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WO2009086012A1 - Inhibiteurs d'aurore contenant une fraction de liaison de zinc - Google Patents

Inhibiteurs d'aurore contenant une fraction de liaison de zinc Download PDF

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Publication number
WO2009086012A1
WO2009086012A1 PCT/US2008/087532 US2008087532W WO2009086012A1 WO 2009086012 A1 WO2009086012 A1 WO 2009086012A1 US 2008087532 W US2008087532 W US 2008087532W WO 2009086012 A1 WO2009086012 A1 WO 2009086012A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
aliphatic
independently selected
aryl
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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.)
Ceased
Application number
PCT/US2008/087532
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English (en)
Inventor
Xiong Cai
Changgeng Qian
Haixiao Zhai
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Curis Inc
Original Assignee
Curis Inc
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Filing date
Publication date
Application filed by Curis Inc filed Critical Curis Inc
Publication of WO2009086012A1 publication Critical patent/WO2009086012A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links

Definitions

  • histones are subject to post-translational acetylation of the, ⁇ -amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HATl).
  • HATl histone acetyl transferase
  • Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure.
  • access of transcription factors to chromatin templates is enhanced by histone hyperacetylation, and enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome (Taunton et al., Science, 1996, 272:408-411).
  • HDAC inhibitors In the case of tumor suppressor genes, transcriptional silencing due to histone modification can lead to oncogenic transformation and cancer.
  • HDAC inhibitors include Suberoylanilide hydroxamic acid (SAHA, Zolinza®) for the treatment of cutaneous T-cell lymphoma (CTCL).
  • SAHA Suberoylanilide hydroxamic acid
  • Other HDAC inhibitors include hydroxamic acid derivatives, PXDlOl, LBH589 and LAQ824, are currently in the clinical development.
  • benzamide class of HDAC inhibitors MS-275, MGCDO 103 and CI-994 have reached clinical trials. Mourne et al.
  • Z is CRioo or N, where Rioo is independently selected from the group consisting of hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, CF 3 , CN, NO 2 , N 3 , substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic;
  • Y 10 -Y 13 are independently selected from CRi 00 , N, NH, S, and O;
  • Xi 0 - X 14 are independently selected from the group consisting of N or CRi 00 , where Ri 00 is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF 3 , CN, NO 2 , N 3 , substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic;
  • X and Y are as previously defined.
  • the compounds of the present invention are compounds represented by formula (X) as illustrated below, or its geometric isomers, or its
  • Representative compounds according to the invention are those selected from the Table A below or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:
  • subject compounds may be combined with antineoplastic agents (e.g. small molecules, monoclonal antibodies, antisense RNA, and fusion proteins) that inhibit one or more biological targets such as Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent, Sprycel, Nexavar, Sorafmib, CNF2024, RG108, BMS387032, Aff ⁇ nitak, Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD 184322, Obatodax, ABT737 and AEE788.
  • antineoplastic agents e.g. small molecules, monoclonal antibodies, antisense RNA, and fusion proteins
  • antineoplastic agents e.g. small molecules, monoclonal antibodies, antisense RNA, and fusion proteins
  • antineoplastic agents e.g. small molecules, monoclonal antibodies, antisense RNA, and fusion proteins
  • alkylating agents such as mustard gas derivatives (Mechlorethamine, cylophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines (thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazines and Triazines (Altretamine, Procarbazine, dacarbazine and Temozolomide), Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide and metal salts (Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloids such as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxel and Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine and Vinorelbine), and Camptothecan analogs (Iri)
  • Suitable agents for adjunctive therapy include a 5HTi agonist, such as a triptan (e.g. sumatriptan or naratriptan); an adenosine Al agonist; an EP ligand; an NMDA modulator, such as a glycine antagonist; a sodium channel blocker (e.g. lamotrigine); a substance P antagonist (e.g. an NKi antagonist); a cannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; a leukotriene receptor antagonist; a DMARD (e.g.
  • a 5HTi agonist such as a triptan (e.g. sumatriptan or naratriptan); an adenosine Al agonist; an EP ligand; an NMDA modulator, such as a glycine antagonist; a sodium channel blocker (e.g. lamotrigine); a substance P antagonist (e.g.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S.
  • Daily administration may be repeated continuously for a period of several days to several years. Oral treatment may continue for between one week and the life of the patient. Preferably the administration may take place for five consecutive days after which time the patient can be evaluated to determine if further administration is required.
  • the administration can be continuous or intermittent, e.g., treatment for a number of consecutive days followed by a rest period.
  • the compounds of the present invention may be administered intravenously on the first day of treatment, with oral administration on the second day and all consecutive days thereafter.
  • acyl refers to hydrogen, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups.
  • acyl includes groups such as (Ci-Ce)alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t- butylacetyl, etc.), (C 3 -Ce)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5 -carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • Step 7b Cyclopropanecarboxylic acid (4-[4-[4-(6-hydroxycarbamoyl-hexyl)- piperazin- 1 -yl]-6-(5 -methyl-2H-pyrazol-3 -ylamino)-pyrimidin-2-ylsulfanyl] - phenyl ⁇ -amide (Compound 22)
  • Step 8a Sodium 3,3-dimethoxy-2-methoxycarbonylprop-l-en-l-oxide (Compound 1)
  • a 500 mL, three neck, round bottom flask equipped with magnetic stirrer and a reflux condenser is purged with nitrogen.
  • the flask is then charged sequentially with methyl 3,3-dimethoxypropionate (0401) (26.1 g, 176 mmol), anhydrous 1,2- dimethoxyethane (125 mL), anhydrous methyl formate (25 mL, 400 mmol), 60% NaH (8.5 g, 212.5 mmol), and the mixture was heated to 40 ⁇ 50°C until evolution of hydrogen gas is observed.
  • the reaction mixture was cooled in an ice bath and slowly warmed to room temperature and stirred for 20 h.
  • the reaction mixture was filtered, washed with anhydrous ether, dried to provide desired product 0402 (25.4 g, 73%) as a white power.
  • Step 8d Methyl 2-(4-(2-(4-(cyclopropanecarboxamido)phenylthio)-6-(3-methyl- 1 H-pyrazol-5 -y lamino)pyrimidin-4-yl)piperazin- 1 -yl)pyrimidine-5 - carboxylate (Compound 0407) A mixture of ⁇ /-(4-(4-chloro-6-(3-methyl-l/-f-pyrazol-5-ylamino) pyrimidin-
  • Precipitated peptides were trapped onto glass fiber B f ⁇ lterplates and excess unlabeled p33 ATP was washed off. Plates were allowed to air-dry prior to addition of 30 uL/well of Packard Microscint 20. The amount of incorporated isotope was measured using a Perkin Elmer TopCount plate reader. Different concentrations of compounds were added to reaction to assess the activity of compounds to inhibit Aurora A kinase. IC50 was calculated using Prism software with sigmoidal dose-response curve fitting. (b) An in vitro assay which determines the ability of a test compound to inhibit HDAC enzymatic activity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des inhibiteurs d'aurore et leur utilisation dans le traitement de maladies prolifératives cellulaires, telles que le cancer. Les dérivés peuvent en outre agir en tant qu'inhibiteurs de HDAC.
PCT/US2008/087532 2007-12-20 2008-12-18 Inhibiteurs d'aurore contenant une fraction de liaison de zinc Ceased WO2009086012A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1527507P 2007-12-20 2007-12-20
US61/015,275 2007-12-20
US3519908P 2008-03-10 2008-03-10
US61/035,199 2008-03-10

Publications (1)

Publication Number Publication Date
WO2009086012A1 true WO2009086012A1 (fr) 2009-07-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/087532 Ceased WO2009086012A1 (fr) 2007-12-20 2008-12-18 Inhibiteurs d'aurore contenant une fraction de liaison de zinc

Country Status (1)

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WO (1) WO2009086012A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8367663B2 (en) 2009-01-08 2013-02-05 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8710219B2 (en) 2011-04-01 2014-04-29 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US11234986B2 (en) 2018-09-11 2022-02-01 Curis, Inc. Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
CN114105958A (zh) * 2021-12-03 2022-03-01 郑州大学第一附属医院 一组含羟肟酸的2-苯氨基嘧啶类衍生物及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060270660A1 (en) * 2002-06-20 2006-11-30 Vertex Pharmaceuticals Incorporated Processes for preparing substituted pyrimidines
US20070259869A1 (en) * 2005-11-03 2007-11-08 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060270660A1 (en) * 2002-06-20 2006-11-30 Vertex Pharmaceuticals Incorporated Processes for preparing substituted pyrimidines
US20070259869A1 (en) * 2005-11-03 2007-11-08 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9796664B2 (en) 2008-09-03 2017-10-24 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US8461157B2 (en) 2009-01-08 2013-06-11 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US11597732B2 (en) 2009-01-08 2023-03-07 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8906909B2 (en) 2009-01-08 2014-12-09 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US11261195B2 (en) 2009-01-08 2022-03-01 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US10894795B2 (en) 2009-01-08 2021-01-19 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8367663B2 (en) 2009-01-08 2013-02-05 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US10280182B2 (en) 2011-02-28 2019-05-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9512143B2 (en) 2011-02-28 2016-12-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10301323B2 (en) 2011-02-28 2019-05-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10981933B2 (en) 2011-02-28 2021-04-20 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10526346B2 (en) 2011-02-28 2020-01-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9908899B2 (en) 2011-02-28 2018-03-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10543197B2 (en) 2011-04-01 2020-01-28 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11135205B2 (en) 2011-04-01 2021-10-05 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US8710219B2 (en) 2011-04-01 2014-04-29 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11654136B2 (en) 2011-04-01 2023-05-23 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US10428028B2 (en) 2013-03-15 2019-10-01 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US11234986B2 (en) 2018-09-11 2022-02-01 Curis, Inc. Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US12403142B2 (en) 2018-09-11 2025-09-02 Curis, Inc. Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
CN114105958A (zh) * 2021-12-03 2022-03-01 郑州大学第一附属医院 一组含羟肟酸的2-苯氨基嘧啶类衍生物及其应用
CN114105958B (zh) * 2021-12-03 2022-11-22 郑州大学第一附属医院 一组含羟肟酸的2-苯氨基嘧啶类衍生物及其应用

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