WO2004067537A1 - Derives de triazole et agents antifongiques renfermant ceux-ci - Google Patents

Derives de triazole et agents antifongiques renfermant ceux-ci Download PDF

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WO2004067537A1
WO2004067537A1 PCT/JP2004/000914 JP2004000914W WO2004067537A1 WO 2004067537 A1 WO2004067537 A1 WO 2004067537A1 JP 2004000914 W JP2004000914 W JP 2004000914W WO 2004067537 A1 WO2004067537 A1 WO 2004067537A1
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group
halogen atom
compound
substituted
methyl
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PCT/JP2004/000914
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English (en)
Japanese (ja)
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Eijiro Umemura
Kazue Sasaki
Fumihito Setsu
Kaori Kaneda
Takafumi Okutomi
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Meiji Seika Kaisha, Ltd.
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Publication of WO2004067537A1 publication Critical patent/WO2004067537A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Triazole derivatives and antifungal agents containing the same [Background of the Invention]
  • the present invention relates to novel triazole derivatives, and more particularly to novel triazole derivatives having antifungal activity.
  • WO97 / 051311 Japanese Unexamined Patent Application Publication No. 10-507505
  • Japanese Patent Application Laid-Open No. 29-19262 have an antifungal activity.
  • a group of compounds is disclosed.
  • This group of triazole derivatives includes a specific triazole derivative in which a 2,4-difluorophenyl group is introduced on the carbon to which the hydroxyl group is bonded, and an aromatic heterocyclic imidazo [2,1-b] thiazole carboxy group. It was a further introduction of Sumid.
  • This group of compounds has a remarkably strong antifungal activity in both the genus Candida and the genus Aspergillus, and this antifungal activity is similar to the known analogs described in the aforementioned WO 97 ZO 5131. It was significantly higher than the activity of the compound. This group of compounds was also effective against fluconazole resistance. The present invention is based on such findings.
  • the present invention relates to a compound having potent antifungal activity
  • An object of the present invention is to provide a compound which has a therapeutic effect on deep-seated mycosis such as candidiasis and aspergillosis, and is also effective against fluconazole-resistant Candida albicans.
  • the compound according to the present invention is a compound of formula (I) or a pharmacologically acceptable salt thereof:
  • n an integer of 0 or 1
  • R 1 represents a hydrogen atom or a C 1 _ 6 alkyl group
  • A represents a halogen atom or an imidazo [2,1-b] thiazole ring which may be substituted by a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic group.
  • this carbocyclic group or heterocyclic group is a C 16 alkyl group which may be substituted by a halogen atom, a cyano group or a halogen atom, or a C 1 6 group which may be substituted by a halogen atom.
  • Substituents at adjacent positions on the imidazo [2,1-b] thiazole ring may together form a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring.
  • This carbocyclic or heterocyclic ring is substituted by a halogen atom, a cyano group, a C 1-6 alkyl group optionally substituted by a halogen atom, or a C 1-6 alkoxy group optionally substituted by a halogen atom. Even if Good]
  • the compounds according to the invention show excellent antifungal activity. Therefore, the compound according to the present invention can be effectively used for preventing or treating superficial or deep fungal infections in all mammals including humans.
  • a pharmaceutical composition comprising the compound of the formula (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.
  • the antifungal agent according to the present invention comprises a compound of the above formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a prophylactically or therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal together with a pharmaceutically acceptable carrier.
  • a method for preventing or treating a fungal infection is provided.
  • ⁇ C 1-6 alkyl group '' or ⁇ C 1-6 alkoxy group '' as a group or a part of a group means that the group is a straight-chain or branched C 1-6 It means an alkyl group or an alkoxy group. Further, here, such an alkyl group and an alkoxy group may be referred to as a lower alkyl group and a lower alkoxy group, respectively.
  • C 1-6 alkyl is preferably C 1-4 alkyl, more preferably C 1-3 alkyl, and still more preferably C 1-2 alkyl.
  • C 1-6 alkoxy J is preferably C 1-4 alkoxy, more preferably C 1-3 alkoxy, and still more preferably C 1-2 alkoxy.
  • Examples of d- 6 alkyl include methyl, ethyl, n-propyl (or 1-port pill), i-propyl (or 2-propyl), n-butyl, i-butyl, s-butyl, t-butyl, n-pentynole, n-hexyl and the like.
  • Examples of d-alkoxy include methoxy, ethoxy, n-propoxy (or 1-propoxy), i-propoxy (or 2-propoxy), n-butoxy, i-butoxy, s-butoxy, t — Butoxy and the like.
  • alkyl optionally substituted with refers to an alkyl in which one or more hydrogen atoms on alkyl are substituted by one or more substituents (which may be the same or different). And unsubstituted alkyl. It will be apparent to one skilled in the art that the maximum number of substituents can be determined depending on the number of substitutable hydrogen atoms on the alkyl. The same applies to a group having a substituent other than alkyl, for example, a carbocyclic ring such as alkoxy and phenyl, and a heterocyclic ring such as imidazo [2,1-b] thiazole ring.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • unsaturated carbocycle and “unsaturated heterocycle” mean a carbocycle and a heterocycle having at least one unsaturated bond such as a double bond.
  • a "5- to 7-membered saturated or unsaturated carbocyclic group” can be a saturated or unsaturated 5- or 6-membered monocyclic carbocyclic group.
  • saturated or unsaturated 5- or 6-membered carbocycles include benzene, cyclopentene, and cyclohexene.
  • 5 to 7 membered saturated or unsaturated heterocyclic group means a saturated or unsaturated 5 to 7 membered (preferably 5 or 6 membered) monocyclic heterocyclic group. I do. That is, a saturated or unsaturated 5- to 7-membered heterocyclic ring may be a heterocyclic ring containing 1 to 4 heteroatoms and the remaining ring members being carbon atoms. As the hetero atom, one or more kinds can be selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • heterocyclic groups include triazolyl, pyridyl, furyl, chenyl, pyrrolyl, pyridazyl, pyrimidyl, pyridinyl, morpholinyl, morpholino, isosoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, isothiazolyl, isothiazolyl, and isothiazolyl.
  • R 1 is preferably a hydrogen atom or a C 1-3 alkyl group. And more preferably a hydrogen atom, a methyl group, an ethyl group, or a monopropyl group, further preferably a hydrogen atom or a methyl group, and particularly preferably a methyl group.
  • A represents an imidazo [2,1-b] thiazole ring which may have a substituent. Therefore, the imidazo [2, 1-b] thiazole ring of A may be bonded to the compound of the formula (I) at any position of the ring as long as it can have a substituent. At this time, the imidazo [2,1-b] thiazole ring may be substituted by a halogen atom or a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic group. Preferably, the imidazo [2,1-b] thiazole ring may be substituted by a halogen atom or a phenyl group.
  • the carbocyclic group or heterocyclic group is substituted by a halogen atom, a cyano group, or a C 16 alkyl group (for example, trifluoromethyl), which may be substituted by a halogen atom, or a halogen atom.
  • An optionally substituted C 16 alkoxy group for example, trifluoromethoxy
  • a C 16 alkylsulfonyl group for example, methylsulfonyl
  • N, N-di (C 1-6 alkyl) amino group
  • an N, N-getylamino group an N, N-getylamino group
  • the carbocyclic or heterocyclic group is condensed with another carbocyclic or heterocyclic ring to form an 8- to 12-membered (preferably 9 or 10-membered) bicyclic saturated or unsaturated carbocyclic ring.
  • a formula group or a heterocyclic group may be formed.
  • the heterocyclic group when the heterocyclic group is condensed with another cyclic group to form a bicyclic group, the heterocyclic group may further contain one or more different types of heteroatoms.
  • bicyclic groups include, for example, naphthyl, quinolyl, quinolinyl, quinoxalyl, 1,2,3,4-tetrahydroquinolyl, 1,4-benzoxaninole, 1,3-benzodioxinol-5- Inole, 2,3-dihydro-1,4-benzodioxin-1,6-inole, indanole, indolinole, indolinyl, 2,1,3-benzozodiazazolyl, imidazopyrimidinyl, and 1,2,3 , 4-tetrahydronaphthyl.
  • the bicyclic group is 1,3-benzodioxyl-5-yl, 2,3-dihydro-1,4-benzodioxin-16-inole.
  • the two substituents may together form a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring, preferably a 5- or 6-membered saturated or unsaturated carbocyclic ring.
  • the carbocyclic or heterocyclic ring is a C 16 alkyl group which may be substituted by a halogen atom, a cyano group, a halogen atom, or a C 1-6 alkyl group which may be substituted by a nitrogen atom. 6 It may be substituted by an alkoxy group (for example, trifluoromethyl).
  • the carbocycle or heterocycle may be substituted by a halogen atom, a cyano group, or a C 1-6 alkoxy group which may be substituted by a halogen atom.
  • A can be represented by the following formula (al) or (a2):
  • RR and R 4 may be the same or different and represent a hydrogen atom, a halogen atom, or a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic group;
  • this carbocyclic group or heterocyclic group is a C 16 alkyl group which may be substituted by a halogen atom, a cyano group, a nitrogen atom, or a C 1 which may be substituted by a halogen atom.
  • the group may be fused with another carbocyclic or heterocyclic ring to form an 8- to 12-membered bicyclic saturated or unsaturated carbocyclic or heterocyclic group, R 2 and R 3 may together form a 5- to 7-membered unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring is a halogen atom, a cyano group, a nitrogen atom. And may be substituted by a C1-6 alkyl group optionally substituted by a halogen atom or a C1-6 alkoxy group optionally substituted by a halogen atom].
  • R 2 , R and R 4 may be the same or different and include a hydrogen atom, a halogen atom, a phenyl group, a 1,3-benzodioxyl-1-yl Represents a group or 2,3-dihydro-1,4-benzodioxin-1 6- ⁇ f
  • the phenyl is a halogen atom, a cyano group, a C 1-6 alkyl group which may be substituted by a halogen atom, a C 1-6 alkoxy group which may be substituted by a halogen atom, It may be substituted by an alkylsulfonyl group or an N, N-di (C 1-6 alkyl) amino group, and this phenyl group is condensed with another heterocyclic ring to form a 9- or 10-membered 2 May form a cyclic unsaturated heterocyclic group,
  • R 2 and R 3 may be taken together to form a 5- or 6-membered unsaturated carbocyclic ring (preferably a benzene, cyclopentene or cyclohexene ring), in which case this carbon
  • the ring may be substituted by a halogen atom, a cyano group, or a C 16 alkoxy group which may be substituted by a halogen atom.
  • R 2 represents a halogen atom or a phenyl group, more preferably a phenyl group.
  • R 3 represents a hydrogen atom or a phenyl group, more preferably a hydrogen atom.
  • R 4 is phenyl, 1,3-benzodioxio ⁇ 5-inole or 2,3-dihydro-l, 4-benzodioxin- 16-yl Represents a group.
  • R 3 when R 3 is a hydrogen atom, R 2 represents a halogen atom or a phenyl group, more preferably a phenyl group. At this time, R 1 is preferably a methyl group.
  • R 4 when R 3 is a hydrogen atom, R 4 is a phenyl group, a 1,3-benzodioxyol-5-yl group, or 2, 3-dihydro 1,4-benzodioxin-16-yl group; more preferably, phenyl group. At this time, R 1 is preferably a methyl group.
  • n is 0. According to another preferred embodiment of the present invention, n is 1.
  • Preferred examples of compounds according to the present invention include compounds of formula (Ia):
  • n an integer of 0 or 1
  • R 11 represents a hydrogen atom, 'or C 1 one 3 alkyl group, preferably a methyl group,
  • R 12 and R 13 may be the same or different, and represent a hydrogen atom, a halogen atom, a phenyl group, a 1,3-benzodioxyol-5-yl group, or a 2,3 —Dihydro-1,4-benzodioxin-16-yl group, preferably a hydrogen atom, a halogen atom or a phenyl group,
  • the phenyl group may be a halogen atom (eg, chlorine atom, fluorine atom), a cyano group, a C 16 alkyl group which may be substituted by a halogen atom (eg, trifluoromethyl), a halogen atom And a C 16 alkoxy group (eg, trifluoromethoxy), a C 16 alkylsulfoyl group, or an N, N-di (C 1-6 alkyl) amino group which may be substituted by Well,
  • the phenyl group is a halogen atom, a cyano group, a C1-3 alkyl group optionally substituted by a halogen atom, or a C1-3 alkoxy group optionally substituted by a halogen atom. May be substituted,
  • R 12 and R 13 may be taken together to form a benzene ring, a cyclopentene ring, or a cyclohexene ring, wherein the benzene ring is substituted by a halogen atom, a cyano group, or a halogen atom. And may be substituted by a C 16 alkoxy group (for example, trifluoromethoxy).
  • R 12 represents a phenyl group, wherein the phenyl group is a halogen atom, a cyano group or a C 1 optionally substituted by halogen atom.
  • R 13 may be substituted by a -6 alkoxy group, and R 13 represents a hydrogen atom.
  • R 12 and R 13 together form a benzene ring, a cyclopentene ring or a cyclohexene ring.
  • Preferred examples of compounds according to the present invention include compounds of formula (Ib):
  • n an integer of 0 or 1
  • R 21 represents a hydrogen atom or a C 1-3 alkyl group, preferably a methyl group,
  • R 23 and R 24 may be the same or different and each represents a hydrogen atom, a halogen atom, a phenyl group, a 1,3-benzodioxyol-5-yl group, or a 23- Dihydro 1,4-benzodioxin 16-yl group, preferably water A hydrogen atom, a phenyl group, a 1,3-benzodioxyl-5-yl group or a 2,3-dihydro-1,4-benzodioxin-16 group;
  • the fluorine group is a halogen atom (for example, chlorine atom, fluorine atom), a cyano group, a C 16 alkyl group which may be substituted by a halogen atom (for example, trifluoromethyl), A C 16 alkoxy group (for example, trifluoromethoxy), a C 1-6 alkylsulfoyl group (for example, methylsulfol) which may be substituted by a halogen atom, or an N, N-di (C 1-6 Alkyl) amino group (eg, N, N-getylamino).
  • a halogen atom for example, chlorine atom, fluorine atom
  • a cyano group for example, a C 16 alkyl group which may be substituted by a halogen atom (for example, trifluoromethyl)
  • a C 16 alkoxy group for example, trifluoromethoxy
  • a C 1-6 alkylsulfoyl group
  • R 23 represents a hydrogen atom
  • R 24 represents a phenyl group, wherein the phenyl group is a halogen atom, a cyano group, or a halogen atom.
  • An optionally substituted C1-6 alkyl group, an optionally substituted C1-6 alkoxy group, a C1-6 alkylsulfonyl group, or N, N-di (C1-6 Alkyl) may be substituted by an amino group.
  • the compound of formula (I) according to the present invention can also be represented as a compound of formula ():
  • n an integer of 0 or 1
  • R S1 represents a hydrogen atom or a lower alkyl group
  • R 52 and R 54 are bonded to CO, and the other may be the same or different from R 53 , a hydrogen atom, a halogen atom, an optionally substituted phenyl group, 1 , 3—benzodioxyl-5-yl, 2,3-dihydro-1 4 represents benzodioxin 1-6-yl, or
  • R 52 and R 53 together form an optionally substituted benzene ring, cyclopentene ring or cyclohexene ring].
  • Preferred specific examples of the compound according to the present invention include compounds 6, 15, 19, 32, 36, and 38 described in Examples.
  • More preferred specific examples of compounds according to the present invention include compounds of the group consisting of:
  • the compounds of formula (I) of the present invention have one or more asymmetric carbons in the molecule.
  • the compounds according to the present invention include those in which these stereoisomers have been separated and those in which mixtures thereof are present.
  • the carbon atom to which the hydroxyl group is bonded is preferably in an R configuration, and The carbon atom to which the group is attached is preferably in the R configuration when n is 0 and in the S configuration when n is 1.
  • the compounds according to the invention can be in the form of their pharmaceutically acceptable salts.
  • Preferred examples of such salts include alkali metal or alkaline earth metal salts such as sodium, potassium or calcium salts, hydrofluoride, hydrochloride, hydrobromide, hydroiodide Inorganic salts such as hydrohalides, nitrates, perchlorates, sulfates, phosphates, such as methanesulfonate, 1, trifluoromethanesulfonate, ethanesulfonate Lower alkyl sulfonates, camphorsulfonic acid, benzenesulfonic acid salt, arylsulfonic acid salts such as p-toluenesulfonic acid salt, fumaric acid, succinate, citrate, tartrate, oxalate, maleic acid Organic acids such as salt, acetate, malate, lactate, ascorbate, and glycine, fenylalanine, gluta
  • the compounds according to the invention can be solvates.
  • Such solvates include hydrates, alcoholates (eg, methanol solvates, ethanol solvates), and ether solvates (eg, getyl ether solvates).
  • the compounds of formula (I) according to the present invention can be prepared according to the following procedure.
  • the compound of the formula (III) and the compound of the formula (III) are combined with 1-hydroxybenzotriazole and dicyclohexylcarposimide or 1- (3- (diaminomethyl) propyl)-
  • 1-hydroxybenzotriazole and dicyclohexylcarposimide or 1- (3- (diaminomethyl) propyl)- By reacting at 0 ° C. to 50 ° C. for 30 minutes to 24 hours in N, N-dimethylformamide in the presence of 3-ethylcarposimidide hydrochloride, the formula (I) A compound can be obtained.
  • the compound of the formula (II) used as a raw material in Scheme A can be obtained, for example, by following any one of the following procedures (1) to (6).
  • (II)-(3) Prepare a compound of formula (IV), which is an output substance.
  • the compound of formula (IV) can be synthesized, for example, according to the method described in JP-A-5-23038.
  • the compound of the formula (IV) and the compound of the formula (V) are refluxed for 10 hours in acetonitrile in the presence of lithium perchlorate (the heating temperature is, for example, 100 ° C.) By doing so, the formula (VI) can be obtained.
  • a compound of the formula (II) wherein n is 0 and R 1 is a monopropyl group can be synthesized according to the following scheme.
  • (VIII) (II)-(5) A compound of the formula (VIII) is prepared as a starting material.
  • the compound of the formula (VIII) is synthesized, for example, according to the method described in JP-A-5-230038. be able to.
  • the compound of the formula (VIII) is reacted with sodium borohydride in methanol in the presence of cobalt chloride for 1 hour at 0 ° C. to obtain the compound of the formula (II) wherein n is 1 , R 1 is a hydrogen atom].
  • (Formula (II)-(5)) can be obtained,
  • the compounds according to the invention inhibit the growth of fungi in vitro and exhibit antifungal activity (see pharmacological test example 1).
  • the compounds according to the invention also show antifungal activity in experiments for the treatment of mouse infection in vivo (see pharmacological test example 2).
  • the compound according to the present invention can be used for various fungi, for example, Candida (for example, Candida. Rubicanth, Candida.Graplata, etc., and Aspergillus (eg, Aspergillus.Fumigatus), etc., and also exhibits extremely excellent antifungal activity against fluconazole-resistant bacteria. It is. Thus, a compound having antifungal activity against both Candida and Aspergillus can be said to be extremely effective in preventing or treating fungal infections including superficial mycosis and deep mycosis. .
  • Candida for example, Candida. Rubicanth, Candida.Graplata, etc.
  • Aspergillus eg, Aspergillus.Fumigatus
  • the compounds according to the invention can be used for the prevention or treatment of fungal infections.
  • fungal infections include superficial and deep mycosis in mammals, including humans.
  • superficial mycosis include tinea, tinea versicolor, tinea, cutaneous candidiasis, cutaneous aspergillosis, and the like.
  • deep mycosis include candidiasis and aspergillosis, and more specific examples are pulmonary taliptococcosis, pulmonary mucormycosis, systemic tricosporonosis, systemic candidiasis and Pulmonary aspergillosis.
  • such fungal infections are deep mycosis, such as candidiasis and aspergillosis.
  • a fungal infection is an infection caused by fluconazole-resistant Candida albicans.
  • a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to the present invention can be used for preventing or treating fungal infections.
  • an antifungal agent comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a compound according to the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a fungal infection.
  • a prophylactically or therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal together with a pharmaceutically acceptable carrier.
  • a method for preventing or treating a fungal infection is provided.
  • Compounds according to the present invention can be administered orally and parenterally (eg, intravenously, intramuscularly, It can be administered to humans and non-human animals by any of the following administration routes: subcutaneous administration, rectal administration, and transdermal administration.
  • parenterally eg, intravenously, intramuscularly, It can be administered to humans and non-human animals by any of the following administration routes: subcutaneous administration, rectal administration, and transdermal administration.
  • a pharmaceutical composition comprising the compound according to the present invention is formulated into an appropriate dosage form depending on the route of administration.
  • oral preparations include tablets, capsules, powders, granules, pills, tablets, troches, syrups, and the like.
  • Parenteral preparations include intravenous injections and intramuscular injections Injections, suppositories, tapes, ointments and the like.
  • These various preparations contain commonly used excipients, extenders, disintegrants, binders, lubricants, coloring agents, diluents, wetting agents, surfactants, dispersants, buffers, It can be manufactured by a conventional method using additives (carriers) such as a preservative, a solubilizer, a preservative, a flavoring agent, a soothing agent, and a stabilizer. These additives can be used in the present invention as pharmacologically acceptable carriers.
  • carriers such as a preservative, a solubilizer, a preservative, a flavoring agent, a soothing agent, and a stabilizer.
  • Excipients include, for example, lactose, fructose, glucose, corn starch, sorbite, crystalline cellulose, etc.
  • Disintegrants include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin
  • examples of the binder include dimethylcellulose or a salt thereof, polyvinyl alcohol, polyvinyl alcohol, polyvinyl alcohol, gelatin alcohol, gelatin, hydroxypropyl cellulose, polypropylpyrrolidone, and the like.
  • examples of the lubricant include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil, and the like.
  • Non-toxic additives include, for example, syrup, petrolatum, lanolin, glycerin, ethanol, propylene glycol, cunic acid, sodium chloride, sodium sulfite, sodium phosphate,] 3-cyclodextrin, Droxypropyl-1] 3-cyclodextrin, Tween 80 and the like.
  • the above injection can be produced by adding a buffer, a pH adjusting agent, a stabilizing agent, an isotonic agent, a preservative and the like as necessary.
  • the content of the compound according to the present invention varies depending on the dosage form, but is usually 1 to 30% by weight, preferably 20 to 30% by weight of the whole composition. .
  • Dosage should be adjusted for patient age, weight, gender, differences in disease, severity of symptoms, etc.
  • the oral dose is usually about 1 to 200 Omg per adult per day, preferably 10 to 100 Omg. It can be administered once or several times daily depending on the symptoms.
  • the compounds according to the invention may be administered in combination with other medicaments, for example, in combination with other antibacterial agents such as ciprofloxacin, or other antifungal agents such as amphotericin B. Good. Administration can be simultaneous or sequential. The type and interval of administration of other drugs can be determined depending on the type of symptoms and the condition of the patient.
  • Example 1 (1 R, 2 R) -N- (2- (2,4-difluorophenyl) -2-hydroxy-1 1-methyl-1 3-(1 H- 1, 2,4 _triazole-1 P) Pill) imidazo [2,1_b] thiazole-6-carboxamide (compound 1)
  • Example 1 (i) Title compound l O Omg (0.5 1 mmo 1) in ethanol (2.5 m 1) was added to a solution of 1 N sodium hydroxide in water: 1.02 ml (1 0.2 mmo 1 ⁇ and stirred for 2 hours at room temperature 1 ⁇ HCl (1.02 ml, 1.02 mmo 1) was added, and the solvent was distilled off to obtain a residue of N, N-dimethylformamide (2 ml) Add (2 R, 3 R) _3-amino-2- (2,4-difluorophenyl) 1 1- (1 H- 1, 2,4-triazole-1 1-yl) in solution Butanol 1 15 mg (0.46 mm o 1) 1-Hydroxybenzotriazolone 10 mg (0.07 mm o 1) and dishex hexyl carpoimide 11 13 mg (0.5 5 mmo 1) was added, and the mixture was stirred at room temperature for 16 hours, filtered to remove insolubles, diluted with ethyl
  • Example 2 (i) title compound 10 Omg (0.43 mmol), 1 N aqueous sodium hydroxide solution 0.86 ml (0.86 mmol), (2 R, 3 R)-2- (2, 4—Difluorophenel) _ 3_ (N-methylamino) 1 1— (1H— 1, 2, 4—Triazono 1 1-inole) _ 2—Butanonole 103 mg (0.3 9 mmol), 1—hydroxy Using 1 Omg (0.07 mmo1) of benzotriazonole and 96.8 mg (0.47 mmo1) of hexylcarboximide in the mouth of the subject, the title was obtained in the same manner as in Example 1 (ii). Thus, 117 mg (yield: 64%) of the compound was obtained.
  • Example 5 (i) title compound 4 Omg (0.13 mmol), IN aqueous sodium hydroxide solution 0.26 ml (0.26 mmol) N (2 R, 3 R) — 3_amino-2— ( 2,4-difluoropheninole) — 1— (1 H-1, 2,4_triazonole 1 —inore) 1—2-ptananole 30. 1 mg (0.1 2 mmo 1), 1-hydroxybenzo Using 10 mg (0.07 mmo 1) of triazole and 28.8 mg (0.14 mmo 1) of dicyclohexynolephenol, the title compound 38.7 mg (yield 6) was obtained in the same manner as in Example 1 (ii). 1%).
  • Example 5 To a solution of 75 mg (0.24 mmo 1) of the title compound of (i) in ethanol (1 ml) was added 0.5 ml (0.5 mmo 1) of a 1 N aqueous sodium hydroxide solution, and the mixture was heated at 60 ° C for 15 min. Stir for a minute. After neutralization by adding 0.5 ml of 1 N hydrochloric acid, the reaction solution was concentrated under reduced pressure.
  • Example 7 The obtained residue was dissolved in N, N-dimethylformamide (2 ml), and the title compound of Example 7 (i), 30 mg (0.1 mmo 1) 1-hydroxybenzotriazole 18 mg (0 Use 12 mgo 1) and 23 mg (0.12 mmo 1) of 1- (3_ (diaminomethyl) propyl) -1-3-ethylcarboimide-hydrochloride, as in Example 1 (ii) Similarly, 13 mg (yield 23%) of the title compound was obtained.
  • Example 4 title compound 1 38 mg (0.5 mmo. 1), potassium carbonate 7 Omg (0.5 mmo 1), 4-methoxypheninolevolonic acid 228 mg (1.5 mmo 1 )) And 58 mg (0.05 mmo 1) of tetrakistriphenylphosphine palladium to give 71 mg (yield 47%) of the title compound in the same manner as in Example 5 (i).
  • Example 9 55 mg (0.19 mmol) of the title compound of Example 9 (i), 0.38 ml (0.38 mmol) of IN aqueous sodium hydroxide solution, (2R, 3R) — 3-amino-2- (2,4-diphenololenophenyl) 1-1-1 (1H-1,2,4-triazonoyl) 1-butanol 42.5 mg (0.17 mm o 1), 1-Hydroxybenzotriazole (10 mg, 0.07 mmo 1) and dicyclohexylcar positimide (43.3 mg, 0.2 lmmo 1) were used as in Example 1 (ii). 56.2 mg (yield 58%) of the title compound were obtained.
  • Example 4 (i) title compound 13 8 mg (0.5 mm o 1), potassium carbonate 7 O mg (0.5 mm o 1), 4 fenoleo pheninolepo nick acid 2 1 O mg (1 5 mmo 1) and 58 mg (0.05 mmo 1) of tetrakistriphenylphosphine palladium were used to obtain 71 mg (yield 49%) of the title compound in the same manner as in Example 5 (i). .
  • Example 10 67.2 mg (0.23 mmo 1) of the title compound of 10 (i), 1 N aqueous sodium hydroxide solution 0.46 ml (0.46 mmo 1), (2R, 3 R) — 3-Amino 1 2— (2,4-diph / leno mouth)-1-(1 H-1, 2,4 triazole-1 1-inole) 1-2-Butanol 5 2.7 mg (0.21 mm o 1), 1-hide mouth benzobenzotriazolone 10 mg (0.07 mm o 1) and dicyclohexyl carpoimide 51.5 mg (0.25 mm Using o 1), 63.8 mg (yield 59%) of the title compound was obtained in the same manner as in Example 1 (ii).
  • Example 10 58 mg (0.2 mmol) of the title compound of 10 (i), 0.4 ml (0.4 mmol) of IN aqueous sodium hydroxide solution, (2R, 3R)-2-(2, 4 1- (N-methylamino) -1- (1H-1, 2,4-triazone-1-one) 1-2-ptano-one 48 mg (0.18 mmol), 1- Use 10 mg (0.07 mmo1) of hydroxybenzotriazole and 45.3 mg (0.22 mmo1) of dicyclohexylcarpoimimid in the same manner as in Example 1 (ii). This gave 64.6 mg (68% yield) of the title compound.
  • Example 4 (i) title compound 1 38 mg (0.5 mmol), potassium carbonate 70 mg (0.5 mmo1), 4 _ triphnoleolomethinorefenoenopopoic nick acid 285 mg (1.5 mm o 1) and 58 mg (0.05 mm o 1) of tetrakis trifluorophenolphosphine palladium were obtained in the same manner as in Example 5 (i) to obtain 56 mg of the title compound (33% yield).
  • Example 12 28.7 mg (0,084 mmol) of the title compound of 2 (i), 1N aqueous sodium hydroxide solution 0.17 ml (0.17 mmol), (2R, 3R) _3— Amino 2- (2,4-difluorophenyl) 1-1- (1H-1,2,4-triazo 1-yl) 1- 2-butanol 2 Omg (0.08 mm o 1) N 1-hydroxybenzotriazolone 5 mg (0.03 5 mm o 1) and dicyclohexynole Using 18 mg (0.088 mmo 1), the title compound 21.2 mg (yield 45%) was obtained in the same manner as in Example 1 (ii).
  • Example 12 28.7 mg (0.084 mmol) of the title compound of (i), 1 N aqueous sodium hydroxide solution 0.17 ml (0.17 mmol), (2R, 3R) -2 -(2,4-difluoropheninole) 1-3- (N-methylamino) 1-1- (1H-1,2,4-triazono-1--1-inole) 1-2-butanol 21 mg (0.O 8mmol) , 1-Hydroxybenzotriazole 5 mg (0.035 mmo 1) and 18 mg (0.088 mmo 1) 3 1. lmg (67% yield) was obtained.
  • Example 4 38 mg (0.5 mmo 1) of the title compound of (i), 70 mg (0.5 mmo 1) of potassium carbonate and 4-09 mg (1.5 mmo 1) Using 58 mg (0.05 mmo 1) of tetrakistriphenylphosphine palladium, 91 mg (yield 51%) of the title compound was obtained in the same manner as in Example 5 (i).
  • Example 14 34.4 mg (0.07 mmol) of the title compound of (i), 1 N aqueous sodium hydroxide solution 0.2 ml (0.2 mmol), (2R 3 R) —3-amino-2- ( 2 4-Difluorophenyl) 1- (1H-1,2,4-triazole- 1-inole) 1- 2-Ptano-nore 22.6 mg (0.09 mm o 1) 1-Hydroxybenzotriazole 5 mg ( 0.03 5 mm o 1) and 20.6 mg (0.1 mm o 1) of dicyclohexynolecarbodiimid in the same manner as in Example 1 (ii), 38.9 mg of the title compound (75% yield) ).
  • Example 14 88 mg (0.25 mmo 1) of the title compound of Example 14 (i), 0.5 ml (0.5 mmo l) of a 1 N aqueous sodium hydroxide solution, (2R, 3R) — 2— (2, 4 —Difluorophenyl) -3- (N-methylamino) — 1— (1H-1,2,4-triazol-1-yl) -1-butanol 61 mg (0.23 mm o 1) s 1 — Using 10 mg (0.07 mm o 1) of hydroxybenzotriazonole and 56 mg (0.27 mm o 1) of dicyclohexylcarbodiimide, 109 mg of the title compound as in Example 1 (ii) Yield 80%).
  • Example 14 (i) title compound 36 mg (0.1 lmmo l), IN sodium hydroxide aqueous solution 0.2 ml (0.2 mmo 1), Example 7 (i) title compound 3 Omg (0.1 mmo 1) 1-Hydroxybenzotriazolone 18 mg (0.12 mmo1) and 1- (3- (diaminomethyl) propyl) -1-3-ethylcarposimidone Using 23 mg (0.12 mmo 1) of the hydrochloride, 13 mg (yield 22%) of the title compound was obtained in the same manner as in Example 1 (ii).
  • Example 17 (1 R, 2 R) -N- (2-(2, 4 difluorophenyl) — 2 _ hydroxy-1- 1 -methyl- 3— — (1H-1,2,4-triazol-1-yl) propyl) (1—propyl) 2 (4 ⁇ trifluoromethyl) —imidazo [2b] thiazole-1 66-potassium lipoxamide ( Compound 17) Title of Example 14 (i) 36 mg (0.1 mmol), IN aqueous sodium hydroxide solution 0.2 ml (0.2 mmo1), Example 8 (i) Title compound 2 5 mg (0.08 mmol), 1-hydroxybenzotriazolone 15 mg (0.09 mmo1) and 1- (3- (diaminomethyl) propyl) -3-ethylcarbo Using 18 mg (0.09 mmol) of dimido hydrochloride, 13 mg (yield 21%) of the title compound was obtained
  • Example 18 45 mg (0.15 mmo 1) of the title compound of (ii), 4 N aqueous lithium hydroxide solution 0.15 ml (0.15 mmo 1), (2R, 3R) 13-amino One 2—
  • EXAMPLE 18 45 mg (0.15 mmo1) of the title compound of 18 (i), 4 N aqueous lithium hydroxide solution 0.15 ml (0.15 mmo1), (2R, 3R) 12 (2,4-difluorophenyl) 1-3- (N-methylamino) 1-11 (1H-1,2,4-triazolone 1-inole) 1-2-butano 13.7.2 mg (0 14 mm o 1), 1-hydroxybenzotriazolone 42 mg (0.15 mm o 1), 1-hydroxybenzobenzotriazono 28 mg (0.18 mm o 1) and 1 — (3- (Diaminomethyl) propyl) 25 mg of the title compound (yield: 35 mg (0.18 mmo 1)) of 1- 3-ethylcarbodiimidol hydrochloride in the same manner as in Example 1 (ii) Rate 3 1%) ⁇ .
  • Example 18 45 mg (0.15 mmo1) of the title compound of 18 (i), 0.15 ml (0.15 mmo1) of 1 N aqueous sodium hydroxide, Example 7 (i) Title compound 4 4 mg
  • Example 1 Using 1 g (7.lmmo 1) of the title compound of Example 22 (i), 1 g (10 mmo 1) of calcium carbonate and 1.2 ml (8.5 mmo 1) of 90% ethyl bromopyruvate, Example 1 ( In the same manner as in i), 537 g (yield 47%) of the title compound was obtained.
  • Example 22 The title compound of (ii) 6 Omg (0.25 mmo 1) N 1 N aqueous sodium hydroxide solution 0.5 ml (0.5 mmol), (2 R, 3R) — 3—amino — 2—
  • Example 2 Title compound of 2 (ii) 6 Omg (0.25 mmo 1) 1 N aqueous solution of sodium hydroxide 0.5 ml (0.5 mmol), (2R, 3R) — 3— (N-methylamino) 1 2— (2,4-diphnoleolopheninole)-1-(1 H-1,2,4—triazol-1-inole) 1-2-butanol 1 6 mg 23 mm o I) 1-Hydroxybenzotriazonore 10 mg (0.07 mm o 1) Use dicyclohexylcarposimid 58 mg (0.28 mm o 1) In the same manner as in Example 1 (ii), 73.7 mg (yield: 68%) of the title compound was obtained.
  • Example 24 Using the title compound of Example 24 (i) 1.lg (7.1 mmo 1), 1 g of calcium carbonate (1 Ommo 1) and 1.2 ml of 90% ethyl bromopyruvate (8.5 mm o 1), In the same manner as in Example 1 (i), 442 mg (yield 42%) of the title compound was obtained.
  • Example 24 62.5 mg (0.25 mmo 1) of the title compound, 1 N aqueous sodium hydroxide solution 0.5 ml (0.5 mmo l), (2R, 3R) — 3-amino-2 1 (2,4-diphnoleolopheninole)-1-(1H-1, 2,4,1 triazono 1-1-inole) 12-ptano-one 56.5 mg (0.23 mm o 1), 1-hi Using 1 mg (0.07 mmo 1) of cibenzotriazonole and 58 mg (0.28 mmo 1) of dicyclohexynole compound, the title compound 68.2 m in the same manner as in Example 1 (ii) g (yield 63%) was obtained.
  • Example 24 (ii) title compound 62.5 mg (0.25 mmo 1), 1 N aqueous sodium hydroxide solution 0.5 ml (0.5 mmo 1), (2 R, 3R) — 2— (2 , 4 difluorophenyl) 1 3-(N-methylamino) 1 1-(1H-1, 2, 4-triazono 1-inole)-2-butano 1 6 1 mg (0.23 mm o 1 ), 1- Using 10 mg (0.07 mmo 1) of hydroxybenzotriazonole and 58 mg (0.28 mmo 1) of dicyclohexylcarpoimide, the title compound as in Example 1 (ii) 69.7 mg (62% yield) were obtained.
  • Example 26 58 mg (0.2 mmol) of the title compound of (i), IN aqueous sodium hydroxide solution 0.5 ml (0.5 mmol), (2R, 3R) -2-(2, 4- Difluorophenyl) 1- (N-methylamino) 1- (1H-1,2,4-triazonole_1-1-yl) 1-butanol 56 mg (0.2 mm o 1), 1-h Doxybenzotriazolle 37 mg (0.24 mm o 1) and 1-Echinodiae 3
  • Example 27 4 mg (0.3 mmol) of the title compound of 7 (i), aqueous solution of sodium hydroxide IN 0.5 ml (0.5 mmol), (2R, 3R), -2-(2, 4- Difluorophenyl) 1 3 _ ( ⁇ -methylamino) 1 1 1 (1 H— 1, 2, 4-triazone 1 — inole) 1 2—butanol 1 8 mg (0.3 mm o 1), 1— Hydroxybenzotriazonole 5 5 mg (0.36 mm o 1) and 1-ethynole 3
  • Example 28 52 mg (0.2 mmol) of the title compound of (i), 0.5 ml (0.5 mmol) of an aqueous solution of sodium hydroxide IN, (2R, 3R) 1 2— (2,4-difluorophenyl) 1) 3- (N-methylamino) 1-1- (1H-1,2,4-triazono-1-one) 1-2-butanol 56mg (0.2mmol), 1-hydroxybenzotriazole 37mg ( 0.24 mm o 1) and 1—ethyl 3—
  • Example 29 6 mg (0.2 mmol) of the title compound of 9 (i), 0.4 mL of 1 N aqueous sodium hydroxide solution (0.4 mmol 1), (2 R, 3 R)-2-(2, 4 1- (N-methylamino) 1-1-1 (1H—1,2,4-triazole-11-yl) 1-2-butanol 56 mg (0.2 mmol), 1-hydro Using 37 mg (0.24 mmo 1) of xybenzotriazole and 46 mg (0.24 mmo 1) of 1- (3- (diaminomethyl) propyl) -3-ethylcarbodiimidide hydrochloride, Example 1 ( 85 mg (yield 76%) of the title compound was obtained in the same manner as in ii).
  • Example 30 73 mg (0.27 mmo 1) s 4 N sodium hydroxide of the title compound of (i) 27 ml (1.08 mm o 1) s (2 R, 3 R)-2-(2,4-difluorophenyl) 1 3-(N-methylamino)-1 (1H-1 , 2,4-triazono 1-isle 56-mg (0.2 mmo 1), 1-hydroxybenzotriazole 76 mg (0.27 mmol) and 1- (3- (diaminomethyl) Using 62 mg (0.32 mmol) of (3-propyl) -13-ethylcarposimidide hydrochloride, 63 mg (yield 46%) of the title compound was obtained in the same manner as in Example 1 (ii).
  • Example 3 To a solution of 344 mg (2 mmo 1) of the title compound of 1 (i) in acetonitrile (10 m 1) was added 466 mg (2 mmo 1) of phenacino rebromide in a single-mouthed solution, and 4, 5 Refluxed for hours. The reaction solution was stirred under ice-cooling, and the precipitated solid was collected by filtration and washed with acetonitrile to obtain 402 mg (yield 66%) of the title compound.
  • Example 31 3 lmg (0.2 lmmol) of 1 (ii) title compound, 0.2 ml (0.2 mmo1) of 1 N aqueous sodium hydroxide solution, (2R, 3R) _3-amino-2- (2,4-difuzoleone) 2 1- (1 H—1,2,4_triazonole 1-yile)-2-ptananole 24.
  • Example 31 15 3 mg (0.5 mm o 1) of 1 (ii) title compound, 0.53 ml (0.53 mmol) of 1 N aqueous sodium hydroxide solution, (2R, 3R) — 2- (2,4-difluorophenol) 1-3- (N-methylamino) 1-11 (1H-1, 2,4-triazono 1-1-inole) 1-2-butanol 1 4 1 mg (0.
  • Example 31 Using 10 O mg (0.58 mmo 1) of the title compound of 1 (i) and 133 mg (0.58 mmo 1) of 4-methoxyphenacyl bromide, Example 3 1 (ii ) To give 54 mg (yield 31%) of the title compound.
  • Example 33 36 mg (0.12 mmo1) of the title compound of 3 (i), 1N aqueous sodium hydroxide solution 0.24 ml (0.24 mmol), (2R, 3R) -2-(2, 4-difluorophenyl) 1 3-(N-methylamino) 1 1-(1H-1, 2, 4-triazono 1-innole) 1-2-butano 1-34mg (0.
  • Example 31 The title compound of 1 (i) was used in the same manner as in Example 31 (ii), using 44 mg '(2 mmo 1) and 4-fluorophenacyl bromide 4 34 mg (2 mmo 1). Thus, 276 mg (yield 47%) of the compound was obtained.
  • Example 3 4 (i) title compound 58 mg (0.2 mm o 1), 1 1 sodium hydroxide aqueous solution 0.2 2 ml (0.22 mm ol), (2 R, 3 R)-2- (2,4-difluorophenyl) 1-3- (N-methylamino) 1-11 (1H-1,2,4-triazono-1-yl) 1-2-butanomono 56 mg (0.
  • Example 31 (ii) Using 28 Omg (1.63 mmo1) of the title compound of 1 (i) and 468 mg (1.63 mmo1) of 4-trifluoromethinolefenacinolepromide, Example 31 (ii) In the same manner as in the above, 295 mg (yield 54%) of the title compound was obtained.
  • Example 31 Using 344 mg (2 mmo1) of the title compound of 1 (i) and 566 mg (2 mmo1) of 4-trifluoromethoxyphenacyl bromide, 342 mg of the title compound was prepared in the same manner as in Example 31 (ii). Yield 48%).
  • Example 36 7 lmg (0.2 mmol) of the title compound of (i), 0.22 ml (0.22 mmol) of IN aqueous sodium hydroxide solution, (2R, 3R) _2— (2,4-difluorophenyl) 1) 3- (N-Methylamino) 1-1- (1H-1,2,4-Triazonore_1-inore) 1-2-Butanole 51 1 mg (0.18 mm o 1), 1-hi
  • Example 1 (ii) using 34 mg (0.22 mmo1) of droxybenzotriazonole and 42 mg (0.22 mmo1) of 1- (3- (diaminomethyl) propyl)-3-ethylcarposimidide hydrochloride In the same manner as in the above, 86 mg (yield: 80%) of the title compound was obtained.
  • Example 31 The title compound of 1 (i) was obtained in the same manner as in Example 3 1 (ii), using 1.0 g (6 mmo1) and 1.4 g (6 mmo1) of 4-cyanophenazole promide. 1.6 g (yield 90%) of the compound was obtained.
  • Example 3 22 mg (0.52 mmo 1) of the title compound of 7 (i) in a mixed solution of 148 mg (0.5 mm o 1) of ethanol (2 m 1) -tetrahydrofuran (2 ml) was added. )) In water (1 ml), (2R, 3R) — 2— (2,4-difluorophenyl) -13- (N-methylamino) 1-1- (1H—1,2,4- Liazono 1-inolate-2-butanomono 141 mg (0.5 mm o 1), 1-hydroxybenzotriazono 9 2 mg (0.6 mm o 1) and 1- (3_ (diaminomethyl) Propyl)-3-ethylcarposimidide hydrochloride (115 mg, 0.6 mmo 1) was used in the same manner as in Example 1 (ii) to give the title compound (172 mg, yield 65%). .
  • Example 31 1 (i) 2-Ethoxycarbonyl 6-phenylimidazo [2, l_b] thiazoe
  • Example 31 1 (i) title compound 10 Omg (0.58 mm 0 1) and phenacylp 87.5 mg (yield: 55%) of the title compound was obtained in the same manner as in Example 31 (ii) using 115 mg (0.58 mmo 1) of lomide.
  • Example 3 54 mg (0.2 mmol) of the title compound of 9 (i), 0.22 ml (0.22 mmol) of an aqueous solution of sodium hydroxide IN, (2R, 3R) —2— (2,4-di) 1- (N-methylamino) _1- (1H—1,2,4-triazonole_1-inole) 1-2-butanomono 56 mg (0.2 mmol), 1-hi
  • Example 1 using 32 mg (0.24 mmo1) of droxybenzotriazole and 46 mg (0.24 mmo1) of 1- (3- (diaminomethyl) propyl) -1-ethylcarbodiimide monohydrochloride In a similar manner to (ii), 46 mg (yield 46%) of the title compound was obtained.
  • Example 31 50 mg (0.29 mmo 1) of the title compound of 1 (i) and 2-promo 1- (4-1 (methinoresnorelephoninole> feninole) -11-ethanone 80 mg (0 In the same manner as in Example 31 (ii), 29 mg of the title compound was used to obtain 33 mg (yield 32%) of the title compound.
  • Example 40 33 mg (0.09 mmo1) of the title compound of (i), 1 N aqueous sodium hydroxide solution 0.19 ml (0.19 mmol), (2R, 3R) — 2- (2,4-difluorophenol) 1-3- (N-methylamino) 1 1 _ (1H-1,2,4-triazono 1-inole) _2-ptananole 27 mg ( 0.0 9mmol), 1-hydroxybenzotriazonole 15 mg (0.1111111101) 1- (3- (diaminomethyl) propyl) -13-ethylcarbodiimidole hydrochloride 27 mg (yield 49%) of the title compound was obtained in the same manner as in Example 1 (ii) using 22 mg (0.1 lmmo 1) of the salt.
  • Example 31 Using 100 mg (0.58 mmo1) of the title compound of 1 (i) and a57-mg (0.58 mmo1) of a-bromo-41- (ethylamino) acetophenone, In a similar manner to Example 31 (ii), 34 mg (yield 17%) of the title compound was obtained.
  • Example 3 Title compound of 1 (i) 5 Omg (0.29 mmo 1) and 1- (1,3-benzodioxonor-1-inole) -2-bromoethane-1-one 70 mg (0.29 mmo 1 ) To give 24 mg (yield 26%) of the title compound in the same manner as in Example 31 (ii).
  • Example 42 53 mg (0.17 mmo 1) of the title compound, 1 N aqueous sodium hydroxide solution 0.3 ml (0.30 mmo 1), (2R, 3R) 1-2 — ( 2,4-difluorophenyl) 1 3- (N-methylamino) 1 1- (1H-1,2,4-triazono-1--1-inole) 2-ptananol 48 mg (0.17mmol), 1 Using 27 mg (0.2 Ommo 1) of 1-hydroxybenzotriazole and 39 mg (0.2 Ommo 1) of 1- (3- (diaminomethyl) propyl) -3-ethylcarboimide monohydrochloride In the same manner as in Example 1 (ii), 48 mg (yield: 51%) of the title compound was obtained.
  • Example 43 67 mg (0.20 mmo1) of the title compound of (i), 1 N aqueous sodium hydroxide solution 0.4 ml (0.4 Ommo1), (2R, 3R) _2— ( 2, 4-difluorophenyl) 1 3- (N-methylamino) — 1— (1H—1, 2, 4-triazonore — 1—inore) — 2-butanomono 57 mg (0.20 mm o 1), 33 mg (0.24 mmo 1) of 1-hydroxybenzotriazole and 47 mg (0.24 mmo 1) of 1- (3- (diaminomethyl) propyl) -1-ethylcarposimide monohydrochloride In the same manner as in Example 1 (i), 87 mg (yield 76%) of the title compound was obtained.
  • Example 14 72 mg (0.2 mmo l) of the title compound of (i), 0.4 ml (0.4 mmo 1) of a 1 N aqueous sodium hydroxide solution, 56 mg (0.2 mmo l) of the title compound of Example 44 (i), 1-Hydroxybenzotriazole 37 mg (0.24 mm o 1> and 1— (3- (diaminomethyl) propyl) _ 3-ethylethyl carposimid Using 46 mg (0.24 mmo 1) of dough hydrochloride, 106 mg (89% yield) of the title compound was obtained in the same manner as in Example 1 (ii).
  • Example 18 45 (i) title compound 45 mg (0.15 mmol), 4 N lithium hydroxide aqueous solution 0.15 ml (0.6 mmo1), Example 44 title compound (i) 4 2 mg (0.15 mmol), 1-hydroxybenzotriazole 28 mg (0.18 mmol 1) and 1- (3- (diaminomethyl) propyl) -13-ethylcarposimidamide Using 35 mg (0.18 mmo 1) of the hydrochloride, 55 mg (yield 68%) of the title compound was obtained in the same manner as in Example 1 (ii).
  • Example 44 62 mg (2.2 mmo 1) of the title compound of (i) was dissolved in acetone (1 Oml), and 0.34 ml (3.3 mmo1) of benzaldehyde was added. Stirred for hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was
  • Example 18 Title Compound 8 (i) 8 9 mg (0.3 mmo 1), 4 N lithium hydroxide aqueous solution 0.3 ml (1.2 mmo 1), Example 46 Title Compound 8 (i) 8 9 mg (0.3 mmol), 1-hydroxybenzotriazolone 55 mg (0.36 mmo1) and 1- (3- (diaminomethyl) propyl) -1-3-ethylcarposi Using 69 mg (0.36 mmo 1) of imido hydrochloride, 11 mg (yield 68%) of the title compound was obtained in the same manner as in Example 1 (ii).
  • Example 37 7 (i) title compound 89 mg (0.3 mmo 1), 4 N lithium hydroxide aqueous solution 0.3 ml (1, 2 mmo 1), Example 46 (i) title compound 89 mg (0.3 mmol), 1-hydroxybenzotriazole 55 mg (0.36 mmo1) and 1- (3- (diaminomethyl) propyl) _3-ethylcarboimide Using 69 mg (0.36 mmo 1) of the hydrochloride, 15 mg (yield 9%) of the title compound was obtained in the same manner as in Example 1 (ii).
  • the antifungal activity of the compounds according to the invention was evaluated by the following pharmacological test examples.
  • the compounds prepared in the examples were arbitrarily selected and used as test drugs.
  • test drugs as comparative examples, fluconazole (obtained from FIZA, Inc.), rabuconazole (manufactured according to Chem. Pharm. Bull.
  • control compound A was used.
  • the control compound A corresponds to the compound of Example 74 of WO97Z0531.
  • the test strains used in each test example were obtained from Teikyo University Medical Fungus Center and ATCC (American Type Culture Collection).
  • Pharmacological test example 1 Measurement of antifungal activity by microfluidic dilution method (In Vito Co., Ltd.) Tests) As test bacteria, Candida albicans (Candida albicans) TIMM1768 (fluconazole-sensitive strain), Candida albicans TIMM3209 (fluconazole-resistant strain), Candida albicans ATCC64124 (fluconazole-resistant strain), and Aspergillus. ) TIMM1775 was used.
  • test drug was prepared using 2% dimethyl sulfoxide R PM I 164 medium, and 100 ⁇ l of this was dispensed into a 96-well microplate. The suspension of the test bacterium was further poured into the suspension for 100/1, stirred, and cultured at 3-5 ° C. If the test bacterium is Asunolegiles fumigass TIMM1775, use alamar blue
  • test drug (Purchased from Trek Diagnostic System, Inc.) Add 20 ⁇ l and culture at 30 ° C for 48 hours.If the test organism is Candida albicans, The cells were cultured at 35 ° C for 24 hours.
  • the dilution series of the test drug was prepared by preparing 11 steps of a two-fold dilution series using 2% dimethyl sulfoxide RPMI 1640, and set to 0.0625 to 64 / ig / m1.
  • the turbidity of the control reaches 0.2, and when the test bacterium is Aspergillus fumigatus, the turbidity of the control reaches 0.5.
  • the absorbance was measured with a microplate reader. At this time, the absorbance was measured at 620 nm for Candida albicans and at 540 nm for Aspergillus fumigatus. The obtained measurement results were calculated by the following formula to calculate a growth inhibitory concentration (IC 8 ) of 80% or more of the test drug.
  • Control compound A ⁇ 0.0625>64>64> 64
  • Pharmacological test example 2 Measurement of antifungal activity by mouse infection treatment experiment (in vivo test)
  • Candida albicans # 1768 was cultured in YPD broth (yeast extract, peptone, glucose) at 35 ° C for 18 hours, followed by centrifugation with PBS for 5 minutes to wash the bacteria. Next, the obtained bacterium was diluted with PBS to obtain 5 ⁇ 10 5 CFUZml to prepare a bacterial solution for inoculation.
  • YPD broth yeast extract, peptone, glucose
  • mice used were DBAZ2N (obtained from Nippon Charl. Ribai Co., Ltd.), 7-week-old males, with 5 mice per group.
  • the bacterial solution for inoculation adjusted to 5 ⁇ 10 5 C FU / m 1 was inoculated from the tail vein of 200 ⁇ l per mouse to cause systemic candidiasis.
  • the dose (2 Omg / kg) of the test drug was increased by 20% Tween 80 / 2.5 ° /.
  • the volume was adjusted to 4 mgZm1 using mannitol, and 100/1 thereof was intravenously administered to a mouse 2 hours after infection.
  • the average survival days of 5 mice per group were determined, and the survival rate against fluconazole was calculated and used as a judgment index.
  • Candida albicans TIMM3209 After culturing Candida albicans TIMM3209 in YPD broh (yeast extract, peptone, glucose) at 35 ° C for 18 hours, the cells were washed by centrifugation with physiological saline for 5 minutes. . Next, the obtained bacterium was diluted with physiological saline to 2 ⁇ 10 6 CFU / ml to prepare a bacterium solution for inoculation.
  • YPD broh yeast extract, peptone, glucose
  • mice used were DBAZ2N (obtained from Nippon Charl. Ribai Co., Ltd.), 7-week-old males, with 5 mice per group.
  • the bacterial solution for inoculation adjusted to 2 ⁇ 10 6 CFU / m 1 was inoculated from the tail vein of 200 1 mouse to induce systemic candidiasis.
  • the dose of the test drug (10 mg / kg) was adjusted to 2 mgZm1 using 20% tween 80 / 2,5% mannitol, and was administered at a rate of 5 m1 / kg 2 hours after infection 1 day
  • Mice were administered intravenously over 3 days. Average of 5 mice per group The surviving days were determined, and the survival rate for fluconazole was calculated and used as a judgment index. The results were as shown in Table 6.
  • mice used were CBA / JN (obtained from Nippon Charles' Riva Co., Ltd.), 7-week-old males, 6 mice per group.
  • the dose (2 Omg / kg) of the test drug was adjusted to 4 mg Zm1 using 20% tween 80/2. 5% mannitol, and the ratio of 5 m1 Zkg was changed from 1 day after infection to 1 day 2 days.
  • Mice were administered intravenously over 3 days. The average survival rate of 6 mice per group was determined, and the survival rate for rabconazole was calculated and used as a judgment index. The results were as shown in Table 6.

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Abstract

L'invention concerne un composé représenté par la formule générale (I) (dans laquelle n représente un nombre entier égal à 0 ou 1 ; R1 désigne un hydrogène ou un alkyle ; et A représente un cycle imidazo[2,1-b] thiazole éventuellement substitué) ou un sel acceptable sur le plan pharmacologique de celui-ci. Les composés sont utiles dans le traitement d'une infection fongique.
PCT/JP2004/000914 2003-01-30 2004-01-30 Derives de triazole et agents antifongiques renfermant ceux-ci WO2004067537A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008082198A1 (fr) * 2006-12-29 2008-07-10 Daewoong Pharmaceutical Co., Ltd. Derivés triazoles antifongiques, leur procédé de préparation et composition pharmaceutique en contenant
CN105198822A (zh) * 2015-10-28 2015-12-30 中国人民解放军第二军医大学 一种甲基取代的新型氮唑类抗真菌化合物及其制备方法和应用
CN109485645A (zh) * 2014-12-10 2019-03-19 沈阳药科大学 苯并噻唑类衍生物及其用途
RU2791043C1 (ru) * 2022-07-20 2023-03-01 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Применение 9-бензоил-8-гидрокси-6-(2-гидроксиэтил)-2-фенил-1-тиа-3,6-диазаспиро[4.4]нон-2,8-диен-4,7-диона в качестве средства, обладающего противогрибковой активностью

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2728316T3 (es) * 2013-12-20 2019-10-23 Syngenta Participations Ag Heterociclos 5,5-bicíclicos sustituidos activos como plaguicidas con sustituyentes que contienen azufre

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027852A1 (fr) * 1998-11-10 2000-05-18 Meiji Seika Kaisha, Ltd. Nouveaux derives d'imidazo[5,1-b]thiazole et fongicides contenant ces derives en qualite de principe actif
JP2001192386A (ja) * 1999-10-29 2001-07-17 Meiji Seika Kaisha Ltd 新規トリアゾール誘導体及びこれを有効成分とする抗真菌剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027852A1 (fr) * 1998-11-10 2000-05-18 Meiji Seika Kaisha, Ltd. Nouveaux derives d'imidazo[5,1-b]thiazole et fongicides contenant ces derives en qualite de principe actif
JP2001192386A (ja) * 1999-10-29 2001-07-17 Meiji Seika Kaisha Ltd 新規トリアゾール誘導体及びこれを有効成分とする抗真菌剤

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008082198A1 (fr) * 2006-12-29 2008-07-10 Daewoong Pharmaceutical Co., Ltd. Derivés triazoles antifongiques, leur procédé de préparation et composition pharmaceutique en contenant
US8063229B2 (en) 2006-12-29 2011-11-22 Daewoong Pharmaceutical Co., Ltd. Antifungal triazole derivatives, method for the preparation thereof and pharmaceutical composition containing same
CN109485645A (zh) * 2014-12-10 2019-03-19 沈阳药科大学 苯并噻唑类衍生物及其用途
CN109485645B (zh) * 2014-12-10 2020-08-04 沈阳药科大学 苯并噻唑类衍生物及其用途
CN105198822A (zh) * 2015-10-28 2015-12-30 中国人民解放军第二军医大学 一种甲基取代的新型氮唑类抗真菌化合物及其制备方法和应用
CN105198822B (zh) * 2015-10-28 2017-11-21 中国人民解放军第二军医大学 一种甲基取代的新型氮唑类抗真菌化合物及其制备方法和应用
RU2791043C1 (ru) * 2022-07-20 2023-03-01 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Применение 9-бензоил-8-гидрокси-6-(2-гидроксиэтил)-2-фенил-1-тиа-3,6-диазаспиро[4.4]нон-2,8-диен-4,7-диона в качестве средства, обладающего противогрибковой активностью

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