GB0306907D0 - Boireductively-activated prodrugs - Google Patents

Boireductively-activated prodrugs

Info

Publication number
GB0306907D0
GB0306907D0 GBGB0306907.7A GB0306907A GB0306907D0 GB 0306907 D0 GB0306907 D0 GB 0306907D0 GB 0306907 A GB0306907 A GB 0306907A GB 0306907 D0 GB0306907 D0 GB 0306907D0
Authority
GB
United Kingdom
Prior art keywords
boireductively
activated prodrugs
prodrugs
activated
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.)
Ceased
Application number
GBGB0306907.7A
Other languages
English (en)
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.)
Angiogene Pharmaceuticals Ltd
Gray Laboratory Cancer Research Trust
Original Assignee
Angiogene Pharmaceuticals Ltd
Gray Laboratory Cancer Research Trust
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
Application filed by Angiogene Pharmaceuticals Ltd, Gray Laboratory Cancer Research Trust filed Critical Angiogene Pharmaceuticals Ltd
Priority to GBGB0306907.7A priority Critical patent/GB0306907D0/en
Publication of GB0306907D0 publication Critical patent/GB0306907D0/en
Priority to CNA2004800139466A priority patent/CN1791591A/zh
Priority to AU2004224070A priority patent/AU2004224070A1/en
Priority to CA002519901A priority patent/CA2519901A1/en
Priority to JP2006506035A priority patent/JP2006523202A/ja
Priority to EP04723650A priority patent/EP1613612A2/en
Priority to PCT/GB2004/001330 priority patent/WO2004085421A2/en
Priority to US10/550,864 priority patent/US20070099871A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with 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
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 with nitro or nitroso radicals directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom
    • C07D473/38—Sulfur atom attached in position 6

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)
GBGB0306907.7A 2003-03-26 2003-03-26 Boireductively-activated prodrugs Ceased GB0306907D0 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
GBGB0306907.7A GB0306907D0 (en) 2003-03-26 2003-03-26 Boireductively-activated prodrugs
CNA2004800139466A CN1791591A (zh) 2003-03-26 2004-03-26 生物还原性－活化前体药物
AU2004224070A AU2004224070A1 (en) 2003-03-26 2004-03-26 Bioreductively-activated prodrugs
CA002519901A CA2519901A1 (en) 2003-03-26 2004-03-26 Bioreductively-activated prodrugs
JP2006506035A JP2006523202A (ja) 2003-03-26 2004-03-26 生体還元により活性化されるプロドラッグ
EP04723650A EP1613612A2 (en) 2003-03-26 2004-03-26 Bioreductively-activated prodrugs
PCT/GB2004/001330 WO2004085421A2 (en) 2003-03-26 2004-03-26 Bioreductively-activated prodrugs
US10/550,864 US20070099871A1 (en) 2003-03-26 2004-03-26 Bioreductively-activated prodrugs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GBGB0306907.7A GB0306907D0 (en) 2003-03-26 2003-03-26 Boireductively-activated prodrugs

Publications (1)

Publication Number Publication Date
GB0306907D0 true GB0306907D0 (en) 2003-04-30

Family

ID=9955527

Family Applications (1)

Application Number Title Priority Date Filing Date
GBGB0306907.7A Ceased GB0306907D0 (en) 2003-03-26 2003-03-26 Boireductively-activated prodrugs

Country Status (8)

Country Link
US (1) US20070099871A1 (https=)
EP (1) EP1613612A2 (https=)
JP (1) JP2006523202A (https=)
CN (1) CN1791591A (https=)
AU (1) AU2004224070A1 (https=)
CA (1) CA2519901A1 (https=)
GB (1) GB0306907D0 (https=)
WO (1) WO2004085421A2 (https=)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2186811A1 (en) 2002-08-23 2010-05-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
CN1720332A (zh) * 2002-10-03 2006-01-11 洛桑生态综合技术联合公司 O6－烷基鸟嘌呤－dna烷基转移酶的底物
ZA200507752B (en) 2003-03-28 2007-01-31 Threshold Pharmaceuticals Inc Compositions and methods for treating cancer
GB0421296D0 (en) * 2004-09-24 2004-10-27 Angiogene Pharm Ltd Bioreductively-activated prodrugs
EP1831225A2 (en) 2004-11-19 2007-09-12 The Regents of the University of California Anti-inflammatory pyrazolopyrimidines
EP1896040B1 (en) 2005-06-29 2012-08-01 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
WO2007114926A2 (en) 2006-04-04 2007-10-11 The Regents Of The University Of California Kinase antagonists
ES2884044T3 (es) 2006-12-26 2021-12-10 Immunogenesis Inc Profármaco alquilante de fosforamidato para el tratamiento del cáncer
GB2467670B (en) 2007-10-04 2012-08-01 Intellikine Inc Chemical entities and therapeutic uses thereof
MX2010007419A (es) 2008-01-04 2010-11-12 Intellikine Inc Ciertas entidades quimicas, composiciones y metodos.
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
EP2252293B1 (en) * 2008-03-14 2018-06-27 Intellikine, LLC Kinase inhibitors and methods of use
BRPI0915231A2 (pt) * 2008-07-08 2018-06-12 Intellikine Inc compostos inibidores de quinase e métodos de uso
US20110224223A1 (en) 2008-07-08 2011-09-15 The Regents Of The University Of California, A California Corporation MTOR Modulators and Uses Thereof
CA2738429C (en) 2008-09-26 2016-10-25 Intellikine, Inc. Heterocyclic kinase inhibitors
EP2358720B1 (en) 2008-10-16 2016-03-02 The Regents of The University of California Fused ring heteroaryl kinase inhibitors
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
JP5789252B2 (ja) 2009-05-07 2015-10-07 インテリカイン， エルエルシー 複素環式化合物およびその使用
NZ598220A (en) 2009-08-17 2014-02-28 Intellikine Llc Heterocyclic compounds and uses thereof
WO2011047048A1 (en) 2009-10-14 2011-04-21 Gemmus Pharma, Inc. Combination therapy treatment for viral infections
WO2011047384A2 (en) 2009-10-16 2011-04-21 The Regents Of The University Of California Methods of inhibiting ire1
CA2799579A1 (en) 2010-05-21 2011-11-24 Intellikine, Inc. Chemical compounds, compositions and methods for kinase modulation
JP2013545749A (ja) 2010-11-10 2013-12-26 インフィニティー ファーマシューティカルズ， インコーポレイテッド 複素環化合物及びその使用
ES2637113T3 (es) 2011-01-10 2017-10-10 Infinity Pharmaceuticals, Inc. Procedimientos para preparar isoquinolinonas y formas sólidas de isoquinolinonas
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
AR088218A1 (es) 2011-07-19 2014-05-21 Infinity Pharmaceuticals Inc Compuestos heterociclicos utiles como inhibidores de pi3k
HK1198443A1 (en) 2011-07-19 2015-04-24 无限药品股份有限公司 Heterocyclic compounds and uses thereof
MX2014002542A (es) 2011-08-29 2014-07-09 Infinity Pharmaceuticals Inc Compuestos heterociclicos y usos de los mismos.
CA2846496C (en) 2011-09-02 2020-07-14 The Regents Of The University Of California Substituted pyrazolo[3,4-d]pyrimidines and uses thereof
CN103998038A (zh) * 2011-11-24 2014-08-20 里皮达特发展研究及咨询公司 具有hsp调节活性的1,4-二氢吡啶衍生物
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
JP2015532287A (ja) 2012-09-26 2015-11-09 ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア Ｉｒｅ１の調節
AU2013337717B2 (en) 2012-11-01 2018-10-25 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
WO2014153509A1 (en) 2013-03-22 2014-09-25 Millennium Pharmaceuticals, Inc. Combination of catalytic mtorc 1/2 inhibitors and selective inhibitors of aurora a kinase
AU2014305843B2 (en) 2013-08-09 2019-08-29 Ardelyx, Inc. Compounds and methods for inhibiting phosphate transport
PT3052485T (pt) 2013-10-04 2021-10-22 Infinity Pharmaceuticals Inc Compostos heterocíclicos e suas utilizações
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
MX382033B (es) 2014-03-19 2025-03-13 Infinity Pharmaceuticals Inc Compuestos heterocíclicos para utilizarlos en el tratamiento de trastornos mediados por pi3k-gamma.
WO2015160975A2 (en) 2014-04-16 2015-10-22 Infinity Pharmaceuticals, Inc. Combination therapies
WO2016054491A1 (en) 2014-10-03 2016-04-07 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2017048702A1 (en) 2015-09-14 2017-03-23 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same
WO2017161116A1 (en) 2016-03-17 2017-09-21 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors
WO2017214269A1 (en) 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
SG11201811237WA (en) 2016-06-24 2019-01-30 Infinity Pharmaceuticals Inc Combination therapies
JP7266304B2 (ja) 2017-04-21 2023-04-28 ユニヴァーシティー オブ タスマニア 治療化合物および方法
CN107513057A (zh) * 2017-09-06 2017-12-26 南京医科大学 一类乐伐替尼的乏氧活化前药及其应用
CN107698639B (zh) * 2017-09-06 2021-04-27 江苏千之康生物医药科技有限公司 一类吉西他滨磷酸酯的n-甲酸酯乏氧活化前药及其应用
CA3102279A1 (en) 2018-06-01 2019-12-05 Cornell University Combination therapy for pi3k-associated disease or disorder
EP4706758A3 (en) 2019-05-21 2026-05-06 Ardelyx, Inc. Methods for inhibiting phosphate transport
CN113336816B (zh) * 2021-06-03 2022-05-17 中国医学科学院医药生物技术研究所 胞苷类化合物及其抗肿瘤用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2122036C (en) * 1991-10-23 2002-09-17 Gillian Anlezark Bacterial nitroreductase for the reduction of cb 1954 and analogues thereof to a cytotoxic form
AU2001296215A1 (en) * 2000-07-17 2002-01-30 Oxi-Gene, Inc. Efficient method of synthesizing combretastatin a-4 prodrugs
AU2002212015B2 (en) * 2000-10-13 2007-01-25 Shire Canada Inc. Dioxolane analogs for improved inter-cellular delivery
EP1351912A2 (en) * 2000-12-21 2003-10-15 Cancer Research Ventures Limited Substituted stilbenes, their reactions and anticancer activity

Also Published As

Publication number Publication date
WO2004085421A2 (en) 2004-10-07
AU2004224070A1 (en) 2004-10-07
JP2006523202A (ja) 2006-10-12
EP1613612A2 (en) 2006-01-11
CA2519901A1 (en) 2004-10-07
CN1791591A (zh) 2006-06-21
WO2004085421A3 (en) 2005-03-24
US20070099871A1 (en) 2007-05-03

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