+

US20130116251A1 - Novel HSP90 Inhibitor - Google Patents

Novel HSP90 Inhibitor Download PDF

Info

Publication number
US20130116251A1
US20130116251A1 US13/669,373 US201213669373A US2013116251A1 US 20130116251 A1 US20130116251 A1 US 20130116251A1 US 201213669373 A US201213669373 A US 201213669373A US 2013116251 A1 US2013116251 A1 US 2013116251A1
Authority
US
United States
Prior art keywords
group
phenyl
optionally substituted
isopropyl
triazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/669,373
Other languages
English (en)
Inventor
Arihiro Tomura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Kayaku Co Ltd
Original Assignee
Nippon Kayaku Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36953377&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20130116251(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Nippon Kayaku Co Ltd filed Critical Nippon Kayaku Co Ltd
Priority to US13/669,373 priority Critical patent/US20130116251A1/en
Publication of US20130116251A1 publication Critical patent/US20130116251A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • C07D249/12—Oxygen or sulfur 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
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/06—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 only aliphatic carbon atoms
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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 a novel triazole derivative and an HSP90 inhibitor containing the triazole derivative as an active ingredient.
  • the triazole derivative of the present invention inhibits the function of HSP90 by binding to its ATP binding site, blocks the binding of HSP90 and its client protein and finally suppresses cellular growth.
  • Molecular chaperones are a general term for proteins that form a complex temporally with client proteins to promote the formation of the conformation of the client proteins. These proteins, the activity of which is to help folding and association of protein and to prevent aggregation, are broadly defined as molecular chaperones and classified into several families according to their molecular weights (HSP90, HSP70, HSP60, HSP40, small HSPs and the like). In particular, HSP90 has been known to interact with many molecules which are involved in the intracellular signal transduction, and it is becoming clear that HSP90 is deeply involved in cell cycle regulation, and carcinogenesis, growth and survival signal of cells.
  • HSP90 is a molecular chaperone present in cells in abundance (occupies 1-2% of total soluble protein), distributed in the cytoplasm evenly and exists mainly as dimers.
  • the activity of HSP90 alone in protein folding is low, and HSP90 functions cooperatively with other molecular chaperones having a folding activity (hereinafter called co-chaperones) such as HSP70 and p23.
  • HSP90 is often needed for its function of client proteins that form a complex, and the action mechanism is based on the biochemical characteristic that HSP90 specifically recognizes a protein under the condition of unstable folding and binds to it.
  • HSP90 performs ATP dependent folding (re-folding) of a denatured protein or a protein that is not folded.
  • GM Geldanamycin
  • Radicicol (hereinafter called RD) is a macrolide natural product which, as a different structure from GM, also acts on HSP90 and inhibits its function. It has been known that GM and RD induce degradation of various key proteins (steroid receptor, Raf, Her2 and the like) which are involved in signal transduction related to cancer and cause growth inhibition of various cancer cells in vitro.
  • HSP90 contains at the N-terminal an ATP/ADP binding site which plays an important role in controlling the chaperone function. This site is specific for and well preserved in the HSP90 family, and does not exist in other molecular chaperones. It has been elucidated by crystallographic analysis that GM and RD directly bind to this ATP/ADP binding site as antagonists (non-patent documents 2 and 3). It is also known that these antagonists inhibit the association with a co-chaperone such as p23 by binding to the ATP/ADP binding site. As the result, the composition of the chaperone complex which contains client proteins and HSP90 is changed, and eventually the client proteins are released from the complex and degraded mainly in the ubiquitin-proteasome pathway. Thus, the antiproliferative action on cancer cells by HSP90 antagonists will be caused by a depression of the client protein of HSP90 and the blocking of signal transduction pathway by the depression.
  • the HSP90 antagonist acts selectively on client proteins folded into HSP90, and does not affect the function and the amount of expression of other proteins at all. Studies have shown that in the process of carcinogenesis, a plurality of gene abnormalities are accumulated, and in many tumor cells, mutated proteins require more of the chaperone activity than normal proteins. HSP90 is overexpressed in various cancers. From the analyses of pharmacokinetics of a GM derivative, 17-AAG, in animal models, more of the 17-AAG is accumulated in cancer in comparison to the normal cells. From these reports, it is expected that the HSP90 antagonist acts on cancer cells specifically, not on normal cells. Also, since cancer cells under a kind of stressful condition such as abnormal protein expression, low oxygen and nutritional starvation are dependent on HSP90 at a higher degree, it would appear that the sensitivity of cancer cells against the HSP90 antagonist is higher.
  • Non-patent document 4 any one of these has problems for use as a pharmaceutical product in physical properties such as molecular weight, stability, and water solubility.
  • a water soluble and low molecular weight HSP90 inhibitor is sought as a useful pharmaceutical product.
  • An adenine derivative, PU3 and its derivatives have been reported to be a low molecular weight HSP90 inhibitor (Patent Document 1, non-patent document 5, non-patent document 6 and non-patent document 7).
  • a 1,3-dihydroxybenzene derivative, to which a 5-member ring is bound has been reported to be a HSP90 inhibitor (patent document 2, patent document 3, patent document 4, patent document 5, patent document 6, and patent document 7), but the antiproliferative activity against cancer cells in vitro is weak (patent document 2).
  • the patent document 8 describes benzene derivatives, to which a 5-member ring is bound, as an antagonist of HSP90, but data of the HSP90 inhibitory activity of a derivative in which the 5-member ring has a triazole skeleton is not disclosed.
  • the fact that the triazole derivatives of the present invention have HSP90 inhibitory activity is not known in literature.
  • HSP90 which is involved in cell growth
  • the inhibitors of HSP90 are expected to be effective against cancer cells selectively as described above, and some of them have been under development, but so far no inhibitor having sufficient stability and efficacy required for pharmaceutical drugs has been obtained, and a HSP90 inhibitor usable as a drug is desired.
  • a prodrug thereof or a pharmaceutically acceptable salt thereof inhibits HSP90 to complete the present invention.
  • the present invention relates to
  • N represents a nitrogen atom
  • X represents a mercapto group, hydroxy group, halogen atom, nitro group, cyano group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, optionally substituted carbocyclic or heterocyclic aryl group, an optionally substituted alkylthio group, an optionally substituted arylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted arylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted sulfamoyl group, an optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted acyloxy group, an optionally substituted alkoxycarbonyloxy group, an optionally substituted carbamoyloxy group, an optional
  • R and Y represent the same meanings as in R and Y of the general formula (1) of the aforementioned (1)
  • X a represents an optionally substituted methylene group
  • n represents an integer from 0 to 3
  • X b represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group, an optionally substituted carbocyclic or heterocyclic aryl group, halogen atom, sulfamoyl group, formyl group, acyl group, carboxyl group, carbamoyl group or silyl group;
  • m is an integer from 0 to 5
  • A is an optionally substituted cyclic or non-cyclic amino group, an optionally substituted cyclic or non-cyclic acylamino group or an optionally substituted cyclic or non-cyclic sulfonylamino group
  • (12) The triazole derivative according to the aforementioned (11) or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1 and A is a cyclic amino group in the general formula (2) of the aforementioned (11);
  • (13) The triazole derivative according to any one of the aforementioned (1) to (10) or a pharmaceutically acceptable salt thereof, wherein R is represented by the following general formula (2-2) in the general formula (1) of the aforementioned (1) or the general formula (1-1) of the aforementioned (4),
  • n a is an integer from 1 to 5
  • a a is an optionally substituted alkyl group having carbons from 1 to 6 and when n a is 2 to 5, the neighboring substituents taken together may form a ring
  • R is an optionally substituted alkyl group in the general formula (1) of the aforementioned (1) or the general formula (1-1) of the aforementioned (4)
  • X represents a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group;
  • Y represents a mercapto group, an optionally substituted alkylsulfonyl group or hydroxy group;
  • m is 0 or 1; and
  • A represents a cyclic amino group;
  • X represents a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group;
  • Ar a represents a 4-methoxyphenyl group, 3-methoxyphenyl group, 3,4-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group or 3,4-methylenedioxyphenyl group;
  • X represents a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group;
  • Alk represents an optionally substituted alkyl group;
  • the present invention can provide a drug composition containing a compound having a superior HSP90 inhibitory activity or a pharmaceutically acceptable salt thereof as an active ingredient, in particular a therapeutic agent for cancer.
  • a halogen atom indicates a fluorine atom, chlorine atom, bromine atom or iodine atom.
  • an alkyl group means, unless specified otherwise, a linear, branched or cyclic alkyl group having 1-20 carbons, preferably 1-8 carbons.
  • the linear alkyl group includes, for example, a methyl group, ethyl group, propyl group, n-butyl group, n-pentyl group, and n-hexyl group.
  • the branched alkyl group includes, for example, an isopropyl group, tert-butyl group, and 2,2-dimethylpropyl group.
  • the cyclic alkyl group includes, for example, a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and adamantyl group.
  • an alkenyl group means a linear, branched or cyclic alkenyl group having a carbon-carbon double bond at one or more places and having 2-20 carbons, preferably 2-8 carbons.
  • the linear alkenyl group includes, for example: a 1-alkenyl group such as an ethenyl group, 1-propenyl group, and 1-butenyl group; and a 2-alkenyl group such as a 2-butenyl group, and 2-pentenyl group.
  • the branched alkenyl group includes, for example, an isopropenyl group, 3-methyl-1-butenyl group, and geranyl group.
  • an alkynyl group means an alkynyl group having a carbon-carbon triple bond at one or more places and having 2-20 carbons, preferably 2-8 carbons.
  • Examples include: a 1-alkynyl group such as ethynyl group, 1-propynyl group, and 3,3-dimethyl-1-butynyl group; and a 2-alkynyl group such as a 2-propynyl group, 2-butynyl group, 3-phenyl-2-propynyl group, 4,4-dimethyl-2-pentynyl group, and 3-trimethylsilyl-2-propynyl group.
  • a carbocyclic aryl group includes, for example, a phenyl group, and naphthyl group.
  • a heterocyclic aryl group includes, for example, a pyridyl group, pyrimidinyl group, quinolyl group, quinazolyl group, naphthyridinyl group, furyl group, pyrrolyl group, indolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, and triazolyl group.
  • the substituent includes, for example, a hydrogen atom, mercapto group, hydroxy group, halogen atom, nitro group, cyano group, alkyl group, alkenyl group, alkynyl group, carbocyclic or heterocyclic aryl group, alkylthio group, arylthio group, alkylsulfinyl group, arylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, sulfamoyl group, alkoxyl group, aryloxy group, acyloxy group, alkoxycarbonyloxy group, carbamoyloxy group, substituted or non-substituted amino group, acylamino group, alkoxycarbonylamino group, ureido group, sulfonylamino group, sulfamoylamino group, formyl group
  • an alkylthio group means the alkylthio group having 1-8 carbons and includes, for example, a methylthio group, isopropylthio group, and benzylthio group.
  • An arylthio group includes, for example, a phenylthio group, naphthylthio group, and pyridylthio group.
  • An alkylsulfinyl group means the alkylsulfinyl group having 1-8 carbons and includes, for example, a methylsulfinyl group, isopropylsulfinyl group, and benzylsulfinyl group.
  • An arylsulfinyl group includes, for example, phenylsulfinyl group, naphthylsulfinyl group, and pyridylsulfinyl group.
  • An optionally substituted sulfonyl group includes, for example, an alkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group, and arylsulfonyl group.
  • An alkylsulfonyl group means the alkylsulfonyl group having 1-8 carbons and includes, for example, a methylsulfonyl group, isopropylsulfonyl group, and benzylsulfonyl group.
  • An arylsulfonyl group includes, for example, a phenylsulfonyl group, naphthylsulfonyl group, and pyridylsulfonyl group.
  • a sulfamoyl group includes, for example, a dimethylsulfamoyl group, and phenylsulfamoyl group.
  • an alkoxyl group means the alkoxyl group having 1-8 carbons and includes, for example, a methoxyl group, isopropoxyl group, and benzyloxy group.
  • An aryloxy group includes, for example, a phenoxyl group, naphthyloxy group, and pyridyloxy group.
  • An acyloxy group means the acyloxy group having 1-8 carbons and includes, for example, an acetoxyl group, and benzoyloxy group.
  • An alkoxycarbonyloxy group means the alkoxycarbonyloxy group having 1-8 carbons and includes, for example, a methoxycarbonyloxy group, and trifluoromethoxycarbonyl group.
  • a carbamoyloxy group includes, for example, a dimethylcarbamoyloxy group, and phenylcarbamoyloxy group.
  • an amino group includes, for example, a non-substituted amino group, dimethylamino group, morpholino group, piperidinyl group, 4-methylpiperazine-1-yl group, and phenylamino group.
  • An acylamino group includes, for example, an acetylamino group, and benzoylamino group.
  • An alkoxycarbonylamino group includes, for example, a methoxycarbonylamino group, ethoxycarbonylamino group, and benzyloxycarbonylamino group.
  • An ureido group includes, for example, a trimethylureido group, and 1-methyl-3-phenyl-ureido group.
  • a sulfonylamino group includes, for example, a methanesulfonylamino group, and benzenesulfonylamino group.
  • a sulfamoylamino group includes, for example, a dimethylsulfamoylamino group.
  • an acyl group includes, for example, an acetyl group, pivaloyl group, benzoyl group, and pyridinecarbonyl group.
  • An alkoxycarbonyl group includes, for example, a methoxycarbonyl group, and benzyloxycarbonyl group.
  • a carbamoyl group includes for example, a dimethylcarbamoyl group, and phenylcarbamoyl group.
  • a silyl group includes, for example, a trimethylsilyl group, triisopropylsilyl group, and tert-butyl-diphenyl-silyl group.
  • R represents an optionally substituted carbocyclic or heterocyclic aryl group or an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group or substituted or non-substituted amino group.
  • An optionally substituted carbocyclic aryl group represented by R includes, for example: a phenyl group; bromophenyl group; aminophenyl group; methylphenyl group; a group represented by the following general formula (2),
  • A represents an optionally substituted cyclic or non-cyclic amino group, an optionally substituted cyclic or non-cyclic acylamino group or an optionally substituted cyclic or non-cyclic sulfonylamino group; and a group represented by the following general formula (2-2),
  • n a represents any one of integer 1-5
  • a a represents an alkyl group having 1-6 carbons that may have a substituent and, when n a is 2-5, the neighboring substituents taken together may form a ring.
  • A includes an amino group, acylamino group, and sulfonylamino group.
  • the amino group includes a cyclic amino group, non-cyclic amino group or aromatic amino group.
  • the cyclic amino group includes, for example, a morpholino group, piperidinyl group, piperazinyl group, 4-methylpiperazin-1-yl group, and pyrrolidinyl group.
  • the non-cyclic amino group includes, for example, dimethylamino group, isopropylamino group, cyclohexylamino group, 2-hydroxyethylamino group, and 2-methoxyethylamino group.
  • the aromatic amino group includes, for example, a phenylamino group.
  • the acylamino group includes, for example, an acetylamino group, and benzoylamino group.
  • the sulfonylamino group includes, for example, a methanesulfonylamino group, and benzenesulfonylamino group.
  • the cyclic amino groups such as the morpholino group, piperidinyl group, piperazinyl group, 4-methylpiperazin-1-yl group, and pyrrolidinyl group are especially preferred.
  • 4-(morpholin-4-yl)-phenyl group, 4-(morpholin-4-ylmethyl)-phenyl group and 4-(4-methyl-piperazin-1-ylmethyl)-phenyl group are especially preferred.
  • n a is preferably 1 and 2.
  • a a includes a methyl group, ethyl group, and methylene group, and among them, the methyl group is especially preferable.
  • an alkoxyphenyl group represented by the general formula (2-2) a 4-methoxyphenyl group, 3-methoxyphenyl group, 3,4-dimethoxyphenyl group and 3,4-methylenedioxyphenyl group are preferable and especially the 4-methoxyphenyl group is preferable.
  • a heterocyclic aryl group represented by R includes, for example, a pyridyl group, pyrimidinyl group, quinolyl group, quinazolyl group, naphthylidinyl group, furyl group, pyrrolyl group, indolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, and triazolyl group, and among them, the pyridyl group and pyrimidinyl group are preferable.
  • a heterocyclic aryl group that has a substituent includes, for example, 2-morpholin-4-yl-pyrimidin-5-yl group.
  • An alkyl group represented by R includes, for example: a linear alkyl group such as a methyl group, ethyl group, propyl group, and butyl group; a branched alkyl group such as an isopropyl group, 2-methyl propyl group, and tert-butyl group; and a cyclic alkyl group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
  • a linear alkyl group such as a methyl group, ethyl group, propyl group, and butyl group
  • a branched alkyl group such as an isopropyl group, 2-methyl propyl group, and tert-butyl group
  • a cyclic alkyl group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
  • the alkyl group, represented by R may have a substituent(s), and the substituent includes, for example: a hydroxy group; a linear alkoxyl group such as a methoxy group, and ethoxy group; a cyclic alkoxyl group such as a tetrahydrofuryl group; an amino group such as a morpholino group; and a cyclic acylamino group such as a 2-oxo-pyrrolidin-1-yl group.
  • the isopropyl group is especially preferable.
  • An amino group represented by R includes, for example: a linear amino group such as a dimethylamino group; and a cyclic amino group such as a piperidino group, and morpholino group, and among them, the cyclic amino groups such as the piperidino group are preferable.
  • an optionally substituted carbocyclic or heterocyclic aryl group and an optionally substituted alkyl group are preferable.
  • an optionally substituted carbocyclic aryl group and represented by the general formulas (2) and (2-2), and an optionally substituted alkyl group are preferable, and especially a 4-methoxyphenyl group, 4-(morpholin-4-yl)-phenyl group, 4-(morpholin-4-ylmethyl)-phenyl group, 4-(4-methyl-piperazin-1-ylmethyl)-phenyl group and isopropyl group are preferable.
  • a substituent represented by Y includes a mercapto group, hydroxy group, halogen atom, cyano group, sulfonyl group, an optionally substituted alkylthio group, an optionally substituted arylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted arylsulfinyl group, an optionally substituted sulfamoyl group, an optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted acyloxy group, an optionally substituted alkoxycarbonyloxy group, an optionally substituted carbamoyloxy group, an optionally substituted amino group, an optionally substituted acylamino group, an optionally substituted alkoxycarbonylamino group, an optionally substituted ureido group, an optionally substituted sulfonylamino group, an optionally substituted sulfamoylamino
  • An optionally substituted alkylsulfonyl group represented by Y includes, for example, a 3-dimethylamino-propane-1-sulfonyl group, 3-piperidin-1-yl-propane-1-sulfonyl group, pyridin-3-yl-methanesulfonyl group, dimethylcarbamoylmethyl group, tetrahydro-pyran-2-yl-methanesulfonyl group, and 2-(2-methoxy-ethoxy)-ethanesulfonyl group, and among them, the 3-dimethylamino-propane-1-sulfonyl group and 3-piperidin-1-yl-propane-1-sulfonyl group are preferable.
  • a sulfonylamino group represented by Y includes, for example, a methanesulfonylamino group, ethanesulfonylamino group, and benzenesulfonylamino group, and among them, the methanesulfonylamino group is preferable.
  • a substituent represented by Y a hydroxy group, mercapto group, an optionally substituted alkylsulfonyl group or sulfonylamino group are preferable, and among them, the hydroxy group is especially preferable.
  • the compound represented by the general formula (1-Y′H) where the substituent represented by Y is Y′—H(Y′ is S: sulfur atom, O: Oxygen atom, or N: nitrogen atom, H represents hydrogen atom) is often described by the general formula (1′-Y′H).
  • (1-Y′H) and (1′-Y′H) are tautomers and the same compounds.
  • a mercapto group can be: a mercapto group; hydroxy group; halogen atom; nitro group; cyano group; an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group; an optionally substituted carbocyclic or heterocyclic aryl group; an optionally substituted alkylthio group; an optionally substituted arylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted arylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted sulfamoyl group, an optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted acyloxy group, an optionally substituted alkoxycarbonyloxy group, an optionally substituted carbamoyloxy group, an optionally
  • An optionally substituted alkyl group represented by X includes, for example, a methyl group, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, cyclopropyl group, N,N-dimethylaminomethyl group, N,N-dimethylaminoethyl group, morpholinylmethyl group, piperidinylmethyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxy-1-methyl-ethyl group, methoxyethyl group, methoxymethyl group, benzyl group, 2-phenylethyl group, and pyridylmethyl group, and the ethyl group, isopropyl group, tert-butyl group and 2,2-dimethylpropyl group are preferable.
  • An acyl group represented by X includes an acetyl group, propionyl group, pivaloyl group, and benzoyl group, and among them, the acetyl group is preferable.
  • a carbamoyl group represented by X includes a dimethylcarbamoyl group, 1-piperidinecarbonyl group, and 4-morpholinecarbonyl group, and among them, the dimethylcarbamoyl group is preferable.
  • An alkenyl group represented by X that may have a substituent includes a 1-alkenyl group, and 2-alkenyl group
  • the 1-alkenyl group includes, for example, an ethenyl group, isopropenyl group, 3-hydroxy-1-propenyl group, 2-acetyl-ethenyl group, and 2-phenyl-ethenyl group
  • the 2-alkenyl group includes, for example, an allyl group, and 2-butenyl group.
  • An optionally substituted alkynyl group represented by X includes a 1-alkynyl group and 2-alkynyl group
  • the 1-alkynyl group includes, for example, an ethynyl group, 3,3-dimethyl-1-butynyl group, 2-phenyl-ethynyl group, and 2-trimethylsilyl-1-ethynyl group
  • the 2-alkynyl group includes, for example, a 2-propynyl group, 2-butynyl group, 3-phenyl-2-propynyl group, 4,4-dimethyl-2-pentynyl group, and 3-trimethylsilyl-2-propynyl group, and the 2-propynyl group and 2-butynyl group are preferable.
  • An optionally substituted carbocyclic aryl group represented by X includes, for example, a phenyl group, naphthyl group, chlorophenyl group, and methoxyphenyl group.
  • An optionally substituted heterocyclic aromatic substituent represented by X includes, for example, a pyridyl group, quinolyl group, pyrimidinyl group, and furyl group.
  • a 2,4-dihydroxyphenyl group may be substituted by one to three Xs at any of the 3, 5, or 6 position, and may be monosubstitution, disubstitution or trisubstitution.
  • a compound in which the 5 position of the 2,4-dihydroxyphenyl group is substituted by X means a 5-monosubstituent represented by the following general formula (3).
  • a compound represented by the general formula (I-1) includes, for example, a compound represented by the following general formula (3-1),
  • R and Y are the same as R and Y as the general formula (1) described above.
  • X 1 , X 2 and X 3 are each independently the same meaning as X of the general formula (1) described above, or the following general formula (3-2),
  • R and Y are the same as R and Y as the general formula (1) described above.
  • X 4 is the same meaning as X of the general formula (1) described above.
  • X 1 and X 2 may be the same or different and are preferably a hydrogen atom, methyl group or 1-propynyl group.
  • X 3 and X 4 are preferably a hydrogen atom or methyl group.
  • a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group is especially preferable.
  • X represents a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group
  • Y represents a mercapto group, an optionally substituted alkylsulfonyl group or hydroxy group
  • m is 0 or 1
  • A represents a cyclic amino group, a compound represented by the following general formula (1-2),
  • X represents a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group; and Ar a represents a 4-methoxyphenyl group, 3-methoxyphenyl group, 3,4-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group or 3,4-methylenedioxyphenyl group, and a compound represented by the following general formula (1-3),
  • X represents a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group; and Alk represents an optionally substituted alkyl group, are preferable.
  • the prodrug of the present invention includes, for example, a compound represented by the following general formula (5),
  • OR 1 and OR 2 represent a substituent which is converted to a hydroxy group easily due to dissociation of O—R 1 bond and O—R 2 bond in vivo; and any one of R 1 and R 2 may be a hydrogen atom.
  • R 1 and R 2 include, for example: an acyl group such as an acetyl group, and trifluoroacetyl group; a carbamoyl group such as a dimethylcarbamoyl group; an alkoxycarbonyl group such as a methoxycarbonyl group; a phosphoryl group such as a (MeO) 2 P( ⁇ O)—; and an alkoxymethyl group such as a methoxymethyl group.
  • the triazole derivative of the present invention may form a salt with an acid or a base, and the present invention includes a HSP90 inhibitor and a cancer therapeutic agent containing a salt of a compound represented by the general formula (1) as an active ingredient.
  • a salt with an acid includes, for example, an inorganic acid salt such as a hydrochloride, hydrobromide, and sulfate and a salt with an organic acid such as a trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • a salt with a base includes, for example, a sodium salt. These salts can be produced by a standard method, and particular examples include for example, the following compounds.
  • the compound of the present invention can be produced, for example, in the following way.
  • X and R have the same meaning as X and R in the general formula (1).
  • Hal represents a halogen atom.
  • Pro represents a protective group of a hydroxy group.
  • Z represents an oxygen atom or sulfur atom.
  • R 3 represents an alkyl group.
  • R 4 represents an alkyl group or aryl group.
  • Step A a step for halogenating a resorcinol derivative represented by the general formula (IM0).
  • the halogen atom includes a chlorine atom, bromine atom or iodine atom, and among them, the bromine atom is preferable.
  • a brominating agent includes N-bromosuccinimide, benzyltrimethylammonium tribromide, and bromine, and among them benzyltrimethylammonium tribromide is preferable.
  • Step B a step for protecting the hydroxy group of the resorcinol derivative represented by the general formula (IM1).
  • a protective group, Pro that may be used in this step includes, for example, an alkoxymethyl group, substituted or non-substituted benzyl group, and silyl group. Among them, the alkoxymethyl group such as a methoxymethyl group, and benzyloxymethyl group are preferable, and the methoxymethyl group is especially preferable.
  • methoxymethylchloride can be used as a methoxymethylating agent, and the reaction can be carried out in a solvent such as a polar non-proton solvent such as dimethylformamide, a halogenated solvent, a nitrile solvent such as acetonitrile or an ether solvent, in the presence of a base such as triethylamine, pyridine, diisopropylethylamine or potassium carbonate, at a temperature from ⁇ 20° C. to 60° C.
  • a solvent such as a polar non-proton solvent such as dimethylformamide, a halogenated solvent, a nitrile solvent such as acetonitrile or an ether solvent
  • a base such as triethylamine, pyridine, diisopropylethylamine or potassium carbonate
  • Step C a step for exchanging the halogen atom in the halogen substituted resorcinol derivative represented by the general formula (IM2) with a metal atom such as lithium, and then converting to a carboxy group.
  • the halogen-lithium exchange reaction is carried out, for example, in an ether solvent such as tetrahydrofuran, and diethylether, using n-butyllithium at a temperature from ⁇ 100° C. to 0° C., preferably from ⁇ 60° C. to ⁇ 30° C. Then dry ice was added to the mixture, and the reaction was performed at a temperature from ⁇ 80° C. to 50° C. to afford a carboxylic acid (IM3).
  • IM3 carboxylic acid
  • Step D a step for synthesizing an acylhydrazide derivative represented by the general formula (IM4) by reacting a carboxylic acid derivative represented by the general formula (IM3) with hydrazine.
  • the present step can be carried out, for example, using carbonyldiimidazole or the like in tetrahydrofuran solution by adding benzylbromide or the like as necessary to produce 1-acyl-3-benzylimidazolium salt, and then reacting with hydrazine.
  • reaction with hydrazine can be carried out, using a carbodiimide such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as a condensation agent, and under coexistence of an activating agent such as 1-hydroxybenzotriazole as necessary, in a solvent such as dimethylformamide.
  • a carbodiimide such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • an activating agent such as 1-hydroxybenzotriazole
  • a compound represented by the general formula (IM5-S) and general formula (IM5-O) can be synthesized from an acylhydrazide derivative represented by the general formula (IM4) by Step E or Step G, or from a carboxylic acid derivative represented by the general formula (IM3) by Step F.
  • the present step can be carried out, for example, by reacting an acylhydrazide derivative and isothiocyanate or isocyanate at a temperature from 0° C. to 150° C., preferably from 50° C. to 100° C. in a solvent such as ethanol, tert-butanol, and dimethylformamide.
  • Step F a step for synthesizing a derivative represented by the general formula (IM5) by reacting a carboxylic acid derivative represented by the general formula (IM3) and a compound represented by the general formula (IM9).
  • the present step can be carried out, for example, by reacting in a solvent such as dimethylformamide, tetrahydrofuran, and N-methylpyrrolidone, using a condensation agent, for example, dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, under the coexistence of an activating agent such as 1-hydroxybenzotriazole as necessary, at a temperature from ⁇ 20° C. to 50° C., preferably from 0° C. to 30° C.
  • a condensation agent for example, dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • Step G a step for synthesizing a derivative represented by the general formula (IM5-S) or general formula (IM5-O) by reacting an acylhydrazide derivative represented by the general formula (IM4) with a thiocarbamate derivative or carbamate derivative represented by the general formula (IM10).
  • the present step can be carried out, for example, by reacting an acylhydrazide derivative with a thiocarbamate derivative or a carbamate derivative represented by the general formula (IM10) in a solvent such as ethanol, tert-butanol, and dimethylformamide at a temperature from 0° C. to 150° C., preferably 50° C. to 100° C.
  • a compound represented by the general formula (IM6-S) or general formula (IM6-O) can be synthesized from a compound represented by the general formula (IM5-S) or general formula (IM5-O) by Step H.
  • Step H a step for synthesizing a triazole derivative represented by the general formula (IM6-S) or (IM6-O) by a ring closure reaction of a compound represented by the general formula (IM5-S) or general formula (IM5-O).
  • the present step can be carried out, for example, by reacting in the presence of a base such as sodium hydroxide, and potassium hydroxide in a solvent such as water, and ethanol at a temperature from 20° C. to 150° C., preferably from 70° C. to 120° C.
  • Step I a step for synthesizing an alkylsulfanyltriazole derivative represented by the general formula (IM7-SR3) by alkylating a triazolethione derivative represented by the general formula (IM6-S) using an alkylating agent.
  • the alkylating agent includes an alkylhalide such as methyl iodide, and a sulfonic acid alkyl ester or the like.
  • the present step can be carried out, for example, by reacting a triazolethione derivative represented by the general formula (IM6-S) and an alkyl halide such as methyl iodide, in a solvent such as an ether solvent such as tetrahydrofuran, and diethyl ether, a polar solvent such as dimethylformamide, a halogen solvent such as dichloromethane, or a hydrocarbon solvent such as toluene.
  • a solvent such as an ether solvent such as tetrahydrofuran, and diethyl ether, a polar solvent such as dimethylformamide, a halogen solvent such as dichloromethane, or a hydrocarbon solvent such as toluene.
  • Step J and Step K steps for deprotecting the protective group of the hydroxy group of a compound in which the hydroxy group is protected, represented by the general formulas (IM6-S), (IM6-O) or (IM7-SR3), and for producing a benzene 1,3-diol derivative represented by the general formulas (1) —SH, (1) —OH or (1) —SR3.
  • the steps can be carried out under an acidic condition.
  • Any of catalysts which are known to deprotect a methoxymethyl group and have no effect other than the protective group, may be used as an acid catalyst which includes: an inorganic acid such as hydrochloric acid, and sulfuric acid; a sulfonic acid such as toluenesulfonic acid, methanesulfonic acid, and trifluorosulfonic acid; a carboxylic acid such as acetic acid, and trifluoroacetic acid; and a strong acid-weak base salt such as pyridiniumparatoluenesulfonate.
  • an inorganic acid such as hydrochloric acid, and sulfuric acid
  • a sulfonic acid such as toluenesulfonic acid, methanesulfonic acid, and trifluorosulfonic acid
  • a carboxylic acid such as acetic acid, and trifluoroacetic acid
  • a strong acid-weak base salt such as pyridiniumparatoluenes
  • the protective group is a methoxymethyl group
  • the derivative (IM9) used in Step F and the carbamate derivative (IM10) used in Step G can be synthesized, for example, according to the method described in Chem. Pharm. Bull. 48 (12) 1935-1946 (2000).
  • a prodrug thereof or a pharmaceutically acceptable salt thereof is used as an anticancer agent, it can be administered safely, orally or parenterally (systemic administration, local administration or the like), in a formulation such as powder, granules, tablets, caplets, capsules, injectables, suppositories, and ointments, singly or mixed with pharmaceutically acceptable additives such as carriers, excipients, disintegrators, binders, lubricants, fluidizers, coating agents, suspending agents, emulsifiers, stabilizers, preservatives, flavoring agents, aroma agents, diluents, and solubilizers.
  • a formulation such as powder, granules, tablets, caplets, capsules, injectables, suppositories, and ointments, singly or mixed with pharmaceutically acceptable additives such as carriers, excipients, disintegrators, binders, lubricants, fluidizers, coating agents, suspending agents, emuls
  • the content of the triazole derivative of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof in a formulation may be different depending on the formulation but normally, it is preferable to be 0.1-100 weight %.
  • the dosage may be different depending on the administration route, the age of a patient, the actual symptom to be prevented or treated and the like, but, for example, in the case where the drug is orally administered to an adult, the dosage can be 0.01 mg to 2000 mg as an active ingredient per day, preferably 0.1 mg to 1000 mg, which can be administered once a day or several times a day.
  • the triazole derivative of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof possess a HSP90 inhibitory activity and are useful as the cancer therapeutic agent.
  • Mobile phase A acetonitrile/formic acid (99.9/0.1)
  • Mobile phase B water/formic acid (99.9/0.1)
  • Mobile phase A acetonitrile/formic acid (99.9/0.1)
  • Mobile phase B water/formic acid (99.9/0.1)
  • IM0-a The material compound, 4-isopropyl-benzene-1,3-diol (IM0-a) was synthesized by the method according to WO 04/72051 (Patent Document 6).
  • IMO2-c (1.41 g, 4 mmol) and dichloromethane (20 mL) were placed in a 300 mL three-neck flask under a atmosphere of nitrogen, cooled to ⁇ 78° C., and a toluene solution of 1.01M diisobutylaluminum hydride (8.8 mL) was slowly added dropwise so that the inside temperature did not rise to ⁇ 70° C. or higher. After stirring for 1 hour, methanol (4 mL) and saturated ammonium chloride solution (20 mL) were added, and the mixture was allowed to come to room temperature. The mixture was extracted twice with chloroform (50 mL) (at this time 2M hydrochloric acid was added until the phases were separated).
  • IM04-c (486 mg, 1.6 mmol) and anhydrous tetrahydrofuran (5 mL) were placed in a 30 mL two-neck flask under a nitrogen atmosphere, and a tetrahydrofuran solution of 0.5M 1-propynylmagnesium bromide (8.0 mL, 4.0 mmol) was added dropwise at 0° C. After stirring for 1 hour, the reaction mixture was mixed with saturated ammonium chloride solution (4 mL) and saturated sodium chloride solution (10 mL), and extracted twice with ethyl ether (20 mL). After washing with saturated sodium chloride solution and drying over anhydrous sodium sulfate, filtration and evaporation gave the crude product of the title compound (IM05-c: 0.55 g).
  • reaction mixture was stirred for 4 hours and allowed to come to room temperature. After completing the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (F461-IM01: 307 mg, 57.5%).
  • the title compound (SH-a08, 12 mg, 62.2%) was obtained by using 5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-[4-methoxy-phenyl]-2,4-dihydro[1,2,4]triazol-3-thione (F53-04, 24.1 mg, 0.054 mmol), in place of 5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-[4-morpholin-4-ylmethyl)-phenyl]-2,4-dihydro[1,2,4]triazol-3-one, and treating in the similar manner as in the fourth step in the Example 2-7.
  • the bis(methoxymethyl) protected compound of the title compound (SH-a22) was obtained in 3 steps by a similar process to that of Example 2-13 using isobutylisothiocyanete in place of isopropylisothiocyanate of Example 2-13. This compound was deprotected by a similar operation to that in the fourth step of Example 1-6 to obtain the title compound (SH-a22).
  • the bis(methoxymethyl) protected compound of the title compound (SH-a23) was obtained in 3 steps by a similar process to that of Example 2-13 using cyclohexylisothiocyanate in place of isopropylisothiocyanate of Example 2-13. This compound was deprotected by a similar operation to that in the fourth step of Example 1-6 to obtain the title compound (SH-a23).
  • Tetrahydrofuran (5 mL), triethylamine (0.086 mL, 1.25 mmol), thiophosgene (0.042 mL, 0.55 mmol) and 4-amino-1-benzyl-piperidine (0.112 mL, 0.55 mmol) were placed in a 10 mL eggplant shaped flask and stirred at room temperature for 2 hours, and then 5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid hydrazide (IM4-a, 149 mg, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. After completing the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was subjected to the next reaction without further purification.
  • IM4-a 5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid hydrazide
  • the bis(methoxymethyl) protected compound of the title compound (SH-a32) was obtained in 2 steps from IM4-a by sequentially following a similar process to that of Example 2-12 reacting (2-methoxyethyl)thiocarbamic acid O-phenyl ester to IM4-a in place of G06-02 of Example 2-12.
  • This compound was deprotected by a similar operation to that of the seventh step of Example 1-1 to obtain the title compound (SH-a32).
  • reaction mixture was added to ice-water (160 mL) and stirred with the addition of hexane (20 mL). The deposited solids were collected by filtration, washed with water and hexane to obtain the title compound (F71-02: pale pink solid, 2.13 g, 68%).
  • the title compound was synthesized in a similar manner to Example 1-6 by using the bis(methoxymethyl) protected compound of 5-tert-butyl-2,4-bis-methoxymethoxy-benzoic acid (F71-02) in place of IM3-a.
  • the title compound (IM5-O-a02-Allyl: white crystals, 232.5 mg, 90%) was obtained by a similar process to that of the first step of Example 2-1A, using 4-[4-(morpholin-4-ylmethyl)-phenyl]semicarbazide (IM9-O-02: 125 mg, 0.5 mmol) in place of 4-[4-(morpholin-4-yl)-phenyl]semicarbazide and 2,4-bisallyloxy-5-isopropyl-benzoic acid (IM3-a-Allyl: 156 mg, 0.5 mmol) in place of 5-isopropyl-2,4-bis-methoxy methoxy-benzoic acid.
  • the title compound (IM6-O-a02-Allyl: colorless syrup, 28.8 mg, 18%) was obtained by a similar process to that of the second step of Example 2-1A, using 4-[4-(morpholin-4-ylmethyl)-phenyl]-1-[2,4-bis-allyloxy-5-isopropyl-benzoyl]semicarbazide (IM5-O-a02-Allyl: 165.6 mg, 0.32 mmol) in place of 4-[4-(morpholin-4-yl)-phenyl]-1-[5-isopropyl-2,4-bis-methoxymethoxy-benzoyl]semicarbazide and potassium hydroxide in place of sodium hydroxide.
  • Triethylamine (4.5 mL, 65.4 mmol) was added to a tetrahydrofuran (500 mL) solution of 4-morpholin-4-ylmethyl-phenylamine (F45-000, 5.16 g, 26.8 mmol). After cooling in ice cold, thiophosgene (2.45 mL, 32.1 mmol) was added. After stirring at room temperature overnight, aqueous sodium hydroxide was added until the reaction mixture became basic. The reaction mixture was extracted with ethyl acetate, washed with water and then washed with saturated sodium chloride.
  • the extract solution was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a red syrup like substance.
  • the syrup like substance was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 4-(4-isothiocyanatobenzyl)-morpholine (F45-00, brown oil, 5.72 g, 91%).
  • the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and then saturated sodium chloride solution. After drying over anhydrous sodium sulfate, sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure to obtain pale yellow solids.
  • the solids thus obtained were suspension purified (hexane, ethyl acetate), collected by filtration and dried under reduced pressure to obtain F45-02 (white solid, 3.39 g, 82%).
  • the reaction system was mixed with water, extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium sulfate, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a pale yellow foam (2.18 g) containing 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F45-04).
  • aqueous sodium hydroxide 1.0 M aqueous solution, 7 mL was added to a dimethylsulfoxide solution (7 mL) of the crude product (1.01 g), which was obtained in the previous step, containing 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-5-methanesulfonyl-4H-[1,2,4]triazole (F45-05).
  • the reaction mixture was heated at 90° C. for 5.5 hours while stirring, cooled to room temperature, extracted with ethyl acetate, and the extract was washed twice with water and then saturated sodium chloride solution.
  • the solution was extracted with a mixed solvent of chloroform-methanol, and the extract was washed with water and saturated sodium chloride solution. After drying the extract over anhydrous sodium sulfate, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain white solids.
  • the solids thus obtained were dissolved in methanol (20 mL) and methylene chloride (100 mL) and insoluble components were removed by filtration.
  • the title compound (OH-c02) was prepared from 2,4-bis-allyloxy-5-(but-2-ynyl)-benzoic acid (IM07-c) via F470-IM13 in a similar manner to Example 2-2.
  • the MS, and NMR spectral data of the title compound (OH-a02) are described in Example 2-3B.
  • Trimethylsilylacetylene (1.04 mL, 7.5 mmol) and anhydrous tetrahydrofuran (15 mL) were placed in a 100 mL three-neck flask under a atmosphere of nitrogen.
  • n-Butyllithium (4.72 mL, 1.59M/hexane) were added to this mixture dropwise over 30 minutes at ⁇ 78° C.
  • a solution of F59-03 (1987 mg, 5 mmol) in tetrahydrofuran (30 mL) was added to this mixture dropwise over 20 minutes at ⁇ 78° C.
  • reaction mixture was mixed with saturated aqueous ammonium chloride (30 mL) and water, and extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride solution, and then dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound (F59-04, 2770 mg).
  • F59-10 (101 mg, 0.15 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) in a 50 mL flask, mixed with tetrabutylammonium fluoride (0.16 mL, 1.0M/tetrahydrofuran) and stirred for 1 hour.
  • the reaction mixture was mixed with saturated aqueous sodium hydrogencarbonate (20 mL) and extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium chloride solution, dried with sodium sulfate, filtered and then concentrated.
  • Triethylamine (5.1 mL, 36.6 mmol) was added to a solution of 4-(4-methylpiperazin-1-ylmethyl)phenylamine (F652-02, 3.14 g, 15.3 mmol) in tetrahydrofuran (250 mL), and after cooling by ice, thiophosgene (1.11 mL, 14.6 mmol) was added. After stirring at room temperature overnight, aqueous sodium hydrogencarbonate was added to the mixture. The reaction mixture was extracted with ethyl acetate, and the extract washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the solvent was distilled off under reduced pressure to obtain brown oil.
  • the brown oil was purified by silica gel column chromatography (chloroform, methanol) to obtain 1-(4-isothiocyanatobenzyl)-4-methylpiperazine (F652-03, brownish oil, 2.64 g, 70%).
  • the resulting mixture was extracted with ethyl acetate, and the extract was washed with water and then with saturated sodium chloride solution. After drying over anhydrous sodium, the extract was filtered to remove sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain pale yellow solids. To the solids thus obtained was added diethylether, and the resulting suspension was stirred at room temperature. The precipitated solid was collected by filtration, and dried under reduced pressure to obtain F652-05 (pale yellow solid, 4.02 g, 83%).
  • 3-chloroperbenzoic acid (3.91 g, 22.7 mmol) was added to a methylene chloride (9 mL) solution of 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-5-methylsulfanyl-[1,2,4]triazole (F652-07, 2.05 g, 3.78 mmol). After stirring at room temperature for 9.5 hours, additional 3-chloroperbenzoic acid (717 mg, 4.15 mmol) was added and stirring was continued overnight.
  • aqueous sodium hydroxide 1.0 M aqueous solution, 5 mL was added to a dimethylsulfoxide (5 mL) solution of 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-5-methanesulfonyl-[1,2,4]triazole (F652-08, 1.07 g, 1.86 mmol), and the mixture was heated for 3 hours under reflux. An additional aqueous sodium hydroxide (1.0 M aqueous solution, 5 mL) was added, and the mixture was heated under flux for further 1 hour.
  • reaction mixture was extracted with ethyl acetate and chloroform.
  • the combined extracts were washed twice with water and then with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure.
  • the extract as washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate and then saturated sodium chloride solution.
  • the extract was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a pale yellow syrup, which was purified by silica gel column chromatography (hexane, ethyl acetate, chloroform, methanol) to obtain F61-02 (pale yellow foam, 1.14 g, 89%).
  • Potassium hydroxide (999 mg, 17.8 mmol) was added to an aqueous solution (10 mL) of F61-02 (1.14 g, 2.17 mmol) that was obtained in the first step, and the mixture was heated for 14 hours under reflux. After cooling to room temperature, 1 N hydrochloric acid was added until the solution became acidic (pH4-5). The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. The extract was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure.
  • Triethylamine (10.6 ⁇ L, 76.1 ⁇ mol) was added and the mixture was stirred for 2.5 hours. After adding water to the reaction mixture, the solvent was distilled off under reduced pressure. The solution was extracted with ethyl acetate, and the extract was washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogencarbonate and then saturated sodium chloride solution.
  • the title compound (F60-01: 2.87 g, 85.3%) was obtained by using 5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-[4-methoxy-phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (F53-04: 3.26 g, 7.3 mmol) in place of 5-(5-isopropyl-2,4-bis-methoxy methoxy-phenyl)-4-[4-(molpholin-4-ylmethyl-phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione, and by processing in the similar manner to the first step of Example 3-1.
  • reaction mixture was returned to room temperature and mixed with n-hexane (250 mL).
  • the precipitates were collected by filtration, washed with diethyl ether and then purified by DIAION HP-20 column chromatography (water-methanol gradient elution), followed by CHP-20 column chromatography (water-methanol gradient elution) to obtain the title compound (OH-all: 370 mg, 14.8%).
  • the fractions which were not sufficiently separated and purified were purified by HPLC fractionation to obtain the title compound (OH-all: 300 mg, total 670 mg, 26.8%).
  • Example 2-6,4-[3-(2,4-bis-allyloxy-5-isopropylphenyl)-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl]-benzoicacid (F61-03, 25 mg, 57 ⁇ mol) and stirred at room temperature for 1.5 hours and then at 45° C. overnight.
  • the solvent was distilled off to some extent under reduced pressure, and azeotropic distillation was carried out after adding toluene and acetonitrile.
  • phenyl chlorothiono-formate (0.180 mL, 231 mg, 1.34 mmol) was added to a dichloromethane (5 mL) solution of G06-01 [Heterocycles Vol. 6 (No. 12), 1999-2004 (1977); 161 mg, 0.893 mmol] and 4-(dimethyl-amino)-benzonitrile (261 mg, 1.79 mmol) and the mixture was stirred for 1 hour under ice cold conditions.
  • the reaction mixture was mixed with saturated sodium chloride solution (5 mL) and 5% aqueous sodium hydrogencarbonate solution (5 mL) and extracted with ethyl acetate.
  • methyl iodide (0.026 mL, 59 mg, 0.414 mmol) was added to a mixture of G06-04 (208 mg, 0.414 mmol), solid potassium carbonate (57 mg, 0.414 mmol), ethanol (3 mL) and tetrahydrofuran (1.5 mL), and stirring was continued at room temperature for 40 minutes. Under ice cold conditions, the reaction mixture was mixed with aqueous ammonium chloride and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • 3-chloroperbenzoic acid (65 mg, 0.38 mmol) was added to a dichloromethane (3 mL) solution of G06-05 (191 mg, 0.37 mmol) and the mixture was stirred under ice cold conditions for 50 minutes.
  • additional 3-chloroperbenzoic acid (27 mg, 0.15 mmol) was added and the mixture was stirred for 70 minutes under ice cold conditions.
  • an additional 3-chloroperbenzoic acid 36 mg, 0.21 mmol was added and the mixture was stirred for 1 hour and 40 minutes under ice cold conditions, and 3 hours at room temperature.
  • DMT-MM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium chloride n hydrate (DMT-MM, 2.34 g) was added to a dimethylformamide (10 mL) solution of 5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid (2.00 g, 7.05 mmol) and F63-01 (984.0 mg, 7.39 mmol) obtained in the first step and stirred. After 3 hours, DMT-MM (250.4 mg) was further added and stirred for 1 hour, and then the reaction was stopped by adding water. The reaction mixture was neutralized by adding an aqueous solution of saturated sodium hydrogencarbonate and extracted with ethyl acetate.
  • the Fifth Step 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-5-methylsulfonyl-4H-[1,2,4]triazole (F63-05)
  • aqueous sodium hydroxide 1.0 M aqueous solution, 9 mL
  • a dimethylsulfoxide 11 mL
  • 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-5-methyl sulfonyl4H-[1,2,4]triazole F63-05, 1.63 g, 3.82 mmol
  • the mixture was heated at 90-100° C. for 12 hours while stirring. After returning to room temperature, water was added.
  • the reaction mixture was extracted with ethyl acetate, and the extract was washed twice with water and then with saturated sodium chloride solution.
  • reaction mixture was allowed to come to room temperature and stirred for 24 hours. After completing the reaction, the reaction mixture was extracted with ethyl acetate, and the extract was washed 4 times with saturated sodium chloride, dried with sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol) followed by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (F67-02: 198 mg, 86.4%).
  • IM3-a (1137 mg, 4 mmol), hydrazine.monohydrate (240 mg, 4.8 mmol) and dimethylformamide (15 mL) were placed in a 100 mL flask, and to this 1-hydroxy benztriazolemonohydrate (656 mg, 4.8 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (932 mg, 4.86 mmol) were added under ice cold conditions, and the mixture was stirred for 20 hours. After adding water (100 mL) and saturated aqueous sodium hydrogencarbonate (15 mL), the reaction mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated sodium chloride solution, dried with sodium sulfate and then concentrated under reduced pressure to obtain the title crude compound (F93-01: 1302 mg).
  • N-(3-isothiocyanatopropyl)-2-pyrrolidinone was obtained by the similar process to that of Example 2-2(B) in 1 step using N-(3-aminopropyl)-2-pyrrolidinone in place of 4-molpholin-4-ylmethyl-phenylamine (F45-000) in Example 2-2 (B).
  • the title compound (OH-a30) was obtained using this compound in the similar process to that of Example 2-13 in 7 steps.
  • the bis(methoxymethyl) protected compound of the title compound (OH-a32) was obtained from the compound of Example 3-14 (SFN-a32) protected by a bis(methoxymethyl) group by the similar manner to that of the sixth step of Example 2-12. This compound was deprotected in the similar manner to that in the seventh step of Example 1-1 to obtain the title compound (OH-a32).
  • the title compound was synthesized from 5-amino-2,2-dimethyl-1,3-dioxane (F77-01) that is known in the literature (Chem. Pharm. Bull. Vol. 44, No. 12, 2205-2212, 1996) by the similar manner to that of the first step of Example 2-12.
  • a dimethylformamide (2 mL) solution of IM4-a (180 mg, 0.603 mmol) and F77-02 [161 mg, 0.603 mmol] was heated at 100° C. for 1.5 hours on an oil bath while stirring.
  • the reaction mixture was mixed with sodium chloride solution and extracted with ethyl acetate.
  • the ethyl acetate extracts were combined, washed with sodium chloride solution and dried over anhydrous sodium sulfate.
  • F69-01 was synthesized by a similar process to that of the first step of Example 3-16 using 2-dimethylamino-ethyl chloride hydrochloride in place of 3-dimethylamino-propyl chloride hydrochloride of Example 3-16.
  • the bis(methoxymethyl) protected title compound (SFN-a26) was obtained in 6 steps by a similar process to that of Example 2-2(B) using 4-(2-aminoethyl)-morpholine in place of 4-molpholin-4-ylmethyl-phenylamine (F45-000) of Example 2-2(B). This compound was deprotected by a similar operation to that of Example 3-9 to obtain the title compound (SFN-a26).
  • the bis(methoxymethyl) protected compound of the title compound (SFN-a29) was obtained in 6 steps by a similar process to that of Example 2-2(B) using 3-(2-aminoethyl)pyridine in place of 4-molpholin-4-ylmethyl-phenylamine (F45-000) of Example 2-2(B). This compound was deprotected by a similar operation to that of Example 3-9 to obtain the title compound (SFN-a29).
  • N-(3-isothiocyanatopropyl)-2-pyrrolidinone was obtained by a similar process to that of Example 2-2(B) in 1 step using N-(3-aminopropyl)-2-pyrrolidinone in place of 4-molpholin-4-ylmethyl-phenylamine (F45-000) of Example 2-2(B).
  • a bis(methoxymethyl) protected title compound (SFN-a30) was obtained in 5 steps by a similar process to that of Example 2-13. This compound was deprotected by a similar operation to that of Example 3-9 to obtain the title compound (SFN-a30).
  • a bis(methoxymethyl) protected title compound (SFN-a32) was obtained by a similar process to that of the fourth and fifth step of Example 2-12 from the bis(methoxymethyl) protected compound (SH-a32) of Example 1-15. This compound was deprotected by a similar operation to that of Example 3-9 to obtain the title compound (SFN-a32).
  • the title compound (SFN3-a08 hydrochloride) can be obtained by a similar process to that of Example 3-16. That is, the title compound (SFN3-a08 hydrochloride) was obtained in 4 steps from F53-04, by reacting 1-(3-chloropropyl)piperidine hydrochloride, in place of 3-dimethylaminopropyl chloride hydrochloride, to F53-04, and by carrying out the reactions sequentially as in Example 3-16.
  • the title compound (SFN4-a08) can be obtained by a similar process to that of Example 3-23. That is, the bis(methoxymethyl) protected title compound (SFN4-a08) and the bis(methoxymethyl) protected compound of Example 3-21 (SFN5-a08) were obtained from F53-04 in 2 steps by reacting 3-(bromomethyl)pyridine hydrobromide, in place of 2-(bromomethyl)tetrahydro-2H-pyran, to F53-04, and carrying out sequentially the reactions similar to those of Example 3-23. After separating both compounds, the bis(methoxymethyl) protected title compound (SFN4-a08) was deprotected by the similar operation to that of Example 3-9 to obtain the title compound (SFN4-a08).
  • the title compound (SFN5-a08) can be obtained by a similar process to that of Example 3-23. That is, the bis(methoxymethyl) protected compound of Example 3-21 (SFN4-a08) and the bis(methoxymethyl) protected title compound (SFN5-a08) were obtained from F53-04 in 2 steps by reacting 3-(bromomethyl)pyridine hydrobromide, in place of 2-(bromomethyl)tetrahydro-2H-pyran, to F53-04, and carrying out sequentially the reactions similar to those of Example 3-23. After separating both compounds, the bis(methoxymethyl) protected title compound (SFN5-a08) was deprotected by the similar operation to that of Example 3-9 to obtain the title compound (SFN5-a08).
  • the title compound (SFN8-a08) can be obtained by a similar process to that of Example 3-23. That is, the title compound (SFN8-a08) was obtained from F53-04 in 3 steps by reacting 1-bromo-2-(2-methoxyethoxy)ethane, in place of 2-(bromomethyl) tetrahydro-2H-pyran, to F53-04 and by carrying out sequentially the similar reactions as in Example 3-23.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US13/669,373 2005-03-09 2012-11-05 Novel HSP90 Inhibitor Abandoned US20130116251A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/669,373 US20130116251A1 (en) 2005-03-09 2012-11-05 Novel HSP90 Inhibitor

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
JP2005065027 2005-03-09
JP2005-065027 2005-03-09
JP2005-183259 2005-06-23
JP2005183259 2005-06-23
PCT/JP2006/304496 WO2006095783A1 (fr) 2005-03-09 2006-03-08 Nouvel inhibiteur de hsp 90
US88557507A 2007-09-04 2007-09-04
US13/669,373 US20130116251A1 (en) 2005-03-09 2012-11-05 Novel HSP90 Inhibitor

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/JP2006/304496 Division WO2006095783A1 (fr) 2005-03-09 2006-03-08 Nouvel inhibiteur de hsp 90
US88557507A Division 2005-03-09 2007-09-04

Publications (1)

Publication Number Publication Date
US20130116251A1 true US20130116251A1 (en) 2013-05-09

Family

ID=36953377

Family Applications (4)

Application Number Title Priority Date Filing Date
US13/669,373 Abandoned US20130116251A1 (en) 2005-03-09 2012-11-05 Novel HSP90 Inhibitor
US13/669,370 Abandoned US20130116431A1 (en) 2005-03-09 2012-11-05 Novel HSP90 Inhibitor
US13/671,185 Abandoned US20130116252A1 (en) 2005-03-09 2012-11-07 Novel HSP90 Inhibitor
US13/671,242 Abandoned US20130116253A1 (en) 2005-03-09 2012-11-07 Novel HSP90 Inhibitor

Family Applications After (3)

Application Number Title Priority Date Filing Date
US13/669,370 Abandoned US20130116431A1 (en) 2005-03-09 2012-11-05 Novel HSP90 Inhibitor
US13/671,185 Abandoned US20130116252A1 (en) 2005-03-09 2012-11-07 Novel HSP90 Inhibitor
US13/671,242 Abandoned US20130116253A1 (en) 2005-03-09 2012-11-07 Novel HSP90 Inhibitor

Country Status (9)

Country Link
US (4) US20130116251A1 (fr)
EP (1) EP1857446B1 (fr)
JP (1) JP5044730B2 (fr)
KR (1) KR20070112400A (fr)
CN (1) CN101160291B (fr)
CA (1) CA2598899A1 (fr)
RU (1) RU2007137133A (fr)
TW (1) TW200700397A (fr)
WO (1) WO2006095783A1 (fr)

Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2410591T3 (es) 2004-09-22 2013-07-02 Nippon Kayaku Kabushiki Kaisha Nuevo copolímero en bloque, preparación micelar y agente antineoplásico que lo contiene como principio activo
WO2006055760A1 (fr) 2004-11-18 2006-05-26 Synta Pharmaceuticals Corp. Composes triazole modulant l'activite de hsp90
WO2007094819A2 (fr) 2005-08-18 2007-08-23 Synta Pharmaceuticals Corp. Dérivés de triazole modulant l'activité de hsp90
KR20080106254A (ko) 2006-03-28 2008-12-04 니폰 가야꾸 가부시끼가이샤 탁산류의 고분자 결합체
CA2652656A1 (fr) 2006-05-18 2007-11-29 Nippon Kayaku Kabushiki Kaisha Conjugue de podophyllotoxines a poids moleculaire eleve
DE102006023337A1 (de) * 2006-05-18 2007-11-22 Merck Patent Gmbh Triazolderivate II
JP5441691B2 (ja) 2006-05-25 2014-03-12 シンタ ファーマシューティカルズ コーポレーション Ｈｓｐ９０活性を調節するトリアゾール化合物
CA2653217A1 (fr) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Procede pour traiter des troubles proliferants associes a des produits protooncogenes
AU2007267847B2 (en) 2006-05-25 2012-04-12 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
AU2007267860B2 (en) * 2006-05-25 2012-08-09 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
TW200806637A (en) * 2006-05-25 2008-02-01 Synta Pharmaceuticals Corp Synthesis of triazole compounds that modulate HSP90 activity
CA2659425C (fr) * 2006-08-17 2017-06-20 Synta Pharmaceuticals Corp. Composes de triazole modulant l'activite de la hsp90
WO2008041610A1 (fr) 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Mélange d'un dérivé de résorcinol avec un polymère
FR2907453B1 (fr) 2006-10-24 2008-12-26 Sanofi Aventis Sa Nouveaux derives du fluorene,compositions les contenant et utilisation
US8334364B2 (en) 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
WO2008056654A1 (fr) 2006-11-08 2008-05-15 Nippon Kayaku Kabushiki Kaisha Dérivé polymère d'un antagoniste métabolique d'acide nucléique
KR101567608B1 (ko) 2007-02-08 2015-11-09 신타 파마슈티칼스 코프. 암과 같은 증식성 질환의 치료에 유용한 트라이아졸 화합물
TW200904417A (en) * 2007-02-20 2009-02-01 Synta Pharmaceuticals Corp Triazole compounds that modulate Hsp90 activity
AU2008287367B2 (en) * 2007-08-13 2012-02-23 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
USRE46190E1 (en) 2007-09-28 2016-11-01 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
WO2009116509A1 (fr) 2008-03-18 2009-09-24 日本化薬株式会社 Conjugué de polymère et de substance physiologiquement active
JP5366940B2 (ja) 2008-05-08 2013-12-11 日本化薬株式会社 葉酸若しくは葉酸誘導体の高分子結合体
US9156836B2 (en) 2008-05-16 2015-10-13 Synta Pharmaceuticals Corp. Tricyclic triazole compounds that modulate HSP90 activity
WO2010017545A2 (fr) 2008-08-08 2010-02-11 Synta Pharamceuticals Corp. Composés de triazole qui modulent l'activité hsp90
JP5544357B2 (ja) 2009-05-15 2014-07-09 日本化薬株式会社 水酸基を有する生理活性物質の高分子結合体
AR077405A1 (es) 2009-07-10 2011-08-24 Sanofi Aventis Derivados del indol inhibidores de hsp90, composiciones que los contienen y utilizacion de los mismos para el tratamiento del cancer
FR2949467B1 (fr) 2009-09-03 2011-11-25 Sanofi Aventis Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation
US9205086B2 (en) 2010-04-19 2015-12-08 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a Hsp90 inhibitory compounds and a EGFR inhibitor
TW201304805A (zh) 2010-11-17 2013-02-01 Nippon Kayaku Kk 新穎之胞核苷系代謝拮抗劑之高分子衍生物
AU2012305405B2 (en) 2011-09-11 2016-01-14 Nippon Kayaku Kabushiki Kaisha Method for manufacturing block copolymer
JP2014240356A (ja) * 2011-10-20 2014-12-25 日本化薬株式会社 トリアゾール−３−オン誘導体の新規な製造法
EP2776025A1 (fr) 2011-11-02 2014-09-17 Synta Pharmaceuticals Corp. Polythérapie d'inhibiteurs de hsp 90 avec des agents contenant du platine
EP2773345A1 (fr) 2011-11-02 2014-09-10 Synta Pharmaceuticals Corp. Thérapie anticancéreuse utilisant une combinaison d'inhibiteurs de hsp 90 et d'inhibiteurs de topoisomérase i
EP2780010A1 (fr) 2011-11-14 2014-09-24 Synta Pharmaceuticals Corp. Association thérapeutique d'inhibiteurs de hsp90 et d'inhibiteurs de braf
CN103172579B (zh) * 2011-12-20 2017-02-22 天津市国际生物医药联合研究院 三氮唑苯胺类化合物的制备和用途
CN103172578B (zh) * 2011-12-20 2016-09-14 天津市国际生物医药联合研究院 4-环末端取代2-1,2,3-三氮唑苯胺类化合物的制备和用途
JP6497767B2 (ja) * 2013-12-16 2019-04-10 日本化薬株式会社 癌治療におけるｈｓｐ９０阻害剤の抗腫瘍効果を予測する方法
WO2015143004A1 (fr) * 2014-03-18 2015-09-24 Synta Pharmaceuticals Corp. Agents thérapeutiques cibles
CN104230845B (zh) * 2014-08-22 2017-01-25 沈阳药科大学 缩氨基脲衍生物及其用途
AU2016263564B2 (en) 2015-05-20 2019-12-05 Amgen Inc. Triazole agonists of the APJ receptor
CN105523955B (zh) * 2015-12-14 2018-08-17 北京嘉林药业股份有限公司 化合物及其在制备药物中的用途
WO2017192485A1 (fr) 2016-05-03 2017-11-09 Amgen Inc. Composés triazole hétérocycliques utilisés en tant qu'agonistes du récepteur apj
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
WO2018093579A1 (fr) * 2016-11-16 2018-05-24 Amgen Inc. Composés phényle triazole en tant qu'agonistes du récepteur apj
MA46824A (fr) 2016-11-16 2019-09-25 Amgen Inc Composés de triazole substitués par alkyle en tant qu'agonistes du récepteur apj
EP3541804B1 (fr) 2016-11-16 2025-01-22 Amgen Inc. Composés de triazole à substitution cycloalkyle en tant qu'agonistes du récepteur apj
WO2018093580A1 (fr) 2016-11-16 2018-05-24 Amgen Inc. Composés de triazole pyridyle en tant qu'agonistes du récepteur apj
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
WO2019089335A1 (fr) 2017-11-03 2019-05-09 Amgen Inc. Agonistes de triazole fusionnés du récepteur apj
MA52487A (fr) 2018-05-01 2021-03-10 Amgen Inc Pyrimidinones substituées en tant qu'agonistes du récepteur apj
EP3653611A1 (fr) * 2018-11-15 2020-05-20 Centre National De La Recherche Scientifique Inhibiteurs de metallo-beta-lactamases
CN113121505B (zh) * 2021-03-02 2023-03-07 中国人民解放军海军军医大学 一种具有抗真菌与抗肿瘤双重作用的三唑酮类化合物及应用

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1501928A (zh) 2000-11-02 2004-06-02 斯隆-凯特林癌症研究所 结合hsp90的小分子组合物
US7247734B2 (en) * 2001-12-21 2007-07-24 Vernalis (Cambridge) Limited 3,4-diarylpyrazoles and their use in the therapy of cancer
GB0228417D0 (en) * 2002-12-05 2003-01-08 Cancer Rec Tech Ltd Pyrazole compounds
GB0229618D0 (en) * 2002-12-19 2003-01-22 Cancer Rec Tech Ltd Pyrazole compounds
GB0309637D0 (en) * 2003-04-28 2003-06-04 Cancer Rec Tech Ltd Pyrazole compounds
GB0315111D0 (en) * 2003-06-27 2003-07-30 Cancer Rec Tech Ltd Substituted 5-membered ring compounds and their use
JP4575294B2 (ja) * 2003-06-27 2010-11-04 協和発酵キリン株式会社 Ｈｓｐ９０ファミリー蛋白質阻害剤
DE102004030658A1 (de) * 2004-06-24 2006-01-19 Meier Vakuumtechnik Gmbh Laminator
WO2006055760A1 (fr) * 2004-11-18 2006-05-26 Synta Pharmaceuticals Corp. Composes triazole modulant l'activite de hsp90
DE102005007304A1 (de) * 2005-02-17 2006-08-24 Merck Patent Gmbh Triazolderivate

Also Published As

Publication number Publication date
US20130116431A1 (en) 2013-05-09
EP1857446A1 (fr) 2007-11-21
CN101160291A (zh) 2008-04-09
WO2006095783A1 (fr) 2006-09-14
JPWO2006095783A1 (ja) 2008-08-14
RU2007137133A (ru) 2009-04-20
CA2598899A1 (fr) 2006-09-14
KR20070112400A (ko) 2007-11-23
EP1857446B1 (fr) 2013-05-01
JP5044730B2 (ja) 2012-10-10
US20130116252A1 (en) 2013-05-09
US20130116253A1 (en) 2013-05-09
TW200700397A (en) 2007-01-01
CN101160291B (zh) 2012-09-05
EP1857446A4 (fr) 2009-06-03

Similar Documents

Publication Publication Date Title
US8399464B2 (en) HSP90 inhibitor
US20130116251A1 (en) Novel HSP90 Inhibitor
KR100790414B1 (ko) 피리미딘 화합물
US8258175B2 (en) Isoindolin-1-one derivatives
EP2496558B1 (fr) Derives de tetrahydroquinolines en tant qu'inhibiteurs du bromodomaine
US9108916B2 (en) Carbazole compounds and therapeutic uses of the compounds
WO2001047890A1 (fr) Quinoline, derives de la quinazoline et medicaments contenant ces substances
US11884656B2 (en) Pyrrole derivatives as PLK1 inhibitors
EA013522B1 (ru) Алкинилпирролопиримидины и их применение в качестве ингибиторов hsp90
US7750019B2 (en) Pyrimidine compound having benzyl(pyridylmethyl)amine structure and medicament comprising the same
US7459475B2 (en) Substituted triazoles as sodium channel blockers
CN103360382B (zh) 喹唑啉衍生物及其用途
TW200526606A (en) Substituted triazole derivatives as oxytocin antagonists
US8222254B2 (en) 1, 2, 4-triazole derivatives as serotonergic modulators
Tapera et al. Design, synthesis, molecular docking and biological evaluation of 1, 2, 4-triazole derivatives possessing a hydrazone moiety as anti-breast cancer agents
KR20180085814A (ko) 치환된 5,6-디히드로-6-페닐벤조[f]이소퀴놀린-2-아민의 제조 방법
US9493423B2 (en) Compounds capable of inhibiting voltage gated calcium ion channel, and pharmaceutical compositions comprising the same
Jawed Ahsan et al. Synthesis and biological potentials of some new 1, 3, 4-oxadiazole analogues
EP3733186B1 (fr) Nouveau composé de dihydroquinazolinone ou sel pharmacologiquement acceptable, et inhibiteur de croissance cellulaire
US7875615B2 (en) Substituted triazole derivatives as oxytocin antagonists
WO2006100557A1 (fr) Derives de triazole substitues en tant qu'antagonistes d'oxytocine

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载