Was obtained as colorless amorphous crystals.
1H NMR (DMSO-d6) δ: 3.46 (2H， brt), 4.33 (2H， brt), 4.74 (2H, s)， 6.56 (1H， brd), 6.69 (1H， brt), 6.76 (IH, brd), 6.84 (3H， brd), 6.86-6.93 (IH, m), 7.25 (2H, brt), 8.46 (IH, brs), 9.37 (1H， brs), 9.49 (1H， brs), 11.29 (IH, brs). 1H NMR (DMSO-d 6 ) δ: 3.46 (2H, brt), 4.33 (2H, brt), 4.74 (2H, s), 6.56 (1H, brd), 6.69 (1H, brt), 6.76 (IH, brd) ), 6.84 (3H, brd), 6.86-6.93 (IH, m), 7.25 (2H, brt), 8.46 (IH, brs), 9.37 (1H, brs), 9.49 (1H, brs), 11.29 (IH, brs).
実施例 3 Example 3
N-フエニル -3-(N-メチル -2-(2-トリフエニルメチルァミノチアゾール -4-ィル)ァセ トアミド）プロパンアミドラゾン 1.13 g、 トリフルォロ酢酸 5 ml及び水 1.25 mlを、 氷冷下混和し、 室温下 2時間反応させた。 反応液をクロ口ホルムで洗浄後、 水酸化 ナトリゥム水溶液で pHを 10に調整し、 クロロホルムで抽出した。有機層を無水硫 酸ナトリウムで脱水後、 濃縮した。 得られた残渣をエタノール 3 mlに溶解し、 氷 冷下、 4N HC1-酢酸ェチル 0.5 mlを加え、 室温まで昇温後、 ジェチルェ一テルを加 えて、 晶出した固体を濾取して、 N-フヱニル -3-(N-メチル -2-(2-ァミノチアゾ一ル -4- ィル)ァセトアミド)プロパンアミドラゾン 二塩酸塩 0.35 gを無色無定結晶として 得た。  1.13 g of N-phenyl-3- (N-methyl-2- (2-triphenylmethylaminothiazol-4-yl) acetamido) propanamidrazone, 5 ml of trifluoroacetic acid and 1.25 ml of water were cooled on ice. The mixture was mixed under the condition and reacted at room temperature for 2 hours. After the reaction solution was washed with chloroform, the pH was adjusted to 10 with an aqueous solution of sodium hydroxide, and extracted with chloroform. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in ethanol (3 ml), and under ice-cooling, 4N HC1-ethyl acetate (0.5 ml) was added.The temperature was raised to room temperature, and getyl ether was added. 0.35 g of -phenyl-3- (N-methyl-2- (2-aminothiazol-4-yl) acetamido) propanamidrazone dihydrochloride was obtained as colorless amorphous crystals.
1H NMR (DMSO-d6) δ: 2.77-2.85 (2H， m)， 3.09 (3H, s), 3.71-3.77 (2H， m)， 3.81 (2H, s)， 6.60-6.65 (IH, m), 6.81-6.92 (3H， m)， 7.22-7.29 (2H， m)， 8.58 (IH, brs), 8.62 (1H， brs), 9.05 (IH, brs), 9.65 (1H， brs), 10.00 (IH, brs), 11.54 (1H， brs), 11.97 (IH, brs). 1H NMR (DMSO-d 6 ) δ: 2.77-2.85 (2H, m), 3.09 (3H, s), 3.71-3.77 (2H, m), 3.81 (2H, s), 6.60-6.65 (IH, m) , 6.81-6.92 (3H, m), 7.22-7.29 (2H, m), 8.58 (IH, brs), 8.62 (1H, brs), 9.05 (IH, brs), 9.65 (1H, brs), 10.00 (IH , brs), 11.54 (1H, brs), 11.97 (IH, brs).
実施例 4 Example 4
2-(2-クロ口- 5-フルォ口- 6-ォキソ -1,6-ジヒドロピリミジン- 1-ィル)ァセトニトリル を用い、 実施例 1と同様にして、 2-(5-フルォ口- 2，6-ジォキソ -3,6-ジヒドロ- 2H-ピリ ミジン- 1-ィル) -N-フエニルァセトアミドラソンを得た。 Using 2- (2-chloro-5-fluoro-6-oxo-1,6-dihydropyrimidin-1-yl) acetonitrile, 2- (5-fluoro-2 , 6-Dioxo-3,6-dihydro-2H-pyri (Midin-1-yl) -N-phenylacetamidolasone was obtained.
実施例 5 Example 5
N一 {4-[(8-ァセトキシ -2-キノリル)メトキシ]フエ二ル}- -シァノメチルベンズアミ ドを用い、 実施例 1と同様にして、 2-(N-{4-[(8-ヒドロキシ -2-キノリル)メトキシ〗フ ェニル }ベンズアミド) -N-フエニルァセトアミドラゾンを得た。  Using N- {4-[(8-acetoxy-2-quinolyl) methoxy] phenyl}-cyanomethylbenzamide, 2- (N- {4-[( 8-Hydroxy-2-quinolyl) methoxydiphenylbenzamido) -N-phenylacetamidourazone was obtained.
実施例 1と同様にして、 表 5〜8に示す実施例 6〜2 3 7の化合物を、 実施例 2 と同様にして、 表 7に示す実施例 2 3 8及び 2 3 9の化合物を合成した。実施例化 合物 1〜 2 3 9の構造、 製造法及び物理化学的データを表 5〜 8に示す。  In the same manner as in Example 1, the compounds of Examples 6 to 23 shown in Tables 5 to 8 were synthesized, and in the same manner as in Example 2, the compounds of Examples 23 and 23 shown in Table 7 were synthesized. did. Tables 5 to 8 show the structures, production methods, and physicochemical data of Examples 1 to 39.
また、 表 9に本発明の別の化合物の構造を示す。 これらは、 上記の製造法や実施 例に記載の方法及び当業者にとって自明である方法、又はこれらの変法を用いるこ とにより、 容易に合成することができる。  Table 9 shows the structure of another compound of the present invention. These can be easily synthesized by using the methods described in the above-mentioned production methods and Examples and methods obvious to those skilled in the art, or modified methods thereof.
表中以下の略号を用いる。 また、 置換基を示す略号の前の数字は置換位置を示し、 数字が複数個あるものは複数の置換を示す。 例えば、 5-EC-2-Phは 5-エトキシカル ボニル -2-フエニルを、 1,2，3，4，5-Fは 1，2,3，4，5-ペン夕フルォロを示す。  The following abbreviations are used in the table. The number before the abbreviation indicating a substituent indicates a substitution position, and a plurality of numbers indicates a plurality of substitutions. For example, 5-EC-2-Ph indicates 5-ethoxycarbonyl-2-phenyl, and 1,2,3,4,5-F indicates 1,2,3,4,5-pentafluoro.
Rex：参考例； Ex：実施例； Cmp：化合物番号； Rex: Reference example; Ex: Example; Cmp: Compound number;
RSyn：参考例化合物の合成ルート （前記と同様） ； RSyn: Synthesis route for Reference Example compound (same as above);
Syn：製造法（それぞれ、 A：実施例 1 ； B：実施例 2； C：実施例 3に準じて製造） ； Sal：塩 （空欄：フリー体； HC1：塩酸塩； ox.：シユウ酸塩） ；  Syn: manufacturing method (A: Example 1; B: Example 2; C: manufactured according to Example 3); Sal: salt (blank: free form; HC1: hydrochloride; ox .: oxalate) );
Dat：物理科学的データ （F： FAB-MS (M+H)+； FN： FAB-MS (M-H)"； E： EI-MS； M：融点 [°C]； (d)：分解） ； Dat: Physical scientific data (F: FAB-MS (M + H) + ; FN: FAB-MS (MH) "; E: EI-MS; M: Melting point [° C]; (d): decomposition);
Ad： 1-ァダマンチル； Ad: 1-adamantyl;
Aon： 5-ァセトアミドメチル -2-ォキソォキサゾリジン- 3-ィル；  Aon: 5-acetamidomethyl-2-oxosoxazolidine-3-yl;
AQM： (8-ァセ卜キシ -2-キノリル)メトキシ；  AQM: (8-acetoxy-2-quinolyl) methoxy;
Aze：ァゼパン- 1-ィル；  Aze: Hazepan-1-yl;
BCH： ビシクロ [2.2.1]ヘプト -5-ェン -2-ィル；  BCH: bicyclo [2.2.1] hept-5-en-2-yl;
Bim： 1H-ベンゾィミダゾ一ル -2-ィル；  Bim: 1H-benzoimidazole-2-yl;
Bn：ベンジル；  Bn: benzyl;
Boa：ベンゾォキサゾール -2-ィル； Bta：ベンゾチアゾール -2-ィル； Boa: Benzoxazole-2-yl; Bta: benzothiazol-2-yl;
BTH：ベンゾ [b]チォフェン- 2-ィル； BTH: benzo [b] thiophen-2-yl;
BTN： 3-ォキソ -3,4-ジヒドロ- 2H-1, 4-ベンゾチアジン- 4-ィル；  BTN: 3-oxo-3,4-dihydro-2H-1,4-benzothiazin-4-yl;
Bz :ベンゾィル；  Bz: Benzoyl;
Car： 9H-力ルバゾール -9-ィル；  Car: 9H-Lybazole-9-yl;
Chr： 4-ォキソ -4H-ク口メン -2-ィル；  Chr: 4-oxo-4H-ku-men-2-yl;
C2P： 2-クロ口フエニル；  C2P: 2-chloro phenyl;
C4P： 4-クロ口フエニル；  C4P: 4-chloro phenyl;
DAM：ジメチルアミノメチリデンァミノ ；  DAM: dimethylaminomethylideneamino;
DB2： 2,3-ジヒドロ- 1，4-ベンゾジォキシン- 2-ィル；  DB2: 2,3-dihydro-1,4-benzodioxin-2-yl;
DB4： 3，4-ジヒドロ- 2H-1,4-ベンゾォキサジン- 4-ィル；  DB4: 3,4-dihydro-2H-1,4-benzoxazin-4-yl;
Ddo： 2,2-ジメチル -1,3-ジォキソラン- 4-ィル；  Ddo: 2,2-dimethyl-1,3-dioxolan-4-yl;
DDP1： 2，6-ジォキソ -2,3,6,7-テトラヒド口- 1H-プリン -1-ィル；  DDP1: 2,6-dioxo-2,3,6,7-tetrahydrido-1H-purine-1-yl;
DDP7： 2,6-ジォキソ -2,3,6,7-テトラヒドロ- 1H-プリン -7ィル；  DDP7: 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-7yl;
DHB： 2-ォキソ -2,3-ジヒドロべンゾォキサゾール -3-ィル；  DHB: 2-oxo-2,3-dihydrobenzozoxazole-3-yl;
Dhe： 1，2-ジヒドロキシェチル；  Dhe: 1,2-dihydroxyethyl;
DHI： 4，5-ジヒド口- 1H-ィミダゾール -2-ィル；  DHI: 4,5-dihydrido-1H-imidazole-2-yl;
DFP： 2，6-ジフルオロフェニル；  DFP: 2,6-difluorophenyl;
DTD： 2,2-ジメチル -6-ヒドロキシメチルテトラヒドロフロ [3，4-d]-l，3-ジォキソ一ル -4-ィル；  DTD: 2,2-dimethyl-6-hydroxymethyltetrahydrofuro [3,4-d] -l, 3-dioxol-4-yl;
EC：エトキシカルポニル；  EC: ethoxycarponyl;
F4P： 4-フルオロフェニル； F4P: 4-fluorophenyl;
Fur： 2-フリル； Fur: 2-furil;
Hon： 5-ヒドロキシメチル -2-ォキソォキサゾリジン- 3-ィル；  Hon: 5-hydroxymethyl-2-oxoxazolidin-3-yl;
HQM： (8-ヒドロキシ -2-キノリル)メトキシ；  HQM: (8-hydroxy-2-quinolyl) methoxy;
Imo： 2-ォキソィミダゾリジン- 1-ィル；  Imo: 2-oxoimidazolidin-1-yl;
Imp：イミダゾ [1,2-a]ピラジン -2-ィル；  Imp: imidazo [1,2-a] pyrazine-2-yl;
Imt：ィミダゾ [2，l-b]チアゾ一ル -6-ィル；  Imt: imidazo [2, l-b] thiazolyl-6-yl;
Ind： 1H-ィンドール- 1-ィル； ΙθΧ：イソォキサゾ一ル -4-ィル； Ind: 1H-indole-1-yl; {Θ}: isoxazole-4-yl;
IPY：イミダゾ [l，2-a]ピリジン- 3-ィル；  IPY: imidazo [l, 2-a] pyridine-3-yl;
ltd：イミダゾ [2，l-b]-l，3,4-チアジアゾール -6-ィル； ltd: imidazo [2, l-b] -l, 3,4-thiadiazole-6-yl;
MC：メトキシカルボニル；  MC: methoxycarbonyl;
Mor4：モルホリノ ；  Mor4: Morpholino;
Mor2：モルホリン -2-ィル；  Mor2: Morpholine-2-yl;
Mpe： 4-メチルピペラジン- 1-ィル；  Mpe: 4-methylpiperazine-1-yl;
Nap： 2-ナフチル；  Nap: 2-naphthyl;
ODB： 3-ォキソ -3，4-ジヒドロ- 2H-1, 4-ベンゾォキサジン- 4-ィル； ODB: 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl;
ODP： 2-ォキソ -1,2-ジヒドロ- 1-ピリジル； ODP: 2-oxo-1,2-dihydro-1-pyridyl;
Ohp： 2-ォキソ -1，2，5,6-テトラヒドロピリミジン- 4-ィル； Ohp: 2-oxo-1,2,5,6-tetrahydropyrimidin-4-yl;
OTP： 2,6-ジォキソ -1,2,3,6-テトラヒドロピリミジン- 1-ィル；OTP: 2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl;
Otr： 5-ォキソ -4,5-ジヒド P-1H-1,2,4-トリアゾール小ィル；Otr: 5-oxo-4,5-dihydrid P-1H-1,2,4-triazole small yl;
OXA： 2-ォキソォキサゾリジン- 3-ィル； OXA: 2-oxosoxazolidine-3-yl;
OXT： 2-チォキソォキサゾリジン- 3-ィル；  OXT: 2-thioxoxazolidine-3-yl;
Pda： 6-ォキソ -1,6-ジヒドロピリダジン- 1-ィル；  Pda: 6-oxo-1,6-dihydropyridazin-1-yl;
PEO： 2- (ピペリジノ）エトキシ；  PEO: 2- (piperidino) ethoxy;
Pip： ピペリジノ ；  Pip: piperidino;
Pip3： 2-ォキソピペリジン- 3-ィル；  Pip3: 2-oxopiperidine-3-yl;
Pipo： 2-ォキソピペリジノ ；  Pipo: 2-oxopiperidino;
Pmn2： ピリミジン- 2-ィル；  Pmn2: pyrimidine-2-yl;
Pmn4：ピリミジン- 4-ィル；  Pmn4: pyrimidine-4-yl;
Ppe： ピぺラジン- 1-ィル；  Ppe: Pyrazine-1-yl;
Prr： ピロ一ル -2-ィル；  Prr: pyrrol-2-yl;
Py2： 2-ピリジル；  Py2: 2-pyridyl;
Py3 : 3-ピリジル；  Py3: 3-pyridyl;
Py4： 4-ピリジル；  Py4: 4-pyridyl;
Pym： 6-ォキソ -1，6-ジヒドロピリミジン- 1-ィル；  Pym: 6-oxo-1,6-dihydropyrimidin-1-yl;
Pyro： ピロリジン- 1-ィル； Pyz： ピラジン- 2-ィル； Pyro: pyrrolidine-1-yl; Pyz: pyrazine-2-yl;
Pzl： ピラゾール -1-ィル； Pzl: pyrazol-1-yl;
Pz2： ピラゾール -2-ィル； Pz2: pyrazol-2-yl;
Qui2 : 2-キノリル； Qui2: 2-quinolyl;
Qui8： 8-キノリル； Qui8: 8-quinolyl;
Tbp： 3a,5a，8a,8b-テトラヒド口- 5H-ビス [1,3]ジォキソロ [4，5-b:4'，5'-d]ピラン- 5-ィル Tfo：テトラヒドロフロ [2，3-d]-l,3-ジォキソール -6ィル；  Tbp: 3a, 5a, 8a, 8b-tetrahydropene-5H-bis [1,3] dioxolo [4,5-b: 4 ', 5'-d] pyran-5-yl Tfo: tetrahydrofuro [2, 3-d] -l, 3-dioxole-6-yl;
Thi2：チアゾール -2-ィル； Thi2: Thiazol-2-yl;
Thi4：チアゾール -4-ィル； Thi4: Thiazole-4-yl;
Tho：テトラヒドロフロ [2，3-d]-l，3-ジォキソ一ル -6-ィル；  Tho: tetrahydrofuro [2,3-d] -l, 3-dioxoyl-6-yl;
Thp：テトラヒドロピラン- 2-ィル；  Thp: tetrahydropyran-2-yl;
Thy： 2-チェニル；  Thy: 2-Chenyl;
Tri： 1H-1,2,4-トリアゾ一ル -1-ィル；  Tri: 1H-1,2,4-triazo-1-yl;
TrN : トリフエニルメチルァミノ ；  TrN: triphenylmethylamino;
ΖΝ：ベンジルォキシカルボニルァミノ。  ΖΝ: benzyloxycarbonylamino.
表 3 Table 3
Figure imgf000028_0001
Figure imgf000029_0001
00
Figure imgf000028_0001
Figure imgf000029_0001
00
Figure imgf000030_0001
Figure imgf000030_0001
Figure imgf000031_0001
表 4
Figure imgf000031_0002
表 5
Figure imgf000031_0001
Table 4
Figure imgf000031_0002
Table 5
Figure imgf000032_0001
Figure imgf000033_0001
表 6
Figure imgf000033_0002
Figure imgf000032_0001
Figure imgf000033_0001
Table 6
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000039_0001
9 9
Figure imgf000040_0001
Figure imgf000040_0001

Claims

請 求 の 範 囲 The scope of the claims
1 . 一般式 （I ) で示されるアミドラゾン誘導体又はその塩。 1. An amidrazone derivative represented by the general formula (I) or a salt thereof.
Figure imgf000041_0001
Figure imgf000041_0001
[式中の記号は以下の意味を有する。  [The symbols in the formula have the following meanings.
Ra： (1) 置換されていてもよい単環乃至三環式ァリール、 （2)置換されていてもよ く、 N、 0及び Sから選択されるへテロ原子を 1個以上有する単環乃至三環式飽 和もしくは不飽和へテロ環、（3)置換されていてもよく、架橋されていてもよい シクロアルキル又は（4)置換されていてもよく、 架橋されていてもよいシクロ アルケニル、 R a : (1) optionally substituted monocyclic to tricyclic aryl, (2) optionally substituted monocyclic having at least one heteroatom selected from N, 0 and S To tricyclic saturated or unsaturated heterocyclic ring, (3) optionally substituted and crosslinked cycloalkyl or (4) optionally substituted and crosslinked cycloalkenyl ,
Rb： (1)置換されていてもよい単環乃至三環式ァリール又は（2)置換されていても よく、 N、 0および Sから選択されるへテロ原子を 1個以上有する単環乃至三環 式飽和もしくは不飽和へテロ環、 R b : (1) monocyclic or tricyclic aryl which may be substituted or (2) monocyclic or monocyclic having one or more hetero atoms selected from N, 0 and S which may be substituted Tricyclic saturated or unsaturated heterocycle,
Re及び Rd : 方は Hであり他方は存在しない、 R e and R d : are H and the other does not exist,
Re： -H又は- OH、 R e : -H or -OH,
Rf ： -H、 -低級アルキル又は- Y-Ral、 R f : -H, -lower alkyl or -YR al ,
― ：単結合又は二重結合、 -: Single bond or double bond,
n： ；!〜 8、 n:; ~ 8,
A：結合又は-低級アルキルで置換されていてもよい低級アルキレン、  A: a lower alkylene which may be substituted with a bond or -lower alkyl,
X：結合、 -CO-、 -C02-、 -CONRg -、 -COCONRgl-、 -CH=CHCONRg2-、 -NRg3-、 -NRg4CO-、X: bond, -CO-, -C0 2 -, -CONR g -, -COCONR gl -, -CH = CHCONR g2 -, -NR g3 -, -NR g4 CO-,
-NRg5C02-、 -NRg6CONRg7-、 -0-、 -OCO-、 -OCONRg8-、 - OCH2CONRg9-、 -S -、 -SO-、 -NR g5 C0 2 -, -NR g6 CONR g7 -, -0-, -OCO-, -OCONR g8 -, - OCH 2 CONR g9 -, -S -, -SO-,
-S02-、 -S02NRgl(J-又は- S02NRgllCO-、 -S0 2- , -S0 2 NR gl (J -or -S0 2 NR gll CO-,
Rg： - H、 -低級アルキル又は- Y-Ra2、 R g : -H, -lower alkyl or -YR a2 ,
Rgi〜Rg"： Rgと同様の基、 Rgi~ R g ": Rg and the same groups,
Ral及び Ra2： Raと同様の基、 R al and R a2 : the same groups as R a
Y：結合、 -CH2-又は- CO-。 但し、 Rbが無置換あるいは- CH3、 -N02もしくは- S03Hで置換されたフエニルの時、 は、 1H-ベンゾイミダゾ一ル -2-ィルスルファニルメチル、 1H-ベン
Figure imgf000042_0001
ゾィミダゾール -2-ィルスルファニルェチル、 ベンゾチアゾール -2-ィルスルファ二 ルメチル、 ベンゾチアゾール -2-ィルスルファニルェチル、 1H-インドール- 2-ィルス ルファニルメチル、 1H-インドール- 2-ィルスルファニルェチル、 1H-インドール- 3- ィルメチル、 2-ピリジルメチルスルファニルェチル、 ベンジルォキシカルポニルァ ミノメチル、 4,5-ジヒドロ- 1H-イミダゾール -2-ィルメチル、 ベンジル又はフエニル (該フエニルは- Cl、 -CH3又は- 0C¾で置換されていてもよい) -ヒドロキシメチルで あることはない。 ] Y: bond, —CH 2 — or —CO—. However, R b is an unsubstituted or - CH 3, -N0 2 or - S0 3 when been phenyl substituted with H, the, 1H-benzoimidazol Ichiru 2 I Rusuru sulfanyl methyl, 1H-ben
Figure imgf000042_0001
Zomidazole-2-ylsulfanylethyl, benzothiazole-2-ylsulfanylmethyl, benzothiazole-2-ylsulfanylethyl, 1H-indole-2-ylsulfanylmethyl, 1H-indole-2-ylsulfanyl Ethyl, 1H-indole-3-ylmethyl, 2-pyridylmethylsulfanylethyl, benzyloxycarbonylaminomethyl, 4,5-dihydro-1H-imidazole-2-ylmethyl, benzyl or phenyl (the phenyl is -Cl, -CH 3 or - may be substituted with 0C¾) - it is not hydroxymethyl. ]
2 . n力 1〜6であり、 Xが結合、 -C0-、 -CONRg -、 -COCONRgl-、 -CH=CHCONRg2-、 -NRg3-、 -NRg4CO-、 -NRg6CONRg乙、 -0-、 -OCONRg8-、 -OCH2CONRg9-, -S-又は- SO2NRgl0_ である請求の範囲 1記載の化合物又はその塩。 . 2 an n power 1 to 6, X is a bond, -C0-, -CONR g -, -COCONR gl -, -CH = CHCONR g2 -, -NR g3 -, -NR g4 CO-, -NR g6 CONR g Otsu, -0-, -OCONR g8 -, -OCH 2 CONR g9 -, -S- or - SO 2 NR compound or a salt thereof according to claim 1, wherein the GL0 _ a is.
3 . Rbがハロゲン及びハロゲンで置換されていてもよい低級アルキルから選択され る置換基で置換されていてもよいフエニルである請求の範囲 2記載の化合物又は その塩。 3. R b is a compound or a salt thereof according to claim 2, wherein a halogen and optionally phenyl substituted by a substituent substituted by halogen Ru is selected from lower alkyl.
4 . Re及び Rfがともに- Hである請求の範囲 3記載の化合物又はその塩。 4. The compound according to claim 3, wherein R e and R f are both —H, or a salt thereof.
5 . 請求の範囲 1記載の化合物又はその塩と、 製薬学的に許容される担体とからな る医薬組成物。  5. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable carrier.
6 . 一般式 （Γ ) で示されるアミドラゾン誘導体又はその塩と、 製薬学的に許容 される担体とからなる真菌症の予防又は治療のための医薬組成物。  6. A pharmaceutical composition for preventing or treating mycosis, comprising an amidrazone derivative represented by the general formula (II) or a salt thereof, and a pharmaceutically acceptable carrier.
( D
Figure imgf000042_0002
(D
Figure imgf000042_0002
[式中、 記号は以下の意味を有する。  [Wherein the symbols have the following meanings.
Ra： (1) 置換されていてもよい単環乃至三環式ァリール、 （2)置換されていてもよ く、 N、 0及び Sから選択されるへテロ原子を 1個以上有する単環乃至三環式飽 和もしくは不飽和へテロ環、（3)置換されていてもよく、架橋されていてもよい シクロアルキル又は（4)置換されていてもよく、 架橋されていてもよいシクロ アルケニル、 R a : (1) optionally substituted monocyclic to tricyclic aryl, (2) optionally substituted monocyclic having at least one heteroatom selected from N, 0 and S Or tricyclic A sum or unsaturated hetero ring, (3) an optionally substituted, cross-linked cycloalkyl or (4) an optionally substituted, cross-linked cycloalkenyl,
Rb： (1)置換されていてもよい単環乃至三環式ァリール又は（2)置換されていても よく、 N、 0および Sから選択されるへテロ原子を 1個以上有する単環乃至三環 式飽和もしくは不飽和へテロ環、 R b : (1) monocyclic or tricyclic aryl which may be substituted or (2) monocyclic or monocyclic having at least one heteroatom selected from N, 0 and S which may be substituted Tricyclic saturated or unsaturated heterocycle,
Re及び Rd :—方は Hであり他方は存在しない、 R e and R d : — are H and the other does not exist,
Re： -H又は- OH、 R e : -H or -OH,
Rf ： -H、 -低級アルキル又は- Y-Ral、 R f : -H, -lower alkyl or -YR al ,
― ：単結合又は二重結合、 -: Single bond or double bond,
n： 1〜 8、 n: 1 to 8,
A：結合又は-低級アルキルで置換されていてもよい低級アルキレン、  A: a lower alkylene which may be substituted with a bond or -lower alkyl,
X：結合、 -CO-、 -C02-、 -CONRg -、 -COCONRgl-、 -CH=CHCONRg2-、 -NRg3-、 -NRg4CO-、X: bond, -CO-, -C0 2 -, -CONR g -, -COCONR gl -, -CH = CHCONR g2 -, -NR g3 -, -NR g4 CO-,
-NRg5C02-、 -NRg6CONRg7-、 -0-、 -OCO-、 -OCONRg8-、 -OC¾CONRg9-、 -S -、 -SO-、 -NR g5 C0 2 -, -NR g6 CONR g7 -, -0-, -OCO-, -OCONR g8 -, -OC¾CONR g9 -, -S -, -SO-,
-S02-、 -S02NRglu-又は- S02NRgllCO-、 -S0 2- , -S0 2 NR glu -or- S0 2 NR gll CO-,
Rg： -H、 -低級アルキル又は- Y-Ra2、 R g : -H, -lower alkyl or -YR a2 ,
Rgl〜Rgll： Rgと同様の基、 Rg l~Rgll: Rg and the same groups,
Ral及び Ra2： Raと同様の基、 R al and R a2 : the same groups as R a
Y：結合、 -CH2-又は- CO-。 ] Y: bond, —CH 2 — or —CO—. ]
7 .真菌症が深在性真菌症である請求の範囲 6記載の予防又は治療のための医薬組 成物。  7. The pharmaceutical composition for prevention or treatment according to claim 6, wherein the mycosis is deep mycosis.
8 . 一般式 （Γ ) で示されるアミドラゾン誘導体又はその塩の有効量を哺乳動物 に投与することからなる真菌症の予防又は治療方法。  8. A method for preventing or treating mycosis, which comprises administering to a mammal an effective amount of the amidrazone derivative represented by the general formula (II) or a salt thereof.
9 . 真菌症が深在性真菌症である請求の範囲 8記載の予防又は治療方法。  9. The method according to claim 8, wherein the mycosis is deep mycosis.
1 0 . 真菌症の予防又は治療用の医薬品を製造するための一般式 （Γ ) で示され るアミドラゾン誘導体又はその塩の使用。  10. Use of an amidrazone derivative represented by the general formula (II) or a salt thereof for producing a medicament for preventing or treating mycosis.
1 1 . 真菌症が深在性真菌症である請求の範囲 1 0記載の使用。  11. The use according to claim 10, wherein the mycosis is a deep mycosis.
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CN108276405A (en) * 2018-03-12 2018-07-13 南安市创培电子科技有限公司 A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester

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Cited By (8)

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WO2000047577A1 (en) * 1999-02-12 2000-08-17 Smithkline Beecham Plc Phenyl urea and phenyl thiourea derivatives as orexin receptor antagonists
US6699879B1 (en) 1999-02-12 2004-03-02 Smithkline Beecham P.L.C. Phenyl urea and phenyl thiourea derivatives as orexin receptor antagonists
JP2005097299A (en) * 2003-09-05 2005-04-14 Toyama Chem Co Ltd New benzamidine derivative or its salt
JP4664634B2 (en) * 2003-09-05 2011-04-06 富山化学工業株式会社 Novel benzamidine derivatives or salts thereof
EP1725523A1 (en) * 2004-03-16 2006-11-29 Wyeth a Corporation of the State of Delaware Ion channel modulators
EP1725523A4 (en) * 2004-03-16 2007-10-10 Wyeth Corp Ion channel modulators
EP3115045A3 (en) * 2008-08-26 2017-05-17 Basf Se Detection and use of low molecular weight modulators of the cold menthol receptor trpm8
CN108276405A (en) * 2018-03-12 2018-07-13 南安市创培电子科技有限公司 A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester

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