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WO2009104152A1 - Traitement combiné du cancer des ovaires - Google Patents

Traitement combiné du cancer des ovaires Download PDF

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Publication number
WO2009104152A1
WO2009104152A1 PCT/IB2009/050682 IB2009050682W WO2009104152A1 WO 2009104152 A1 WO2009104152 A1 WO 2009104152A1 IB 2009050682 W IB2009050682 W IB 2009050682W WO 2009104152 A1 WO2009104152 A1 WO 2009104152A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
paclitaxel
ovarian cancer
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/IB2009/050682
Other languages
English (en)
Inventor
Martine Clozel
Urs Regenass
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.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals 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
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2009104152A1 publication Critical patent/WO2009104152A1/fr
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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention concerns the combination of an endothelin receptor antagonist of formula (I)
  • paclitaxel for therapeutic use, simultaneously, separately or over a period of time, in the treatment of ovarian cancer.
  • Ovarian cancer is one of the most common cancers in women. A common complication of ovarian cancer is ascite formation. Today, there is no satisfactory treatment for ovarian cancer or for its complications such as ascite formation.
  • endothelin receptor antagonists including the compound of formula (I) and the use of said endothelin receptor antagonists in the treatment of various diseases, including cancer in general.
  • Paclitaxel (the active principle of a medicament sold under the trademark Taxol ® in the United States) is an anti-microtubule agent extracted from the needles and bark of the Pacific yew tree, Taxus brevifolia. This compound is currently approved in the European Union and the United States for, among others, the treatment of advanced cancer of the ovary.
  • ET A R endothelin receptor A
  • L. Rosano et al (MoI. Cancer Ther. (2007), 6(7), 2003-2011) disclosed that ZD4054, a specific ET A R antagonist, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo.
  • the compound of formula (I) which is both an ET A R and an ET B R antagonist, produces surprisingly high effects in an in vivo model of ovarian cancer when combined with paclitaxel.
  • the applicant found that the use of the combination of the compound of formula (I) with paclitaxel prevents the formation of ascites.
  • the compound of formula (I) in combination with paclitaxel may be used for the preparation of a medicament, and is suitable, for the treatment of ovarian cancer and/or the prevention or treatment of ascite formation associated with ovarian cancer.
  • the invention thus firstly relates to a product containing the compound of formula (I) below
  • pharmaceutically acceptable salt refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • “Simultaneously” or “simultaneous”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients by the same route and at the same time.
  • “Separately” or “separate”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients at approximately the same time by at least two different routes.
  • Therapeutic administration over a period of time” also encompasses situations wherein the ingredients are not given with the same periodicity
  • prevention of ascite formation or "preventing ascite formation” is meant in the present application that, following the administration of the appropriate preventive treatment according to this invention, the formation of ascites is either avoided or that this formation is reduced, or, alternatively, that the ascites nevertheless formed are eliminated or reduced.
  • treatment of ascite formation or “treating ascite formation” is meant in the present application that, following the administration of the appropriate treatment according to this invention, the ascites present in the patient are eliminated or reduced.
  • the product containing the abovementioned compound of formula (I) or a pharmaceutically acceptable salt of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof will be for therapeutic use, simultaneously, separately or over a period of time, in the prevention or treatment of ascite formation in patients having ovarian cancer.
  • the compound of formula (I) or its pharmaceutically acceptable salt will be intended to be administered by intravenous or intraperitoneal route.
  • the compound of formula (I) or its pharmaceutically acceptable salt will be intended to be administered by oral route.
  • Paclitaxel or its pharmaceutically acceptable salt will preferably be administered by intravenous or intraperitoneal route.
  • a dose of 0.01 to 10 mg (and preferably 0.1 to 5 mg and more preferably 0.1 to 1 mg) of compound of formula (I) per kg of patient body weight per day combined with a dose of 0.1 to 10 mg (and preferably 1 to 3 mg) of paclitaxel per kg of patient body weight per day, will be appropriate.
  • the invention also relates to a pharmaceutical composition containing, as active principles, the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, as well as at least one non-toxic excipient.
  • such a pharmaceutical composition will be in a liquid form suitable for intravenous or intraperitoneal administration.
  • said pharmaceutical composition may contain the compound of formula (I) or a pharmaceutically acceptable salt of this compound and paclitaxel or a pharmaceutically acceptable salt thereof, in solution in a mixture of polyoxyethylated castor oil (e.g. Cremophor ® EL) and ethanol (said mixture containing for example from 40 to 60% in volume of polyoxyethylated castor oil in ethanol).
  • polyoxyethylated castor oil e.g. Cremophor ® EL
  • ethanol e.g. Cremophor ® EL
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing"
  • the invention further relates to the use of the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to treat ovarian cancer. It also relates to the use of the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to prevent or treat ascite formation in patients having ovarian cancer.
  • the invention further relates to a method of treating a patient having an ovarian cancer by administering to said patient a combination of the compound of formula (I) as defined previously or a pharmaceutically acceptable salt of this compound, with paclitaxel or a pharmaceutically acceptable salt thereof. It also relates to a method of preventing or treating the formation of ascites in a patient having an ovarian cancer by administering to said patient a combination of the compound of formula (I) as defined previously or a pharmaceutically acceptable salt of this compound, with paclitaxel or a pharmaceutically acceptable salt thereof.
  • Vehicle solution An aqueous 0.5% (by weight) solution of methylcellulose is prepared by stirring the appropriate quantity of methylcellulose in the appropriate quantity of water for 4 hours. This solution can be prepared up to 3 days in advance. On the day of the experiment, 0.05% (by volume) of Tween 80 is dissolved in the methylcellulose solution previously obtained to yield the vehicle solution.
  • mice 43 mice are injected i.p. with 10 6 SKOV3ipl cells. Ten days later, the tumor weight is evaluated in three of the mice.
  • ⁇ paclitaxel 5 mg/kg (125 ⁇ g paclitaxel in 200 ⁇ L PBS per mouse), once a week, i.p. route; ⁇ ⁇ compound of formula (I): 100 mg/kg (as suspension in the vehicle solution at a concentration of up to 25 mg/mL), once a day, oral route.
  • the combination of the compound of formula (I) with paclitaxel markedly increased the response to the paclitaxel treatment alone: two out often mice were tumor-free after the combination treatment while all mice still had tumors in the paclitaxel-treated group; the average tumor weight in the combination treatment group was reduced compared to the mice treated with the compound of formula (I) alone or with paclitaxel alone; and no mouse treated with the combination developed ascites even though 8 out of 10 still had tumors, whereas ascites were present in 4 out of 9 mice treated with paclitaxel alone and in 6 out of 9 mice treated with the compound of formula (I) alone.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une combinaison d'un antagoniste récepteur d'endothéline de formule (I) avec du paclitaxel, et plus particulièrement, cette combinaison à usage thérapeutique, simultanément, séparément ou durant une certaine période, dans le traitement du cancer des ovaires.
PCT/IB2009/050682 2008-02-20 2009-02-19 Traitement combiné du cancer des ovaires Ceased WO2009104152A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IB2008050609 2008-02-20
IBPCT/IB2008/050609 2008-02-20

Publications (1)

Publication Number Publication Date
WO2009104152A1 true WO2009104152A1 (fr) 2009-08-27

Family

ID=40600259

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/050682 Ceased WO2009104152A1 (fr) 2008-02-20 2009-02-19 Traitement combiné du cancer des ovaires

Country Status (1)

Country Link
WO (1) WO2009104152A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2702057A4 (fr) * 2011-04-25 2015-03-04 Savvipharm Inc Compositions pharmaceutiques contenant de l'orotate de paclitaxel

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008200A2 (fr) * 2000-07-21 2002-01-31 Actelion Pharmaceuticals Ltd Nouveaux sulfonamides arylethene

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008200A2 (fr) * 2000-07-21 2002-01-31 Actelion Pharmaceuticals Ltd Nouveaux sulfonamides arylethene

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GODARA GEETA ET AL: "Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma", PROSTATE, vol. 65, no. 1, September 2005 (2005-09-01), pages 27 - 34, XP002527398, ISSN: 0270-4137 *
ROSANO LAURA ET AL: "ZD4054, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma cell proliferation", EXPERIMENTAL BIOLOGY AND MEDICINE (MAYWOOD), vol. 231, no. 6, June 2006 (2006-06-01), pages 1132 - 1135, XP002527397, ISSN: 1535-3702 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2702057A4 (fr) * 2011-04-25 2015-03-04 Savvipharm Inc Compositions pharmaceutiques contenant de l'orotate de paclitaxel
KR101819596B1 (ko) 2011-04-25 2018-02-22 사비팜 인크. 파클리탁셀 오로테이트를 포함하는 약제학적 조성물

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