WO2007088895A1 - Derive de 3-arylamino-1,2,4-triazole - Google Patents

Derive de 3-arylamino-1,2,4-triazole Download PDF

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Publication number
WO2007088895A1
WO2007088895A1 PCT/JP2007/051611 JP2007051611W WO2007088895A1 WO 2007088895 A1 WO2007088895 A1 WO 2007088895A1 JP 2007051611 W JP2007051611 W JP 2007051611W WO 2007088895 A1 WO2007088895 A1 WO 2007088895A1
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group
methyl
alkyl
triazole
methylamino
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PCT/JP2007/051611
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English (en)
Japanese (ja)
Inventor
Manabu Itoh
Masahiko Ohta
Yutaka Miyazaki
Yuka Sawama
Shigeki Matsumoto
Fumiaki Yamasaki
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Mochida Pharmaceutical Co., Ltd.
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Priority claimed from PCT/JP2006/301586 external-priority patent/WO2006080533A1/fr
Application filed by Mochida Pharmaceutical Co., Ltd. filed Critical Mochida Pharmaceutical Co., Ltd.
Publication of WO2007088895A1 publication Critical patent/WO2007088895A1/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
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to the use of substituted 3-arylamino-1,1,4-triazole derivatives in the medical field and the activity of 1- ⁇ -hydroxysteroid dehydrogenase 'type 1 enzyme (hereinafter referred to as 11 ⁇ -HSDl).
  • the present invention relates to a pharmaceutical composition comprising as an active ingredient the derivative used for the treatment of diseases caused by control, and a method for producing the derivative.
  • Obesity is an important factor in syndrome X and most type 2 diabetes, and it is speculated that the network plays a central role.
  • Abdominal obesity is closely related to factors such as glucose sensitivity, hyperinsulinism, hyperglyceridemia, and other so-called syndrome X (e.g., increased blood pressure, decreased HDL levels, and increased VLDL levels).
  • syndrome X e.g., increased blood pressure, decreased HDL levels, and increased VLDL levels.
  • 11 ⁇ -HSD1 inhibition may have a positive effect on recognition and dementia, possibility of using immunoregulatory function, possibility of intraocular pressure adjustment, application to osteoporosis (Patent Document 1). It is also suggested that 11 ⁇ -HSD1 inhibitory drugs can be applied to dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscle atrophy, and neurodegenerative diseases (patents) Reference 2).
  • Equation (1) (see Patent Document 3)
  • IT represents an adamantyl group or an optionally substituted OCH, OCF, CH, CF,
  • 3 3 3 3 3 represents a phenyl group, and X represents CH or a single bond.
  • R 2 is a hydrogen atom or substituted
  • 1-10 2-10 3-9 represents kill, YC bicycloalkyl, Y adamantyl, Y aryl, Y is-(CH)-or
  • 5-12 2 0-2 represents —CH ⁇ CH—.
  • Equation (2) (see Patent Documents 4 and 5)
  • R 1 is a group for which a hydroxyl group and a halogen atom isotropic force are selected
  • a and B are groups for which a halogen atom and a C alkyl group isotropic force are selected
  • R 2 is an optionally substituted C alkyl group.
  • Power is the group chosen.
  • Equation (3) (see Patent Documents 6, 7, and 8)
  • R 1 is aryl reel, (CH) aryl, (CH) hetero reel (n is 0-2)
  • R 2 is a group selected such as C alkyl group, C alkenyl group, etc.
  • R 3 is a group selected from C alkyl group, C alkenyl group, etc.
  • R 4 is C
  • Equation (4) (see Patent Document 9)
  • Arl and Ar2 represent an aryl group or a heteroaryl group
  • R 1 is a group selected from an alkyl or cycloalkyl force, which may be substituted with a halogen atom, an alkoxy group or the like.
  • the ring containing Y may be substituted with a halogen atom, an alkyl group, or the like, and represents a cycloalkyl group or a heterocycloalkyl group
  • R 2 and R 3 are groups selected from a halogen atom, an alkyl group, or the like.
  • ⁇ is-(CH (R 14 )) p,-(CH (R 14 )) p- N (R 16 )-(CH (R 15 )) q- (where p and q are 0-3)
  • R 14 , R 15 , and R 16 represent groups selected from a halogen atom, a haloalkyl group, etc., and are adjacent to triazole. At the position, it has the feature of forming a cyclic group including Y.
  • Equation (5) (see Patent Document 10)
  • R 1 is a hydrogen atom or an optionally substituted cyclic group
  • R 2 is an optionally substituted cyclic group
  • Ar is further substituted, optionally 5 or 6 membered
  • An aromatic heterocycle, L 1 and L 2 are the same or different and may be a bond or a divalent hydrocarbon group which may be substituted;-(C) -X- (C)-(where m, n Is 0 or 1, X is an oxygen atom, sulfur atom, SO,
  • SO, NR, SO NR, NRSO, R 3 represents a hydrogen atom or an optionally substituted C
  • Equation (6) (see Patent Document 11)
  • R 1 is an optionally substituted cycloalkyl or heterocyclic group
  • R 2 and R 3 are the same or different from each other, and each optionally substituted lower alkyl, lower alkenyl, Nitrogen containing lower alkynyl, cycloalkyl, aryl or hetero ring group, etc., or R 2 and R 3 are in the form of a nitro group and carbon atom to which they are bonded
  • a and B, which may form a heterocycle are the same or different from each other, and represent halogen, OH, NH, or the like.
  • R 1 is a methyl group or a methoxy group
  • R 2 is a phenol group, a benzyl group, or a butyl group
  • R 3 is an aryl optionally substituted with a methoxy group, a nitro group, or the like. Represents a group.
  • Patent Document 1 International Publication No. 2001Z090090 Pamphlet
  • Patent Document 2 International Publication No. 2004Z089367 Pamphlet
  • Patent Document 3 International Publication No. 2003Z065983 Pamphlet
  • Patent Document 4 International Publication No. 2003Z104207 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 2003Z104208
  • Patent Document 6 International Publication No. 2004Z058730 Pamphlet
  • Patent Document 7 International Publication No. 2004Z058741 Pamphlet
  • Patent Document 8 International Publication No. 2004Z106294 Pamphlet
  • Patent Document 9 Pamphlet of International Publication No. 2005Z044192
  • Patent Document 10 Published Patent Publication No. 2005Z170939 Pamphlet
  • Patent Document 11 International Publication No. 2006Z30805 Pamphlet
  • Non-Patent Literature l Jamieson et al., J. Endocrinol, 2000, 165: p.685-692
  • Non-Patent Document 2 Kotelevtsev, Y. et al., Proc. Natl. Acad. Sci., USA, 1997, 94: 14924-14
  • Non-Patent Document 3 Montague & O'Rahilly, Diabetes, 2000, 49: 883-888
  • Non-Patent Document 4 Bujalska, I.J., S. Kumar and P.M.Stewart, Lancet, 1997, 349: 1210
  • Non-patent document 5 Halleux, C.M. et al., J. Clin. Endocrinol. Metab., 1999, 84: 4097-4105
  • Non-patent document 6 Walker, B.R. et al., Hypertension, 1998, 31: 891-895
  • Non-Patent Document 7 Fraser, R. et al., Hypertension, 1999, 33: 1364-1368
  • Non-Patent Document 8 Woods, SC et al., Science, 1998, 280: 1378-1383
  • Non-Patent Document 9 Davani, B. et al., J. Biol. Chem., November 10, 2000; 275 (45): 34841-4
  • Non-Patent Document 10 Billaudel, B. and BCJ Sutter, Horm. Metab Res., 1979, 11: 55 5-560
  • Non-Patent Document l l Jun-Ke Wang et al., Tetrahedron Letters, 2005, 46, 5139-5141 Disclosure of Invention
  • a 3-arylamino-1,2,4-triazole derivative represented by the formula (I) or a salt thereof, a prodrug or a solvate thereof, or a pharmaceutically acceptable salt or prodrug thereof A pharmaceutical composition comprising a drug or a solvate thereof as an active ingredient.
  • the present inventors have intensively studied paying attention to the compound represented by the formula (I), a 3-arylamino-1,2,4-triazole derivative, and the compound group has an excellent 11 ⁇ -HSD1 inhibitory action. It was found that Furthermore, it has been found that the compound shown in (I) exhibits excellent pharmacokinetics and has high potential as a medicine.
  • the present invention relates to a pharmaceutical composition shown in the following embodiment, a novel compound or a combination thereof. It is a pharmaceutical use and a method for producing the compound.
  • X is arbitrarily selected from the following substituent group
  • the substituent group is
  • n an integer of 1 3
  • R is chosen as Ra), Rb), Rc), Rd) force
  • Y in Ra is selected from the following substituent group:
  • the substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.
  • a C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group
  • the substituent group is
  • R 1 is a group selected from the following substituent group
  • the substituent group is
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 3 is a group selected from the following substituent group
  • the substituent group is
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R 2 and R 3 are bonded
  • the alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,
  • the substituent group is
  • Killcarbonylamino group including nitrogen atom, N, 0, S force
  • An aminocarbonyl group that may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1-2 children,
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 4 is a group selected from the following substituent group
  • the substituent group is
  • Z3 is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is
  • a hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.
  • C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di
  • alicyclic heterohydrocarbon group may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom of the amino group.
  • the alicyclic heterohydrocarbon group may be substituted with 12 groups optionally selected from the following forces,
  • the substituent group is
  • the hydrogen atom on the mino group, hydroxyl group, or nitrogen atom is a c alkyl group that is mono- or di-substituted.
  • a 5- to 7-membered alicyclic complex hydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S may be formed on the aminoamino group and the nitrogen atom. From an aminocarbol group optionally substituted mono- or di- with a C alkyl group
  • R 5 is arbitrarily selected from the following substituent group:
  • the substituent group is
  • a hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.
  • R 6 and R 7 are each independently selected from the following substituent group, and the substituent group is:
  • Substituted with hydrogen atom, hydroxyl group, C alkoxy group, C alkoxy group or hydroxyl group V, may be substituted with benzyloxy group, C alkoxy group or hydroxyl group !, may! /!
  • Phenoxy group C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al
  • Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including the nitrogen atom to which R 6 and R 7 are bonded
  • the alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups or C alkoxy groups.
  • R 8 and R 9 are hydrogen atoms or C alkyl groups, or R 8 and R 9 are bonded.
  • It may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including nitrogen atoms to be combined
  • the alicyclic heterocycle is further a hydroxyl group, a C alkyl group, or a C alkoxy group.
  • Power is the group chosen
  • R 1Q in Rb) is arbitrarily selected from the following substituent group:
  • R 1Q is bonded to either the 3rd or 4th position of the adamantyl group
  • the substituent group is
  • Halogen atom hydroxyl group, C alkyl group, C alkoxy group, C alkyl carbo-
  • Aminocarbons in which the hydrogen atom may be mono- or di-substituted with a c alkyl group
  • aminosulfol group a phenyl group, a phenyl C alkyl group, and an alicyclic hydrocarbon group, which may be mono- or di-substituted by a group,
  • R 11 in Rc is arbitrarily selected from the following substituent group:
  • the substituent group is
  • a hydroxyl group, a C alkoxy group, a halogen atom, and a hydrogen atom
  • n represents an integer of 1—2, Provided that when R is Rc), at least one of (X) n or (R 11 ) !!! is a hydroxyl group;
  • Y in Rd) is the same as the definition of Y in Ra)
  • R is 2-methylphenyl, 2-chlorophenol, 2-methoxyphenyl, or 1 (4-fluorophenyl) 1 methylethyl, where “ ⁇ ” is a bond. Represents. )
  • n 1 or 2
  • X is bonded to the 3-position and / or 4-position of the phenyl group.
  • R is Ra
  • Z defined in the above is selected from the substituent group of Z1 to Z6 Or a pharmaceutically acceptable salt, prodrug or solvate thereof. That is, in embodiment 1, only Z7 and Z8 are not included! /.
  • Examples not included in this embodiment 1-1 include the following compounds, or pharmaceutically acceptable salts, prodrugs or solvates thereof.
  • ⁇ is arbitrarily selected from the following substituent group force
  • the substituent group is
  • n an integer from 1 to 3
  • Y is selected from the following substituent group:
  • the substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.
  • a C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group
  • the substituent group is
  • R 1 is a group selected from the following substituent group
  • the substituent group is Consisting of a hydrogen atom, a C alkyl group, and a full group,
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 3 is a group selected from the following substituent group
  • the substituent group is
  • a 5 7-membered alicyclic heterohydrocarbon group containing a nitrogen atom to which R 2 and R 3 are bonded and containing 12 heteroatoms arbitrarily selected from N 0 S is formed,
  • the cyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,
  • the substituent group is
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 4 is a group selected from the following substituent group
  • the substituent group is
  • 1 to 6 1 to 6 may be substituted with 1 or 2 groups arbitrarily selected from an alkyl group or a phenyl group, and may be an amino group,
  • Power is the group chosen
  • Z3 is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is
  • a hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.
  • C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S is formed, including the nitrogen atom of the amino group.
  • the alicyclic heterohydrocarbon group may be substituted with 12 groups selected arbitrarily in the following force,
  • a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S may form an aminocarbo group and hydrogen on the nitrogen atom Atom is C
  • alkyl group which may be an aminocarbol group
  • R 5 is arbitrarily selected from the following substituent group:
  • the substituent group is
  • a hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.
  • R 6 and R 7 are each independently selected from the following substituent group, and the substituent group is:
  • V may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ⁇
  • Phenoxy group C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al
  • Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including the nitrogen atom to which R 6 and R 7 are bonded
  • the alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups or C alkoxy groups.
  • R 8 0 R 8 and R 9 are hydrogen atoms or C alkyl groups, or R 8 and R 9 are bonded.
  • It may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including nitrogen atoms to be combined
  • the alicyclic heterocycle is further a hydroxyl group, a C alkyl group, or a C alkoxy group.
  • Power is the group chosen
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 3 is a group selected from the following substituent group
  • the substituent group is
  • the alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,
  • the substituent group includes
  • 1 to 6 1 to 6 1 to 6 1 to 6 may comprise a carbonyl group, and a nitrogen atom may be used to form an alicyclic heterocycle or an aminocarbo group)
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 4 is a group selected from the following substituent group
  • the substituent group includes
  • 1 to 6 1 to 6 may be substituted with 1 or 2 groups arbitrarily selected from an alkyl group or a phenyl group, and may be an amino group,
  • Power is the group chosen. Or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • n is 1 or 2
  • X the phenyl group substituted with n is in the 3-position or X is mono-substituted at position 4 Or a phenyl group in which any X is di-substituted at the 3- or 4-position, and the definitions of other Y, ⁇ , R 2 , R 3 and R 4 are as described above.
  • n At least one of n is XI) a hydroxyl group. Or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • n is 1 or 2
  • a phenyl group substituted with (X) Are compounds in which X is mono-substituted on the 3- or 4-position, or any X is di-substituted on the 3, 4-position or a pharmaceutically acceptable compound thereof. Salt, prodrug or solvate thereof.
  • the compounds defined by the formula ( ⁇ -a) or the pharmaceutically acceptable compounds thereof are similarly defined except that the substituent group strengths of ⁇ 7 and Z8 are selected. Salts, prodrugs or solvates thereof.
  • this embodiment 3-1 has the same definition as the formula (II) of the formula (II) in the formula (II-a), and the Z,
  • the substituent group force is the group that is selected
  • R is chosen as Rb), Rc), Rd) force, respectively
  • R 1Q in Rb) is arbitrarily selected from the following substituent group:
  • R 1Q is bonded to either the 3rd or 4th position of the adamantyl group
  • the substituent group is
  • Halogen atom hydroxyl group, C alkyl group, C alkoxy group, C alkyl carbonyl
  • Aminocarbons in which the hydrogen atom may be mono- or di-substituted with a c alkyl group
  • Aminosulfol groups phenol groups, phenols which may be mono- or di-substituted by groups
  • R 11 in Rc is arbitrarily selected from the following substituent group:
  • the substituent group includes A hydroxyl group, c an alkoxy group, a halogen atom, and a hydrogen atom,
  • n an integer of 1 2
  • Y is selected from the following substituent group:
  • the substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.
  • the n-substituted phenyl group is a 4-hydroxyphenyl group, a 3-hydroxyphenyl group, a 2-hydroxyphenyl group, a 4-fluoro-3 hydroxyphenyl group, a 4-chloro-3-hydroxyphenyl group.
  • R is a 2-methylphenol group, a 2-chlorophenol group, a 2-methoxyphenyl group, or a 14-fluorophenyl group).
  • n 1 or 2
  • X is bonded to the 3-position and Z- or 4-position of the phenyl group.
  • X is arbitrarily selected from the following substituent group
  • the substituent group is
  • n an integer of 1 3
  • Y is selected from the following substituent group:
  • the substituent group includes c alkoxy group, C alkyl group, trihalogenomethyl group, C
  • 1 to 3 1 to 3 1 to 3 consisting of an alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group
  • the substituent group is
  • R 1 is a group selected from the following substituent group
  • the substituent group is
  • R 2 is a group selected from the following substituent group, The substituent group is
  • R 3 is a group selected from the following substituent group
  • the substituent group includes
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including the nitrogen atom to which R 2 and R 3 are bonded.
  • the alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,
  • the substituent group includes
  • R 2 is a group selected from the following substituent group
  • the substituent group includes
  • R 4 is a group selected from the following substituent group
  • the substituent group is
  • C alkyl group full group, alicyclic hydrocarbon group, torino, logenomethyl group, and C An amino group, which may be substituted with 12 or more groups arbitrarily selected from an alkyl group or a phenyl group;
  • Power is the group chosen
  • Z3 is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is
  • a hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.
  • C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S is formed, including the nitrogen atom of the amino group.
  • the alicyclic heterohydrocarbon group may be substituted with 12 groups selected arbitrarily in the following force,
  • the substituent group includes
  • C alkoxyamino carbo group including nitrogen atom, optionally from N, 0, S
  • a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 selected heteroatoms may be formed, and the hydrogen atom on the nitrogen atom is a C alkyl group.
  • Mono- or di-substituted which may be an aminocarbonyl group
  • R 5 is arbitrarily selected from the following substituent group:
  • the substituent group is [0080] C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen
  • a hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.
  • R 6 and R 7 are each independently selected from the following substituent group, and the substituent group is:
  • V may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ⁇
  • Phenoxy group C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al
  • Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R 6 and R 7 are bonded
  • the alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups or C alkoxy groups.
  • R 8 and R 9 are hydrogen atoms or C alkyl groups, or R 8 and R 9 are bonded.
  • It may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including nitrogen atoms to be combined
  • the alicyclic heterocycle is further substituted with a hydroxyl group, a C alkyl group, or a C alkoxy group.
  • Power is the group chosen
  • R 2 , Y and n have the same definition as in formula (III) of embodiment 2,
  • X is X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen
  • R 2 , R 4 , Y and n have the same definition as in formula (IV) of embodiment 2, X is X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen
  • n 1 or 2
  • (X) n-substituted phenyl group is a mono-substituted phenyl group at the 3- or 4-position, or any X-disubstituted at the 3- or 4-position This is a ferrule group.
  • X is arbitrarily selected from the following substituent group
  • the substituent group is
  • n an integer of 1 3
  • Y is selected from the following substituent group:
  • the substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.
  • a C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group
  • the substituent group is
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 3 is a group selected from the following substituent group
  • the substituent group includes
  • Z3 is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is
  • it may contain a nitrogen atom of the amino group to form a 2-oxoxazolidine 3-yl group.
  • R5 is arbitrarily selected from the following substituent group forces:
  • the substituent group includes
  • R 6 and R 7 are each independently selected from the following substituent group, and the substituent group is:
  • At least one of ( ⁇ ) ⁇ and ⁇ is a hydroxyl group.
  • X is arbitrarily selected from the following substituent group
  • the substituent group is
  • n an integer of 1 3
  • Y is selected from the following substituent group:
  • the substituent group includes c alkoxy group, C alkyl group, trihalogenomethyl group, C
  • Z is selected from the substituent groups Zl), Z2), Z3), Z4), Z5), Z6), and Z7) in the formula (II) of Embodiment 2.
  • n 1 or 2
  • X is bonded to the 3-position and Z- or 4-position of the phenyl group.
  • X is arbitrarily selected from the following substituent group
  • the substituent group includes
  • n an integer of 1 3
  • Y is selected from the following substituent group:
  • the substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.
  • Cyano group nitro group, C alkylcarbonylamino group, C alkylsulfonyl group, c consisting of an alkylthio group, a trifluoromethoxy group, and an aminocarbol group,
  • the substituent group is
  • R 1 is a group selected from the following substituent group
  • the substituent group is
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 3 is a group selected from the following substituent group
  • the substituent group includes
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including the nitrogen atom to which R 2 and R 3 are bonded.
  • the alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,
  • the substituent group is
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 4 is a group selected from the following substituent group
  • the substituent group is
  • 1 to 6 1 to 6 may be substituted with 1 or 2 groups arbitrarily selected from an alkyl group or a phenyl group, and may be an amino group,
  • Power is the group chosen
  • [0101] Z3) is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen
  • a hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.
  • C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di
  • a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S including the nitrogen atom of the amino group may be formed Yogu
  • the alicyclic heterohydrocarbon group is a 2-oxoxazolidine 3-yl group, a morpholino group, a 4- (4-1 morpholinocarbo) piperidine-1-yl group, or a 4 Acetyl rubiperazine
  • the alicyclic heterohydrocarbon group may be substituted with 12 groups optionally selected as follows.
  • the substituent group includes
  • C alkoxyamino carbo group including nitrogen atom, optionally from N, 0, S
  • a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 selected heteroatoms may be formed, and the hydrogen atom on the nitrogen atom is a C alkyl group.
  • Mono- or di-substituted which may be an aminocarbonyl group
  • R 5 is arbitrarily selected from the following substituent group:
  • the substituent group includes
  • a hydrogen atom on the atom may be mono- or di-substituted with a c alkyl group.
  • R 6 and R 7 are each independently selected arbitrarily from the following substituent groups:
  • the substituent group includes
  • V may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ⁇
  • Phenoxy group C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al
  • Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono
  • alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R 6 and R 7 are bonded, is formed.
  • the alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups and C alkoxy groups.
  • R 6 , R 7a — is a hydrogen atom
  • the other is not a hydrogen atom, methoxy group or ethoxy group.
  • R 8 0 R 8 and R 9 are a hydrogen atom or a C alkyl group, or contain the nitrogen atom.
  • It may form a 5- to 7-membered alicyclic complex hydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, provided that the alicyclic heterohydrocarbon group Is not a morpholino group
  • the alicyclic heterohydrocarbon group further includes a hydroxyl group, a C alkyl group, and a C alkoxy group.
  • 1 to 3 1 to 3 groups may be substituted with 1 or 2 groups
  • Power is the group chosen
  • n 1 or 2
  • X is bonded to the 3-position and / or 4-position of the phenyl group.
  • X is arbitrarily selected from the following substituent group
  • the substituent group is
  • n an integer of 1 3
  • Y is selected from the following substituent group,
  • the substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.
  • Cyano group nitro group, C alkyl carbolumino group, C alkyl sulfol group, c consisting of an alkylthio group, a trifluoromethoxy group, and an aminocarbol group,
  • the substituent group is
  • R 1 is a group selected from the following substituent group
  • the substituent group is
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 3 is a group selected from the following substituent group
  • the substituent group is
  • amino-C alkyl group optionally mono- or di-substituted with 1 to 6 groups, and an amino
  • a 5-7 alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R 2 and R 3 are bonded, is formed, and
  • the cyclic heterohydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,
  • the substituent group is
  • R 2 is a group selected from the following substituent group
  • the substituent group is
  • R 4 is a group selected from the following substituent group
  • the substituent group is
  • Power is the group chosen
  • the hydrogen atom on the nitrogen atom may be mono- or disubstituted with a C alkyl group.
  • a 5 7-membered alicyclic heterohydrocarbon group or alicyclic heterohydrocarbon group containing 12 heteroatoms arbitrarily selected from N 0 S including the nitrogen atom of the amino group is formed. You may, however, the alicyclic heterohydrocarbon group is removed with a 2-oxoxazolidine 3-yl group.
  • the alicyclic heterohydrocarbon group may be substituted with 12 groups optionally selected as follows. Often,
  • the substituent group is
  • the hydrogen atom on the mino group, hydroxyl group, or nitrogen atom is a c alkyl group that is mono- or di-substituted.
  • the amino group which may be substituted, the hydrogen atom on the nitrogen atom is mono- or c-alkyl group
  • 1 to 6 1 to 6 containing an alkylsulfonylamino group, a C alkoxyaminocarbonyl group, and a nitrogen atom
  • R 5 is arbitrarily selected from the following substituent group:
  • the substituent group is
  • the hydrogen atom on the nitrogen atom may be mono- or disubstituted with a C alkyl group.
  • R 6 and R 7 are each independently selected arbitrarily from the following substituent groups:
  • the substituent group includes
  • R 8 and R 9 are a hydrogen atom or a C alkyl group
  • the alicyclic heterocycle may be further formed with a hydroxyl group, a C alkyl group, or a C alkoxy group.
  • Power is the group chosen
  • n 1 or 2
  • X is bonded to the 3-position and / or 4-position of the phenyl group.
  • X is arbitrarily selected from the following substituent group
  • the substituent group is
  • n an integer of 1 3
  • R is chosen as Rb), Rc), Rd) force, respectively
  • R 1Q in Rb is arbitrarily selected from the following substituent group:
  • R 1Q is bonded to either the 3rd or 4th position of the adamantyl group
  • the substituent group includes
  • Halogen atom hydroxyl group, amino group, C alkyl group, C alkoxy group, C alkyl

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Abstract

L'invention concerne une composition pharmaceutique susceptible d'être administrée à un patient qui nécessite l'inhibition de 11β-HSD1 ou le contrôle de l'activité de 11β-HSD1. La composition pharmaceutique comprend un dérivé de 3-arylamino-1,2,4-triazole représenté par la formule (I), un sel ou un promédicament du dérivé pharmaceutiquement acceptables, ou un solvate du dérivé, un sel ou un promédicament en tant qu'ingrédient actif. Le dérivé de 3-arylamino-1,2,4-triazole est remarquablement stable dans un sérum humain et constitue un agent pharmaceutique extrêmement prometteur.
PCT/JP2007/051611 2006-01-31 2007-01-31 Derive de 3-arylamino-1,2,4-triazole WO2007088895A1 (fr)

Applications Claiming Priority (4)

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PCT/JP2006/301586 WO2006080533A1 (fr) 2005-01-31 2006-01-31 Dérivé de 3-amino-1,2,4-triazole
JPPCT/JP2006/301586 2006-01-31
JP2006-207255 2006-07-28
JP2006207255 2006-07-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010518085A (ja) * 2007-02-08 2010-05-27 シンタ ファーマシューティカルズ コーポレーション 癌などの増殖障害の治療に有用なトリアゾール化合物
WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide

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Publication number Priority date Publication date Assignee Title
WO2003104208A1 (fr) * 2002-06-10 2003-12-18 Merck & Co., Inc. Inhibiteurs de la 11-beta-hydroxysteroide-deshydrogenase 1 convenant au traitement du diabete, de l'obesite et de la dyslipidemie
WO2004058741A1 (fr) * 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de triazole en tant qu'inhibiteurs de la 11-beta-hydroxysteroide dehydrogenase 1
WO2004089367A1 (fr) * 2003-04-11 2004-10-21 Novo Nordisk A/S Utilisation pharmaceutique de 1,2,4-triazoles substituees
WO2005044192A2 (fr) * 2003-10-28 2005-05-19 Amgen Inc. Composes triazole et utilisations associees
JP2005525326A (ja) * 2002-02-01 2005-08-25 メルク　エンド　カムパニー　インコーポレーテッド 糖尿病、肥満症および脂質代謝異常の治療に有用な１１−ベータ−ヒドロキシステロイドデヒドロゲナーゼ１阻害剤
WO2006080533A1 (fr) * 2005-01-31 2006-08-03 Mochida Pharmaceutical Co., Ltd. Dérivé de 3-amino-1,2,4-triazole

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JP2005525326A (ja) * 2002-02-01 2005-08-25 メルク　エンド　カムパニー　インコーポレーテッド 糖尿病、肥満症および脂質代謝異常の治療に有用な１１−ベータ−ヒドロキシステロイドデヒドロゲナーゼ１阻害剤
WO2003104208A1 (fr) * 2002-06-10 2003-12-18 Merck & Co., Inc. Inhibiteurs de la 11-beta-hydroxysteroide-deshydrogenase 1 convenant au traitement du diabete, de l'obesite et de la dyslipidemie
WO2004058741A1 (fr) * 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de triazole en tant qu'inhibiteurs de la 11-beta-hydroxysteroide dehydrogenase 1
WO2004089367A1 (fr) * 2003-04-11 2004-10-21 Novo Nordisk A/S Utilisation pharmaceutique de 1,2,4-triazoles substituees
WO2005044192A2 (fr) * 2003-10-28 2005-05-19 Amgen Inc. Composes triazole et utilisations associees
WO2006080533A1 (fr) * 2005-01-31 2006-08-03 Mochida Pharmaceutical Co., Ltd. Dérivé de 3-amino-1,2,4-triazole

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010518085A (ja) * 2007-02-08 2010-05-27 シンタ ファーマシューティカルズ コーポレーション 癌などの増殖障害の治療に有用なトリアゾール化合物
US8748424B2 (en) 2007-02-08 2014-06-10 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide

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