WO2002066038A1 - Treatment of refractory tumors using epothilone derivatives - Google Patents

Treatment of refractory tumors using epothilone derivatives Download PDF

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Publication number
WO2002066038A1
WO2002066038A1 PCT/US2002/004255 US0204255W WO02066038A1 WO 2002066038 A1 WO2002066038 A1 WO 2002066038A1 US 0204255 W US0204255 W US 0204255W WO 02066038 A1 WO02066038 A1 WO 02066038A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
dihydroxy
thiazolyl
ethenyl
dione
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
PCT/US2002/004255
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English (en)
French (fr)
Inventor
Francis Y. F. Lee
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.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
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=23028846&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2002066038(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to JP2002565596A priority Critical patent/JP2004522774A/ja
Priority to HU0303175A priority patent/HUP0303175A2/hu
Priority to EP02714885A priority patent/EP1385529A4/en
Priority to CA002438610A priority patent/CA2438610A1/en
Priority to PL02363362A priority patent/PL363362A1/xx
Priority to BR0207487-7A priority patent/BR0207487A/pt
Priority to CNA02805251XA priority patent/CN1774253A/zh
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to MXPA03007394A priority patent/MXPA03007394A/es
Priority to EEP200300396A priority patent/EE200300396A/xx
Priority to KR10-2003-7010871A priority patent/KR20040025895A/ko
Priority to IL15698802A priority patent/IL156988A0/xx
Publication of WO2002066038A1 publication Critical patent/WO2002066038A1/en
Priority to IS6918A priority patent/IS6918A/is
Priority to NO20033684A priority patent/NO20033684L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • TAXOL ® paclitaxel
  • cytotoxic activity against rapidly proliferating cells such as tumor cells or other hyperproliferative cellular diseases. See, Hofle et al., Angew. Chem. Int. Ed. Engl., Vol. 35, No.13/14, 1567-1569 (1996); WO93/10121 published May 27, 1993; and WO97/19086 published May 29, 1997.
  • epothilones A and B have been synthesized and may be used to treat a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle et al., Id.; Nicolaou et al., Angew. Chem. Int. Ed. Engl., Vol. 36, No. 19, 2097-2103 (1997); and Su et al., Angew. Chem. Int. Ed. Engl., Vol. 36, No. 19, 2093-2097 (1997). In some instances, epothilone derivatives have demonstrated enhanced properties over epothilones A and B. The present invention is concerned with the discovery that certain epothilone derivatives may be utilized to treat cancers that have demonstrated resistance to other chemotherapeutic agents, such as oncolytic agents of the taxane family of compounds.
  • chemotherapeutic agents such as oncolytic agents of the taxane family of compounds.
  • tumors demonstrating a clinical resistance to treatment with other chemotherapeutic agents may be treated with an epothilone derivative selected from those represented by formula I:
  • Figure 1 is a bar graph showing the cytotoxicity spectrum of a compound of the invention against a panel of tumor cell lines.
  • Figure 2 is a bar graph showing the cytotoxicity of a compound of the invention against paclitaxel-resistant tumors.
  • Q is selected from the group consisting of
  • D is selected from the group consisting of NR 28 R 9 , NR 0 COR 3 ⁇ and saturated heterocycle; each R R 2 , R 3 , i, R 5 , R 6 , R 7 , R 13 , R 14 , R 18 , R 19 , R 20 , R 21 , R 22 , 26 and R 27 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when Ri and R 2 are alkyl they can be joined to form cycloalkyl, and when R 3 and Rj are alkyl they can be joined to form cycloalkyl; each R , Rio, R ⁇ 6 , R ⁇ , R24, R2 and R 3 ⁇ is, independently, selected from the group consisting of H, alkyl, and substituted alkyl; each R 8 , R ⁇ , R12, R2 8 , R 30 , R32, and R 33 is, independently, selected from the group consisting of H, alkyl, substitute
  • substituents themselves are further substituted, such further substituents are selected from the group consisting of halogen, alkyl, alkoxy, aryl and aralkyl.
  • alkyl and substituted alkyl apply as well to the alkyl portion of alkoxy groups.
  • alkenyl refers to optionally substituted unsaturated aliphatic hydrocarbon groups having from 1 to about 9 carbons and one or more double bonds.
  • Substituents may include one or more substituent groups as described above for substituted alkyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl,
  • substituents for the terms “ring system,” “heterocycle,” “heterocyclic,” and “heterocyclo” include one or more substituent groups as described above for substituted alkyl or substituted aryl, and smaller heterocyclos, such as, epoxides, aziridines and the like.
  • the compounds represented by formula I above are microtubule-stabilizing agents. Therefore, they are useful in the treatment of a variety of cancers and other proliferative diseases including, but not limited to, the following; carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdom
  • Oncology therapy refers to treatment of cancer or tumors with chemotherapeutic agents that exert a cytotoxic effect in cells.
  • An example of a chemotherapeutic agent is an oncology agent of the taxane family of compounds. It is known, for example, that a considerable number of patients initially responsive to oncology therapy with taxane compounds develop resistance over a course of therapy and that not all cancers respond to treatment with taxane therapy as is the case with virtually all oncology agents. Further, certain diseases, such as colorectal cancers or melanoma, are known to be innately resistant to taxane therapy.
  • the subject epothilone compounds are highly potent cytotoxic agents capable of killing cancer cells at low nanometer concentrations and are approximately twice as potent as paclitaxel in inducing tubulin polymerization. More important, the subject compounds seem to possess the capacity to retain their antineoplastic activity against human cancers that are naturally insensitive to paclitaxel or have developed resistance to it, both in vitro and in vivo.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2002/004255 2001-02-20 2002-02-06 Treatment of refractory tumors using epothilone derivatives Ceased WO2002066038A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
IL15698802A IL156988A0 (en) 2001-02-20 2002-02-06 Pharmaceutical compositions containing epothilone derivatives
MXPA03007394A MXPA03007394A (es) 2001-02-20 2002-02-06 Tratamiento de tumores refractarios mediante uso de derivados de epotilona.
EP02714885A EP1385529A4 (en) 2001-02-20 2002-02-06 TREATMENT OF REFRACTORY TUMORS USING EPOTHILONE DERIVATIVES
CA002438610A CA2438610A1 (en) 2001-02-20 2002-02-06 Treatment of refractory tumors using epothilone derivatives
PL02363362A PL363362A1 (en) 2001-02-20 2002-02-06 Treatment of refractory tumors using epothilone derivatives
BR0207487-7A BR0207487A (pt) 2001-02-20 2002-02-06 Método de tratamento de tumores em mamìferos e uso de compostos de epotilona
CNA02805251XA CN1774253A (zh) 2001-02-20 2002-02-06 用环氧丙酯酮衍生物治疗顽固性肿瘤
JP2002565596A JP2004522774A (ja) 2001-02-20 2002-02-06 エポチロン誘導体を用いる耐性腫瘍の治療
KR10-2003-7010871A KR20040025895A (ko) 2001-02-20 2002-02-06 에포틸론 유도체를 사용하는 치료불응성 종양의 치료
HU0303175A HUP0303175A2 (hu) 2001-02-20 2002-02-06 Epotilonszármazékok alkalmazása makacs tumorok kezelésére alkalmas gyógyszerkészítmény előállítására
EEP200300396A EE200300396A (et) 2001-02-20 2002-02-06 Epotilooni derivaatide kasutamine refraktaarsete kasvajate raviks
IS6918A IS6918A (is) 2001-02-20 2003-08-18 Meðferð erfiðra æxla með notkun epóþílon afleiða
NO20033684A NO20033684L (no) 2001-02-20 2003-08-19 Behandling av refrakt¶re tumorer ved anvendelse av epotilonderivater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US26983601P 2001-02-20 2001-02-20
US60/269,836 2001-02-20

Publications (1)

Publication Number Publication Date
WO2002066038A1 true WO2002066038A1 (en) 2002-08-29

Family

ID=23028846

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/004255 Ceased WO2002066038A1 (en) 2001-02-20 2002-02-06 Treatment of refractory tumors using epothilone derivatives

Country Status (18)

Country Link
US (2) US6686380B2 (enExample)
EP (1) EP1385529A4 (enExample)
JP (1) JP2004522774A (enExample)
KR (1) KR20040025895A (enExample)
CN (1) CN1774253A (enExample)
BG (1) BG108075A (enExample)
BR (1) BR0207487A (enExample)
CA (1) CA2438610A1 (enExample)
EE (1) EE200300396A (enExample)
HU (1) HUP0303175A2 (enExample)
IL (1) IL156988A0 (enExample)
IS (1) IS6918A (enExample)
MX (1) MXPA03007394A (enExample)
NO (1) NO20033684L (enExample)
PL (1) PL363362A1 (enExample)
RU (1) RU2003128311A (enExample)
WO (1) WO2002066038A1 (enExample)
ZA (1) ZA200306173B (enExample)

Cited By (6)

* Cited by examiner, † Cited by third party
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US6849651B2 (en) 1996-12-03 2005-02-01 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
JP2005035977A (ja) * 2003-07-16 2005-02-10 Buddhist Tzu Chi General Hospital 新規なγ−ブチロラクトン化合物及びその医薬組成物
US6921769B2 (en) 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6965034B2 (en) 1996-12-03 2005-11-15 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7091193B2 (en) 2002-10-09 2006-08-15 Kosan Biosciences Incorporated Therapeutic formulations
JP2008505982A (ja) * 2004-05-18 2008-02-28 ブリストル−マイヤーズ　スクイブ　カンパニー ラクタム化合物含有ナノ粒子分散体

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US6605599B1 (en) 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
US6780620B1 (en) * 1998-12-23 2004-08-24 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US20020058286A1 (en) * 1999-02-24 2002-05-16 Danishefsky Samuel J. Synthesis of epothilones, intermediates thereto and analogues thereof
RU2003126171A (ru) * 2001-01-25 2005-02-27 Бристол-Маерс Сквибб Компани (Us) Парентеральный состав, содержащий аналоги эпотилона
WO2002072085A1 (en) * 2001-03-14 2002-09-19 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
TW200403994A (en) * 2002-04-04 2004-03-16 Bristol Myers Squibb Co Oral administration of EPOTHILONES
TW200400191A (en) * 2002-05-15 2004-01-01 Bristol Myers Squibb Co Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
WO2004018478A2 (en) * 2002-08-23 2004-03-04 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US20050171167A1 (en) * 2003-11-04 2005-08-04 Haby Thomas A. Process and formulation containing epothilones and analogs thereof
WO2006017761A2 (en) * 2004-08-05 2006-02-16 Emory University Epothilone analogues as therapeutic agents
EP1824458A1 (en) * 2004-11-18 2007-08-29 Bristol-Myers Squibb Company Enteric coated bead comprising epothilone or an epothilone analog, and preparation and administration thereof
BRPI0518286A2 (pt) * 2004-11-18 2008-11-11 Bristol Myers Squibb Co microesfera com revestimento entÉrico contendo ixabepilona e sua preparaÇço
EP1856255A4 (en) 2005-02-11 2010-01-27 Univ Southern California PROCESS FOR EXPRESSING PROTEINS VIA DISULPHIDE BRIDGES
EP2029156A4 (en) * 2006-05-01 2010-07-21 Univ Southern California COMBINATION THERAPY FOR CANCER TREATMENT
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6849651B2 (en) 1996-12-03 2005-02-01 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6965034B2 (en) 1996-12-03 2005-11-15 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
USRE41990E1 (en) 1996-12-03 2010-12-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6921769B2 (en) 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7091193B2 (en) 2002-10-09 2006-08-15 Kosan Biosciences Incorporated Therapeutic formulations
JP2005035977A (ja) * 2003-07-16 2005-02-10 Buddhist Tzu Chi General Hospital 新規なγ−ブチロラクトン化合物及びその医薬組成物
JP2008505982A (ja) * 2004-05-18 2008-02-28 ブリストル−マイヤーズ　スクイブ　カンパニー ラクタム化合物含有ナノ粒子分散体

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BR0207487A (pt) 2004-08-10
KR20040025895A (ko) 2004-03-26
US20020165258A1 (en) 2002-11-07
USRE41393E1 (en) 2010-06-22
EP1385529A4 (en) 2007-05-09
BG108075A (bg) 2005-04-30
ZA200306173B (en) 2004-11-23
PL363362A1 (en) 2004-11-15
CA2438610A1 (en) 2002-08-29
US6686380B2 (en) 2004-02-03
NO20033684L (no) 2003-10-13
JP2004522774A (ja) 2004-07-29
RU2003128311A (ru) 2005-03-10
MXPA03007394A (es) 2003-12-04
EE200300396A (et) 2003-12-15
HUP0303175A2 (hu) 2003-12-29
IL156988A0 (en) 2004-02-08
CN1774253A (zh) 2006-05-17
EP1385529A1 (en) 2004-02-04
NO20033684D0 (no) 2003-08-19
IS6918A (is) 2003-08-18

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