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WO2004026862A1 - Compose hydrosoluble de triazole - Google Patents

Compose hydrosoluble de triazole Download PDF

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Publication number
WO2004026862A1
WO2004026862A1 PCT/JP2003/012032 JP0312032W WO2004026862A1 WO 2004026862 A1 WO2004026862 A1 WO 2004026862A1 JP 0312032 W JP0312032 W JP 0312032W WO 2004026862 A1 WO2004026862 A1 WO 2004026862A1
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WIPO (PCT)
Prior art keywords
group
pip
piz
methyl
acceptable salt
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PCT/JP2003/012032
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English (en)
Japanese (ja)
Inventor
Takuya Uchida
Yoshiko Kagoshima
Toshiyuki Konosu
Takahiro Shibayama
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Sankyo Company, Limited
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Priority to AU2003264533A priority Critical patent/AU2003264533A1/en
Publication of WO2004026862A1 publication Critical patent/WO2004026862A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a novel water-soluble triazole compound and a pharmacologically acceptable salt having excellent pharmacokinetics and antifungal activity as a medicament (particularly an injection), and a medicament containing the same as an active ingredient (particularly an antifungal agent) About.
  • JP-A-8-333350, JP-A-11-80135, JP-A-10-279567, JP-A-2001-342187 and ⁇ ) 02/40472 disclose a tertiary hydroxyl group. Triazole compounds are described.
  • JP-A-62-14766 discloses that 2- (2,4-difluorophenyl) 1-1,3-bis (1H-1,2,4-triazole-11-yl) -12-propanol (fluconazole) Is described.
  • JP-A-8-53426 discloses that 3- [4- (4-cyanophenyl) thiazo-ru 21-yl] -12- (2,4-difluorophenyl) 1-11 (1H-1,2,4 —Triazole-1-yl) 1-2 butanol (Rabconazole) is described.
  • WO 99X45008 discloses that 2- (2,5-difluorophenyl) — 3— [4- (4-Cyanophenyl) thiazol —2-yl] 1-11 (1H-1,2,4,1 ′) J-Azul 1-yl) 1-2-Buy Noor (RO0094815) is described.
  • 2625584 discloses that 2- (2,4-difluorophenyl) 13- (5-fluoro- 4-pyrimigel)-1- (1H- 1,2,4_triazole-l ⁇ ) 1 2 —Butanol (polyconazole) is described.
  • Japanese Patent Application Laid-Open No. Hei 9-183769 discloses that 1 [(1R, 2R) -2- (2,4 difluorophenyl) —2-hydroxy-1-methyl-3- (1H-1,2,4-triazole— 1-yl) propyl] —3— [4- (1H-1-tetrazolyl) phenyl] -2-imidazolidinone (TAK-456).
  • 11-240871 discloses that 2- (2,4-difluorophenyl) -111 (ethylsulfonyl) —1,1-difluoro One 3- (1H-1,2,4-triazole-1-yl) -2-propanol (SS750) is described.
  • WO 98/31675 discloses that (2R, 3R) —2— (2,4 difluorophenyl) 1-3— [4— [4- [3-oxo-2 -— (4-trifluoromethoxy) benzyl) Single 2H-1, 2, 4 one Toriazoru - 4 one I le] phenylene Le] one 1-piperazinyl] -1 one (1H-1, 2, 4-Toriazoru one 1 one I le) - 2 - Bed Evening knoll ( syn — 2869) is listed.
  • WO 97/05130 publication states that 7-chloro-3-[(1R, 2R) -2- (2,4-difluorophenyl) -1-hydroxy-1-methyl-3- (1H-1,2, 4-triazo-1-yl) propyl] quinazoline-4 (3H) -one (UR-9825) is described.
  • EP1083175A2 discloses that (2R, 3 R) — 3— [[trans- 1 — [(1 E, 3 E) -4- (4-cyano 2-fluorophenyl)-1, 3-butadiene — 1-yl ] ⁇ 1,3-dioxane-1-5-yl] thio] 1-2- (2,4-difluorophenyl)-1- (1H-1,2,4-triazole-1-yl) 1-2-butanol Is described.
  • Patent Nos. 3050982, WO95Z25107, WO00 / 27852, WO01Z66551, and WO01Z79196 also disclose triazole compounds having a tertiary hydroxyl group.
  • the dosage form of the therapeutic agent for fungal infection varies depending on the type of fungus to be treated and the mode of infection.
  • the dosage form for example, there are oral and injectable administration, since in these administration methods have advantages and disadvantages, fungal infection therapeutic agent, but D is desirably any possible oral and injection administration,
  • the above-mentioned agents for treating a triazole fungal infection shown above have excellent antifungal activity, but have a drawback that they are difficult to administer as an injection due to low water solubility. '
  • WO 00/30655 and WO 99/61017 disclose acylal carbonate ester derivatives having a substituted benzoyl group in the side chain.
  • these compounds can be fully satisfactory as pharmaceuticals (antifungal agents for injection) in terms of physical properties, chemical stability, pharmacokinetics, safety, and ease of synthesis.
  • the compounds of the present invention differ from these compounds in that they have an aliphatic acyl group in the side chain.
  • WO 0 Z 0 365 5 and WO 99/610 17 do not disclose or suggest an acylal carbonate having an aliphatic acyl group.
  • As water-soluble triazole derivatives for example, Japanese Patent Application Laid-Open No. 2002-322176 discloses ester derivatives. However, these compounds are the same as those of the present invention in which the acylal is adjacent to one oxygen atom. The structure differs from that of the acylal derivative.
  • WO 01/56653 discloses a compound obtained by chemically modifying an agricultural chemical compound with an acylal carbonate group (an imparting group).
  • an imparting group is a group for imparting physical properties suitable for agrochemicals, and is different from the imparting group of the compound of the present invention modified with a group suitable for an antifungal agent for injection. Therefore, the disclosed compounds are useful for pharmaceuticals (antifungal agents for injection) in terms of antifungal activity (particularly spectrum and strength), physical properties (particularly water solubility and chemical stability), pharmacokinetics and safety. It cannot be used as.
  • WO 01 X566358 does not disclose or suggest chemical modification for pharmaceuticals (injectable antifungal agents). Disclosure of the invention
  • the problem to be solved by the present invention is that it has high water solubility, is converted into an active substance at a preferred site in a living body, has a fast conversion rate, has excellent organ selectivity for conversion, has excellent conversion rate, and has high safety.
  • An object of the present invention is to provide an injectable triazole compound which is high and chemically stable and is esterified at a tertiary hydroxyl group.
  • the present inventors have intensively studied, devised and synthesized an ester carbonate compound according to the present invention, and found that the compound according to the present invention is useful as a medicine (especially an antifungal agent for injection). The inventors have found that the present invention has been completed.
  • the present invention
  • L 1 represents a C 3 -C 7 cycloalkyl group, a CC 6 alkylene group or a C 2 -alkenylene group
  • L represents a single bond, a double bond, a C 3 -C 7 cycloalkyl group, or a 4- to 7-membered heterocyclic group, and is a single bond, a double bond, a C r C 6 alkylene group or a C 2 -C 6 Represents an alkenylene group,
  • A is Karupokishi group, one S0 3 H group, one 0s0 3 H group, - S0 2 NH 2 group, - 0P0 3 H 2 group, a nitrogen-containing heterocyclic group, selected from Substituent group monument and Substituent Group 3 Or a nitrogen-containing heterocyclic group substituted by 1 or 2 substituents with the same or different substituents, or a group represented by the formula: NR 2 R 2 ′ (wherein R 2 is a hydrogen atom, an amidino group, a 1-iminoethyl group, a C r C 6 alkyl group, substituent group] CC 6 alkyl group substituted with 1 or 2 same or different substituents selected from the group selected from the group consisting of: C r (, a logenated alkyl group, a C 6- aryl group, indicates r C 14 Ararukiru group, R 2 'is hydrogen, C r C 6 alkyl group, 1 or 2 substituted by identical
  • Ar is Cs-C ,.
  • Ra is an organic group ( ⁇ , the following formula (II) ′
  • Ar is a phenyl group or a phenyl group substituted with 1 to 3 same or different substituent (s) selected from the group consisting of an octylogen atom and a trifluoromethyl group, or a pharmaceutically acceptable salt thereof. Is an acceptable salt, '
  • R a is a compound represented by the following formula or a pharmacologically acceptable salt thereof,
  • Ra is represented by the following formula:
  • Ra is any one selected from (1) to (4).
  • Ra is represented by the following formula:
  • R a is
  • Ra is represented by the following formula (III):
  • R 3 and R 4 independently represent a hydrogen atom or a ⁇ -Ce alkyl group
  • Ar 2 is a phenyl group substituted by 1 to 5 with the same or different substituent (s) selected from the group consisting of a phenyl group and a substituent group, a monocyclic heteroaryl group, and the same or different substituent (s) selected from a substituent group r
  • E 1 represents a methylene group or a group represented by the formula —S ( ⁇ ) nl — (wherein n 1 represents an integer of 0 to 2);
  • E 2 represents a C 4 -C 7 cycloalkyl group or a heterocyclyl group
  • E 3 is the formula (Ga)
  • R 5 , R 6 , R 7 and R 8 independently represent a hydrogen atom, a C ⁇ -C 6 alkyl group, or a -C 6 halogenated alkyl group;
  • p 0 or 1
  • q represents an integer of 0 to 3
  • r and s each independently represent an integer of 0 to 2.
  • Ar 3 is a phenylene group, a phenylene group substituted with 1 or 2 same or different substituents selected from a substituent group consisting of (a fluorine atom and a chlorine atom), a naphthylene group, or Represents a naphthylene group substituted by 1 or 2 with the same or different substituent (s) selected from a group of substituents consisting of (fluorine atom and chlorine atom);
  • R 9 represents a hydrogen atom or a C 6 alkyl group
  • T represents a single bond or a C 8 alkylene group.
  • R 3 is a C 1 -C 4 alkyl group
  • R 4 is a hydrogen atom or a ( ⁇ -alkyl group
  • Ar 2 is a phenyl group substituted by 1 to 5 with the same or different substituent (s) selected from the phenyl group, the substituent group a, a monocyclic heteroaryl group, or the same or different from the substituent group a A monocyclic heteroaryl group substituted with 1 to 5 substituents;
  • 'E 1 is a group of the formula —S (0) nl — (wherein n 1 is an integer of 0 to 2) A group represented by
  • R 5A R 6 ⁇ R 7A and R 8A independently represent a hydrogen atom, a C ⁇ —C 6 alkyl group, or
  • P A represents 0 or 1
  • q A r A and s A each independently represent an integer of 0 to 2.
  • E 3 is the formula (Ga B )
  • Q b represents an integer of 0 to 3
  • r B and s B independently represent an integer of 0 to 2.
  • the sum of Q B r B and s B is 3 or less.
  • R 4 is a hydrogen atom
  • Ar 2 is the same or a different substituent selected from a naphthyl group and a substituent group a, and 1 to 5 A substituted naphthyl group, a fused bicyclic heteroaryl group, or a fused bicyclic heteroaryl group substituted with 1 to 5 same or different substituents selected from a substituent group r,
  • E 1 is a group represented by the formula: S (O) nl — (wherein, n 1 represents an integer of 0 to 2.)
  • E 3 is the formula (Ga c )
  • R 5C , R 6C , 7C , and R 8e independently represent a hydrogen atom, (a C 6 alkyl group, or a C ⁇ C 6 halogenated alkyl group;
  • Pe 0 or 1
  • R 4 is a hydrogen atom
  • Ar 2 is a phenyl group, a naphthyl group, or the same or a different substituent selected from 1 to 5 substituted with the same or different substituents selected from a phenyl group and a substituent group a; 1 to 5 substituted naphthyl groups,
  • E 1 is a methylene group or a sulfur atom
  • E 3 is the formula (Gb) '
  • Ar 3 is a phenylene group, a phenylene group substituted with 1 or 2 same or different substituents selected from a substituent group consisting of (a fluorine atom and a chlorine atom), a naphthylene group, or Represents a naphthylene group substituted by 1 or 2 with the same or different substituent (s) selected from a substituent group consisting of
  • R 9 represents a hydrogen atom or a C 6 alkyl group
  • T represents a single bond, or, ( ⁇ -. Where C 8 represents an alkylene group) or a compound of a group represented by is a pharmacologically acceptable salt thereof,
  • R 1 () and R 11 are Each independently represents a hydrogen atom or a Ci—Ce alkyl group, or R 1 () and R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen-containing heterocyclic ring
  • a group represented by the formula: S ( ⁇ ) 1 — R 13 (wherein 1 represents an integer of 0 to 2, and R 13 represents —C 6 alkyl group or hydrogen atom , And a hydroxyl group), and represents a C 1 -C 6 alkyl group substituted with 1 to 5 same or different substituents selected from the group consisting of:
  • Pyrazolyl group triazolyl group, pyrazolyl group substituted by the same or different substituent selected from imidazolyl group, pyrazolyl group, substituent group Lil group, the same selected from Substituent group [delta] or different substituents 1 or 2-substituted Toriazoriru group, tetrazolyl group, 1-substituted tetrazolyl group with a substituent selected from Substituent group [delta], C 2 - A C 6 -alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 6 cycloalkyl group, and a C 3 -C 6 alkyl group substituted with a C 3 -C 6 cycloalkyl group.
  • R 1 is a hydrogen atom Or a compound that is a methyl group or a pharmacologically acceptable salt thereof,
  • a salt L 1 is allowed compound or a pharmacologically a C 2 7 alkylene group
  • A is Karupokishi group, - S0 3 H group, - 0s0 3 H group, - S0 2 N group, - 0 2 group, Azechijiniru group , Pirorijieru group, Pi Perijiniru group, piperazinyl group, morpholinyl group, 1-substituted Azechijini Le group with a substituent (the substituent: methyl group, _0S0 3 H group or _0P0 3 H 2 group), monosubstituted with a substituent It was piperazinyl lysinyl group (the substituent: methyl group, - 0s0 3 H radical or - 0P0 3 H 2 group), and 1 substituted with a substituent a piperazinyl group [the substituent: methyl group, monosubstituted with a substituent and C 2 - C 6 alkyl group (those the substituents: -
  • A is Karupokishi group, - S0 3 H group, - 0s0 3 H group, _0P0 3 H 2 group, 1 one Azechijiniru group, 1 one Pyrrolidinyl group, piperidino group (ie, 1-piperidinyl group), morpholino group (ie, 41-morpholinyl group), 1-methyl-3-azetidinyl group, 3- (sulfoxy) -1-1azetidinyl group, 31 (phosphonooxy) Azetidinyl, 1-methyl-4-piperidinyl, 1-methyl-4-piperidinylidene, 3- (sulfoxy) 1-1-piperidinyl,
  • A is Karupokishi group, - S0 3 H group, - 0P0 3 H 2 group, 4 one methyl - 1-piperazinyl or 4 one ( 2-hydroxyl) a compound which is a 1-piperazinyl group or a pharmacologically acceptable salt thereof, wherein (39) in any one selected from (1) to (35), A OP0 3 H 2 group, compound or a pharmacologically acceptable salt thereof, - group, one S0 3 H group or
  • Ar is a 2,4-difluorophenyl group
  • R 1 is a hydrogen atom or a methyl group
  • L 2 is a single bond, is L 3 single bond, _C - or - C CH 2 - and is, a is a carboxy group, one S0 3 H group, -0S0 3 H group, -0P0 3 H 2 group, 1 one Azechijiniru group, a 1-pyrrolidinyl group, a piperidino group , Morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfoxy) -1-azetidinyl group, 3- (
  • Ar is a 2,4-difluorophenyl group
  • R 1 is a hydrogen atom or a methyl group
  • L 2 is a single bond
  • L 3 is a single bond, -C- or -CH 2 CH 2-
  • A is carboxy groups, one S0 3 H group, - 0s0 3 H group, - 0P0 3 H 2 group, 1-Azechijiniru group, 1 one pylori Jiniru group, piperidino group, morpholino group, 1-methyl-3-Azechijiniru group, 3- (scan Rhuoxy) 1-1-azetidinyl group, 3- (phosphonoxy) -1-1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperid
  • Ar is a 2,4-difluorophenyl group
  • R 1 is a hydrogen atom or a methyl group
  • L 2 is a single bond
  • L 3 is a single bond, - C - or _CH 2 CH 2 - and is, a is Karupokishi group one S0 3 H group, one 0s0 3 H group, -0P0 3 H 2 group, 1 one Azechijiniru group, 1 _ pyrrolidine group, piperidino group, morpholino group, 1-methyl 3-Azechijiniru group, 3- (scan Ruhookishi) - 1 one Azechijiniru Group, 3- (phosphonooxy) 1-1-azetidinyl group, 1-1-methyl-4-piperidinyl group, 1_methyl-4
  • Ar is a 2,4-difluorophenyl group
  • R 1 is a hydrogen atom or a methyl group
  • L 1 is a C 2 alkylene group
  • -. NH- or a carbonyl group located
  • L 2 is a single bond
  • L 3 is a single bond
  • - CH 2 - or - CH 2 C3 ⁇ 4 - a and, a is a carboxy group, one S0 3 H group, - 0s0 3 H group, - 0P0 3 H 2 group, 1 one Azechijiniru group, 1 one pyrrolidinyl, pin Perijino group, morpholino group, 1-methyl 3-Azechijiniru group, 3 - (Suruhookishi) 11-azetidinyl group, 3- (phosphonoxy) 1-1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-14-
  • Ar is a 2,4-difluorophenyl group
  • R 1 is a hydrogen atom or a methyl group
  • L 1 is a C 2 alkylene group
  • L 2 is a single bond
  • L 3 is - C - or - C CH 2 - and is, a is Karupokishi group one S0 3 H group, _0P0 3 H 2 group
  • 4 A compound which is a monomethyl-1-piperazinyl group or a 4-(-hydroxyethyl) -1-piperazinyl group or a pharmacologically acceptable salt thereof,
  • Ar is a 2,4-difluorophenyl group
  • R 1 is a hydrogen atom or a methyl group
  • L 1 is a C 2 alkylene group
  • - a NH- L 2 is a single bond
  • L 3 is - CH 2 - or - CH 2 CH 2 - and is, a is a carboxy group, - a 0P0 3 H 2 group - S0 3 H group or A compound or a pharmacologically acceptable salt thereof,
  • Ar is a 2,4-difluorophenyl group
  • R 1 is a hydrogen atom or a methyl group
  • L 1 is a C 2 alkylene group
  • -NH- L 2 is a single bond
  • a pharmaceutical composition comprising, as an active ingredient, a triazole compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (49),
  • An antifungal agent comprising as an active ingredient a triazole compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (49),
  • the “rC ⁇ —C e alkyl group” in the above is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl 1,1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl Butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethyl It is a linear or branched alkyl group having 1 to 6 carbon atoms such as butyl and 2-ethylbutyl, preferably a linear or
  • the “C r C 6 halogenated alkyl group” in the above is a group in which the same or different 1 to 5 halogen atoms are substituted for the “C r C 6 alkyl group”, for example, trifluoromethyl, trichloromethyl , Difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-odoethyl, Examples thereof include 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, and 2,2-dibromoethyl, and preferably, trifluoromethyl.
  • the "aryl group” is, for example, an aromatic hydrocarbon group having 6 to 10 carbon atoms such as phenyl, indenyl and naphthyl, and is preferably a phenyl group.
  • the “C 7 -C w 7 aralkyl group” in the above is a group in which the above rc, -C 6 T alkyl group is bonded to the above “C 6 -.aryl group”, for example, benzyl, ⁇ -naphthylmethyl, ⁇ -naphthylmethyl, indenylmethyl, 1-phenyl, 2-phenethyl, 1-naphthylethyl, 2naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2 1-naphthylpropyl, 3-naphthylpropyl, 1-naphth
  • the “cycloalkyl group” of the “C 2 —C 6 alkyl group substituted with a C 3 —C 6 cycloalkyl group” in the substituent group a is a saturated cyclic hydrocarbon group which may be condensed, "C 4 ten 6 cycloalkyl group", for example, cyclobutyl, cyclopentyl, include key sill group cycloheteroalkyl, "C 4 - C 7 cycloalkyl group", in addition to these, include Shikurohepu ethyl group And “C 3 — (: 7 cycloalkyl group” ”further includes, in addition to these, a cyclopropyl group.
  • the “-C 6 alkylene group” in the above is, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene And a straight-chain or branched-chain alkylene group having 1 to 6 carbon atoms such as hexamethylene, and in L 1 , preferably a straight-chain or branched-chain alkylene group having 2 to 6 carbon atoms. And more preferably a straight-chain or branched-chain alkylene group having 2 carbon atoms.
  • L 3 it is preferably methylene or ethylene, and more preferably methylene.
  • the “( ⁇ alkylene group” in the above refers to, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene.
  • a straight-chain or branched alkylene group having 1 to 8 carbon atoms such as xamethylene, heptamethylene and octamethylene; preferably a straight-chain or branched alkylene group having 2 to 6 carbon atoms; More preferably, it is a straight-chain or branched-chain alkylene group having 2 carbon atoms, preferably methylene or ethylene, and more preferably methylene.
  • the “C 2 -alkenylene group” in the above is, for example, a linear or branched chain alkylene group having 1 to 6 carbon atoms such as pinylene, propylenylene, butenylene, and hexenylene. Preferably, it is a linear or branched chain alkenylene group having 1 to 4 carbon atoms, and more preferably, vinylene.
  • C 2 —C 4 alkanoinole group in the above substituent group, “N— (C 2 -C 7 alkanoyl) amino group” in the substituent group
  • C 2 -C 7 alkanoyl groups preferred are straight-chain or branched-chain alkanoyl groups having 2 to 4 carbon atoms, and more preferred are acetyl groups.
  • C 2 -C 4 alkyl groups an acetyl group is preferred.
  • halogen atom in the above is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.
  • the “4- to 7-membered heterocyclic group” in the above is a 4- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms or Z and nitrogen atoms, and is, for example, furyl, chenyl, pyrrolyl, azepinyl, pyrazolyl, Aromatic heterocyclic groups such as imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, pyrazinyl, pyrimidinyl Partially reduced heterocyclic groups and oxenyl, tetrahydrofuryl, tetrahydroviranyl, azetidinyl, morpholinyl, thiomorpholin
  • the “nitrogen-containing heterocyclic group” in the above includes at least one nitrogen atom in the above “4- to 7-membered heterocyclic group”, and examples of such a group include pyrrolyl, azepinyl, pyrazolyl, and imidazolyl.
  • Ri Oh identical or different radicals selected from the group ⁇ and substituent group ⁇ is 1 or 2 substituted groups, suitably monosubstituted with a substituent a Azechijiniru (the substituent: methyl group, -0S0 3 H group or - 0P0 3 H 2 group), 1 substituents substituted piperidines lysinyl (the substituent: methyl group, -0S0 3 H radical or - 0P0 3 group), 1-substituted piperazinyl substituents [ the substituent methyl groups, C being monosubstituted at location substituent 2 - C 6 alkyl group (the substituent: - S0 3 H group, - 0S0 3 H group, - S0 2 NH 2 group, -OP0 3 H 2 groups or -NMe 2 groups)], and more preferably, .1-methyl-3-azetidinyl,
  • N- (C 2 -C 7 alkanoyl) amino group in the above is a group in which one of the above “C 2 -C 7 alkenyl groups” is substituted on an amino group, and is preferably an acetylamino group.
  • ⁇ - (C, - C 6 alkyl) in the above -N- (C 2 - C 7 Arukanoiru) amino group "above ⁇ - (C 2 - C 7 Arukanoiru) the nitrogen atom of the Amino group""- C 6 “Alkyl” is a group substituted by one, and is preferably an acetylmethylamino group.
  • the “monocyclic heteroaryl group” in the above includes, for example, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxaziazolyl, triazolyl, tetrazolyl, tetrazolyl, , Pyranyl, pyridyl, pyridazinyl, pyrimidinyl, and virazinyl, and is a 5- to 7-membered aromatic heterocyclic group containing 1 to 4 sulfur atoms, oxygen atoms or nitrogen and nitrogen atoms, and is preferably pyridyl.
  • the “fused bicyclic heteroaryl group” is a fused bicyclic aromatic ring having 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • Groups such as isobenzofuranyl, benzofuranyl, isobenzothiophenyl, benzothiophenyl, indolizinyl, isoindolyl, 9-membered polycyclic heteroaryls such as indolyl, benzoxazolyl, and benzothiazolyl; and 10-membered polycyclic heteroaryls such as chromenyl, isoquinolyl, quinolyl, and quinazolinyl; and preferably quinolyl, benzothiol Phenyl or indolyl.
  • the “C 6 C 6 alkyl group” substituted by 1 or 2 with the same or different substituent selected from the substituent group 3 is the same as the above “-alkyl group” Or a group obtained by substituting one or two different substituents, preferably, cyanomethyl, 2-cyanoethyl, 2- (acetylamino) ethyl, 2- (N-acetyl-N-methylamino) ethyl, carbamoylmethyl, Rubamoylethyl or 2- (rubylmoyloxy) ethyl, more preferably 2- (acetylamino) ethyl or carbamoylmethyl.
  • Aryl group is the above “C 6 -C 1 () ⁇ an aryl group "in the above” halogen atom "or the" C r (V, halogenated alkyl group "is 1 to 3 have been substituted, preferably, phenyl group, or consists of a halogen atom and Torifuruoro methyl
  • the phenyl group substituted by 1 to 5 with the same or different substituent (s) selected from the group of substituents is a substituent on the phenyl group.
  • the same selected from the group 1 or 5 substituents are substituted by 1 to 5 different substituents, preferably, fluorophenyl, cyclophenyl, difluorophenyl, dichlorophenyl, (trifluoromethyl) phenyl, (trichloromethyl) phenyl, Fluoro (trifluoromethyl) phenyl, (difluoromethoxy) phenyl, (trifluoromethoxy) phenyl, (2,2,2-trifluoroethoxy) phenyl, (1,1,2,2-tetrafluoroethoxy) Phenyl, (2,2,3,3-tetrafluoropropoxy) phenyl, fluoro (2,2,3,3-tetrafluoropropoxy) phenyl, nitrophenyl
  • the “monocyclic heteroaryl group substituted by 1 to 5 with the same or different substituent (s) selected from the group of substituents” is selected from the above “monocyclic heteroaryl group”.
  • the same or different substituents to be substituted are 1 to 5 substituents, preferably 5-chloro-2-phenyl, 6-chloro-3-pyridyl or 6- (2,2,3,3-tetrafluoro). Lopropoxy) is 3-pyridyl.
  • the “naphthyl group substituted by 1 to 5 with the same or different substituent selected from the substituent group a” means that the naphthyl group has 1 to 5 identical or different substituents selected from the substituent group a.
  • a substituted group preferably a 6-chloro-2-2-naphthyl, 6-promo One 2-naphthyl, 6-cyano 2-naphthyl, 6- (trifluoromethyl) -2-naphthyl, 6- (trifluoromethoxy) -2-naphthyl, 6— (2,2,3,3- Tetrafluoropropoxy) -2-naphthyl, 6-[(trifluoromethyl) thio] -1-2-naphthyl or 6-[(trifluoromethyl) sulfonyl] -12-naphthyl, more preferably Is 6-promo 2-naphthyl or 6- (2,2,3,3-tetrafluoropropoxy) -1-2-naphthyl.
  • T is a group in which 1 to 5 identical or different substituents selected from T are substituted, and preferably, 6-chloro-2-quinolyl, 61- (trifluoromethyl) -12-quinolyl, 6- (trifluoromethoxy) 1) 2-quinolyl, 6- (2,2,3,3-tetrafluoropropoxy) 1-2-quinolyl, 71- (trifluoromethyl) 13-isoquinolyl, 5- (trifluoromethyl) benzo [b] Furan-2-yl, 2- (trifluoromethyl) benzo [b] furan 6-yl, 2-bromobenzo [b] thiophene-1-yl, 5- (trifluoromethyl) benzo [b] thiophene One 2-yl, 2- (trifluoromethyl) be
  • Heterocyclyl in the above is a 4- to 7-membered aliphatic heterocyclic group having at least one nitrogen, oxygen or sulfur atom, and is preferably azetidine, piperidine, 1,3-diene.
  • a phenylene group substituted by 1 or 2 same or different substituents selected from a substituent group consisting of (a fluorine atom and a chlorine atom) means “a fluorine atom and a chlorine atom Or a group substituted by one or two same or different substituents selected from the group consisting of the substituents, and preferably 2-fluoro-1,4-phenylene, and 3-fluoro-1,4.
  • “2,6-difluoro-1,4-phenylene” is represented by the following formula (G b)
  • the “naphthylene group substituted by 1 or 2 with the same or different substituents selected from the substituent group consisting of (fluorine atom and chlorine atom)” means that the naphthylene group is composed of It is a group substituted by one or two same or different substituents selected from the group of groups, and is preferably 1-fluoro-2,6-naphthylene.
  • the formula (G b) is It is.
  • G, L 2 and L 3 “single bond” followed by two or more “-single bond-single bond-” And "-single bond-single bond-single bond-single bond-” represent one single bond.
  • a preferred Ar is a 2,4-difluorophenyl group or a 2,5-difluorophenyl group, and a more preferred Ar is a 2,4-difluorophenyl group.
  • preferred R 1 is a hydrogen atom or a methyl group, and more preferred R 1 is a methyl group.
  • preferred L 2 is a single bond, a double bond, or a 4- to 7-membered heterocyclic group, and more preferred L 2 is a single bond.
  • preferred L 3 is a single bond, a double bond, or a CC 6 alkylene group, and more preferred L 3 is a single bond, a double bond, —CH 2 — or —C3 ⁇ 4C—. And even more preferred L 3 is A single bond, —CH 2 — or —CC—, particularly preferred L 3 is —C— or —CH 2 C—, and most preferred L 3 is —CH 2 —.
  • preferred A includes Karupokishi group, - S0 3 H group, - 0s0 3 H group, - S0 2 NH 2 group, -0P0 3 H 2 group, Azechijiniru group, a pyrrolidinyl group, a piperidinyl group, piperazinyl group, Moruhori group, 1-substituted Azechijiniru group with a substituent (the substituent: methyl group, - 0s0 3 H group or - 0P0 3 H 2 group), 1-substituted piperidinyl group (said substituted with a substituent group: methyl group, -0S0 3 H radical or - 0P0 3 group), monosubstituted with a substituent a piperazinyl group [the substituent: methyl, C 2 is monosubstituted with a substituent - C 6 alkyl group (said substituents ⁇ ⁇ -
  • Antifungal activity means that a therapeutic effect can be expected against fungal infections (mycosis) such as deep mycosis, deep dermatomycosis, and superficial mycosis. Those skilled in the art can easily determine whether or not there is any effect according to, for example, the following method.
  • the hanging method is a measurement method standardized by the National Committee for Clinical Laboratory Standards (NCCLS) in the United States (M27-A, M38-P) or a literature (Journal of Clinical Microbiology, Vol. 38, p. 341-344 (2000)). If the concentration is less than a predetermined value (preferably 64 g / mL), there is a method to judge that it has antifungal activity. Can be.
  • NCLS National Committee for Clinical Laboratory Standards
  • salts commonly used in pharmaceutical compounds for basic groups such as triazole, amino and piperidyl groups.
  • Examples of such a salt for the acidic group in the general formula (I) include an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; Metal salts such as salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; inorganic salts such as ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenylglycine alkyls Ester salt, Ethylenediamine salt, N-methyldalcamine salt, Guanidine salt, Getylamine salt, To salt, Black mouth pro-force salt, Pro-force salt, Diethanolamine salt, N-benzyl-N-phenethylamine salt, Piperazi salt, Organic amine salts such as tetramethylammonium salt, tris (hydroxymethyl) amino methane salt
  • Such salts for basic groups include, for example, hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodide; nitrates, perchlorates, Inorganic acid salts such as sulfates and phosphates; salts of lower alkanesulfonic acids such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; benzenesulfonate and p-toluenesulfonate Such as aryl sulfonates; amino acid salts such as lunitate, glutamate; and such as fumarate, succinate, citrate, tartrate, oxalate, maleate Carboxylates can be mentioned.
  • the compound according to the present invention may be left in the air or recrystallized to absorb water and become adsorbed water or form a hydrate.
  • the triazole compound and the pharmacologically acceptable salt according to the present invention each include such a hydrate.
  • the compound according to the present invention may absorb some other solvent and form a solvate in some cases.
  • the triazole compound and the pharmacologically acceptable salt according to the present invention each include such a solvate.
  • the compounds of the present invention also include various isomers.
  • various stereoisomers based on the asymmetric carbon exist.
  • the compounds according to the present invention there are various stereoisomers. Either each of them or a mixture in any proportion thereof is encompassed in the present invention.
  • Such a stereoisomer may be obtained by using a stereospecific raw material compound, or by synthesizing the compound of the present invention using an asymmetric synthesis or asymmetric induction technique, or by synthesizing the compound of the present invention. Can be obtained, if desired, by isolation using a conventional optical resolution method or separation method.
  • Examples of the compound according to the present invention include the compounds shown in the following Tables 1 to 9, but the present invention is not limited to these groups.
  • Az t represents a 1-azetidinyl group
  • 3-Azt represents a 3-azetidinyl group
  • 1,3-Azt represents a 1,3-azetidinediyl group
  • 1-Azt represents a 3, 1-azetidine diyl group
  • N—tBu represents a t-butyl group
  • Car represents a carbamoyl group
  • Hx represents a hexyl group
  • cHx represents a cyclohexyl group
  • 1,4-cHx represents a 1,4-cyclohexylene group
  • Et represents an ethyl group
  • Me represents a methyl group
  • 4-Mor represents 4 morpholinyl groups (ie morpholino groups)
  • Ph represents a phenyl group
  • 1-Pip represents a 1-piperidyl group (ie, a piperidino group),
  • 4-Pip represents a 4-piperidyl group
  • 1,4-Pip represents a 1,4-piperidinyl group
  • Pip represents a 4,1-piperidinediyl group
  • 4-Pip represents a 4-piperidinylidene group
  • 1, 4-Piz represents a 1,4-pirazazine diyl group
  • Pr represents a propyl group
  • iPr represents an isopropyl group.
  • Me -CH CH- -CH)-4-Pip-CH-0P0 3 3 ⁇ 4
  • H -CH CH- -C (-O)-1 4-P LP together H 2 — _wake 6 2

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Abstract

L'invention porte sur un composé de triazole de formule générale (I) dans laquelle: L1 représente C1-6 alkylène, etc.; G représente -C(=O)-NH-, -C(=O)-N(CH3)-, carbonyle, etc.; L2 représente une liaison simple, etc.; L3 représente C1-6 alkylène, etc.; A représente carboxy, -SO3H, -OSO3H, -SO2NH2, -OPO3H2, etc.; R1 représente hydrogène ou C1-6 alkyle; Ar représente C6-10 aryle facultativement substitué par un à trois substituants identiques ou différents choisis parmi des atomes d'halogènes et des C1-6 alkyles halogénés; et Ra représente un groupe organique. L'invention porte également sur un sel pharmacocompatible dudit composé.
PCT/JP2003/012032 2002-09-20 2003-09-19 Compose hydrosoluble de triazole WO2004026862A1 (fr)

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AU2003264533A AU2003264533A1 (en) 2002-09-20 2003-09-19 Water-soluble triazole compound

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622944A (en) * 1992-06-12 1997-04-22 Affymax Technologies N.V. Testosterone prodrugs for improved drug delivery
WO1999002524A1 (fr) * 1997-07-08 1999-01-21 Sankyo Company, Limited Composes antifongiques a base de triazole
WO2001005819A1 (fr) * 1999-07-15 2001-01-25 Kuhnil Pharm. Co., Ltd. Nouveaux composes conjugues a base de cyclosporine hydrosoluble
WO2001072743A1 (fr) * 2000-03-27 2001-10-04 Sankyo Company, Limited Composes triazoles possedant une liaison amide
WO2002066465A1 (fr) * 2001-02-22 2002-08-29 Sankyo Company, Limited Fongicide triazole hydrosoluble

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622944A (en) * 1992-06-12 1997-04-22 Affymax Technologies N.V. Testosterone prodrugs for improved drug delivery
WO1999002524A1 (fr) * 1997-07-08 1999-01-21 Sankyo Company, Limited Composes antifongiques a base de triazole
WO2001005819A1 (fr) * 1999-07-15 2001-01-25 Kuhnil Pharm. Co., Ltd. Nouveaux composes conjugues a base de cyclosporine hydrosoluble
WO2001072743A1 (fr) * 2000-03-27 2001-10-04 Sankyo Company, Limited Composes triazoles possedant une liaison amide
WO2002066465A1 (fr) * 2001-02-22 2002-08-29 Sankyo Company, Limited Fongicide triazole hydrosoluble

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