WO2001089516A1 - Combinaison pharmaceutique de bicalutamide et d'anastrozole permettant d'obtenir un effet anti-androgene et l'inhibition de l'aromatase - Google Patents

Combinaison pharmaceutique de bicalutamide et d'anastrozole permettant d'obtenir un effet anti-androgene et l'inhibition de l'aromatase Download PDF

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Publication number
WO2001089516A1
WO2001089516A1 PCT/SE2001/001163 SE0101163W WO0189516A1 WO 2001089516 A1 WO2001089516 A1 WO 2001089516A1 SE 0101163 W SE0101163 W SE 0101163W WO 0189516 A1 WO0189516 A1 WO 0189516A1
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WO
WIPO (PCT)
Prior art keywords
patient
solvate
pharmaceutically acceptable
acceptable salt
compound
Prior art date
Application number
PCT/SE2001/001163
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English (en)
Inventor
Ian Cockshott
Barrington Furr
Original Assignee
Astrazeneca Ab
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 Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP01937066A priority Critical patent/EP1292297A1/fr
Priority to AU2001262834A priority patent/AU2001262834A1/en
Priority to JP2001585760A priority patent/JP2003534279A/ja
Priority to US10/276,112 priority patent/US20030114519A1/en
Publication of WO2001089516A1 publication Critical patent/WO2001089516A1/fr

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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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens

Definitions

  • the present invention relates to a pharmaceutical product, daily dose or dose regimen comprising 4'-cyano- ⁇ ' 5 ⁇ ', ⁇ '-trifluoro-3-(4-fiuorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide and anastrozole.
  • the invention also relates to a method of providing an anti-androgenic effect and aromatase inhibition in a patient, wherein the aromatase inhibition is provided substantially without causing an additional increase in the levels of circulating androgens.
  • the invention relates to the use of 4'-cyano- r , ',a '-trifluoro-3 -(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-r ⁇ -toluidide and anastrozole in the manufacture of a pharmaceutical product for this purpose.
  • Bicalutamide a non-steroidal anti-androgen, is the racemate of 4'-cyano- ', ', '- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and is
  • EP-100172 discloses 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide (named in EP-100172 as 4-cyano-3-trifluoromethyl-N-(3- ⁇ -fluorophenylsulphonyl-2- hydroxy-2-methylpropionyl)aniline) as the 8 th compound listed in the table in Example 6.
  • the corresponding structure is shown in formula I:-
  • R-enantiomer is the (-) isomer and is the pharmacologically active compound in vivo.
  • EP-100172 provides a disclosure (without supporting examples) of a pharmaceutical composition comprising 4-cyano-3-trifluoromethyl-N-(3-j3- fluorophenylsulphonyl-2-hydroxy-2-methylpropionyl)aniline in combination with "one or more drugs selected from anti-oestrogens, for example tamoxifen; aromatase inhibitors, for example testolactone or aminoglutethamide; progestins, for example medroxyprogesterone acetate; inhibitors of gonadotrophin secretion, for example danazol; LH-RH-analogues, for example buserelin; cytotoxic agents, for example cyclophosphamide; antibiotics, for example penicillin or oxytetracyclin; and anti-inflammatory agents, for example, especially for topical use, fluocinolone acetonide".
  • anti-oestrogens for example tamoxifen
  • aromatase inhibitors for example test
  • Anastrozole an aromatase inhibitor
  • AstraZeneca trade name an aromatase inhibitor
  • Anastrozole is known as 2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3- phenylene]di(2-methyl-propionitrile), which is disclosed in US re-issue No. 36,617.
  • An alternative name is 2,2'-dimethyl-2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3- phenylene]bis(propiononitrile).
  • the corresponding structure is shown in formula II:-
  • Bicalutamide can be used for the treatment of prostate cancer in combination with an inhibitor of gonadotrophin secretion, for example a luteinising hormone releasing hormone (LHRH) agonist such as goserelin, buserelin, leuprorelin or triptorelin.
  • LHRH luteinising hormone releasing hormone
  • the properties and usefulness of bicalutamide as an anti-androgen have been reviewed in B J A Furr et al., Urology, 1996, 47 (Suppl. 1 A), 13-25, and G J C Kolvenbag et al, Urology, 1996, 47 (Suppl. 1A), 70-79.
  • Aromatase enzyme in fat and other tissues converts some of the increased concentration of testosterone to oestradiol, which results in increased concentrations of oestrogen in the blood. Further discussion of this is provided by C Mahler et al, Clinical Pharmacokinetics, 1998, 34(5), pp 405-417.
  • a disadvantageous effect is produced. Namely, the increase in the levels of circulating oestrogen may cause one or more of the side effects of gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido.
  • a discussion on gynaecomastia can be found in C J Tyrrell, Prostate Cancer and Prostatic Diseases, 1999, 2(4): pp 167-171.
  • the present invention fulfils this need by providing a pharmaceutical product for administration to a patient for providing an anti-androgenic effect and aromatase inhibition in the patient, the product comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and anastrozole or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula I and anastrozole are provided in a ratio of 25 to 350 : 0.005 to 100 respectively.
  • the aromatase inhibition is provided substantially without causing an additional increase in the levels of circulating androgens.
  • the androgen levels eg, as indicated by total or free testosterone in blood
  • the androgen levels in the patient do not substantially increase above the level usually observed when the anti- androgen alone is administered to patients.
  • the present invention also provides a daily pharmaceutical dose for administration to a patient for providing an anti-androgenic effect and aromatase inhibition in the patient, the dose comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and from 0.005 to 100 mg of anastrozole or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a dose regimen for such purpose comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (eg, 150 mg thereof) and from 0.005 to 100 mg of anastrozole or a pharmaceutically acceptable salt or solvate thereof for simultaneous or sequential administration to the patient.
  • a dose regimen for such purpose comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (eg, 150 mg thereof) and from 0.005 to 100 mg of anastrozole or a pharmaceutically acceptable salt or solvate thereof for simultaneous or sequential administration to the patient.
  • aspects of the invention relate to the use in the manufacture of a pharmaceutical product of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and anastrozole or a pharmaceutically acceptable salt or solvate thereof that are simultaneously or sequentially administrable to a patient, for:-
  • the present invention further provides a method of providing an anti-androgenic effect in a patient comprising simultaneously or sequentially administering a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and anastrozole or a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the method further provides aromatase inhibition in the patient substantially without causing an additional increase in the levels of circulating androgens.
  • the compound of formula I and anastrozole are provided in a ratio respectively of 25 to 350 (preferably the lower end of the range being 50; preferably the upper end of the range being 300, 150 or 50; suitable values in the ranges being 150 or 50) : 0.005 to 100 (preferably the lower end of the range being 0.05 or 0.5; preferably the upper end of the range being 50, 10 or 1 ; the most preferred range being 0.5 to 1; a suitable value in the range being 1).
  • the term "product" is intended to mean either a mixture of the compound of formula I and anastrozole (eg, provided as a capsule or tablet containing both compounds) or a kit comprising separate amounts of the compounds (eg, a set of anastrozole tablets and a separate set of tablets of the other compound).
  • the latter product can be used for simultaneous or sequential (ie, temporally spaced) administration of the compounds to the patient, while the pre-mixed compounds are for simultaneous administration.
  • Factors such as the rate of absorption, metabolism and the rate of excretion of each agent will affect their presence at the tumour site. Such factors are routinely considered by, and are well within the ordinary skill of, the clinician when he contemplates the treatment of a medical condition which requires the conjoint administration of two agents in order to obtain a beneficial effect.
  • the compound of formula I is included to provide an anti-androgenic effect, in that this compound blocks androgen activity.
  • the anastrozole is included to provide aromatase inhibition, in that this compound inhibits conversion of testosterone to oestradiol by aromatase enzyme.
  • the anti-androgenic effect is useful for treating cancer, for example prostate cancer.
  • cancer for example prostate cancer.
  • Particular examples are advanced prostate cancer and early prostate cancer.
  • the anti- androgenic effect may be useful for prophylaxis, in order to reduce the risk of prostate cancer occurrence in patients. This could be especially useful in men genetically predisposed to prostate cancer.
  • Conventional methods are available to classify patients according to their risk of contracting prostate cancer, for example by assessment of family history and measurements over time of particular blood proteins such as prostate specific antigen (PSA).
  • PSA prostate specific antigen
  • Other uses for the anti-androgenic effect are the treatment of a non- malignant disease of the prostate gland (eg, benign prostatic hyperplasia or hypertrophy) and acne.
  • the aromatase inhibition is useful for suppressing increase in the incidence or severity of a side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence, reduction in libido, nausea, vomiting, fatigue and diarrhoea.
  • a side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence, reduction in libido, nausea, vomiting, fatigue and diarrhoea.
  • a side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence, reduction in libido, nausea, vomiting, fatigue and diarrhoea.
  • the side effect is one or both of gynaecomastia and breast tenderness.
  • a suitable dose regimen or daily pharmaceutical dose comprises the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and from 0.005 to 100 mg of anastrozole or a pharmaceutically acceptable salt or solvate thereof.
  • the lower end of the range is 0.05 or 0.5 mg; preferably the upper end of the range is 50, 10 or 1 mg; the most preferred range is 0.5 to 1 mg; a suitable value in the range being 1 mg.
  • the dose or the regimen preferably comprises from 25 to 350 mg of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof.
  • the lower end of the range is 50 mg; preferably the upper end of the range is 300, 150 or 50 mg; suitable values in the ranges are 150 or 50 mg.
  • each compound is preferably administered daily.
  • Another possible regime would be dosing of the compound of formula I on alternate days and dosing of the anastrozole also on (the same or different) alternate days.
  • the regimen may include administration instructions.
  • a dose of the compound of formula I is administered every 3, 4, 5, 6 or 7 days and the anastrozole is administered every 3, 4, 5, 6 or 7 days (eg, on the same day as the compound of formula I).
  • the compound of formula I consists of 90 to 100% of the R-enantiomer and 10 to 0% of the S-enantiomer thereof. In a preferred embodiment, 100% of the R-enantiomer is used.
  • the compound of formula I consists of a racemic mixture of the R- and S-enantiomers thereof.
  • the patient can be a human male, eg an adult, but the treatment of other mammals (except rats) is also contemplated.
  • the products, doses and regimens of the invention may be in a form suitable for oral use (for example as tablets,, capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions; for example for use within a transdermal patch), for parenteral administration (for example as a sterile aqueous or oily solution or suspension for intravenous, subcutaneous, intramuscular or intravascular dosing), or as a suppository for rectal dosing.
  • the compositions of the invention are in a form suitable for oral use, for example as tablets or capsules.
  • the products, doses and regimens of the invention may be obtained by conventional procedures using conventional pharmaceutically-acceptable diluents or carriers that are well known in the art.
  • Suitable pharmaceutically-acceptable diluents or carriers for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as gelatin or starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl O-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • CASODEXTM was administered daily at a dose of 150 mg and the
  • ARIMIDEX was administered daily at a dose of 1 mg. All treatments were in tablet form and taken once daily. Daily treatment with CASODEX was for 6 weeks, and with
  • ARIMIDEX for the final 2 weeks of this period.
  • the treatment periods were selected as the minimum time to attain steady-state plasma concentrations for the drugs.
  • Day 1 samples were drawn before dosing, and therefore act as a baseline measurement.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un produit pharmaceutique, une dose quotidienne ou un schéma posologique, comprenant du 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophénylsulphonyl)-2-hydroxy-2-méthylpropriono-m-toluidide (composé I) et de l'anastrozole. L'invention concerne également une méthode permettant d'obtenir sensiblement un effet anti-androgène et l'inhibition de l'aromatase sans causer d'augmentation supplémentaire des niveaux d'androgènes circulant.
PCT/SE2001/001163 2000-05-23 2001-05-22 Combinaison pharmaceutique de bicalutamide et d'anastrozole permettant d'obtenir un effet anti-androgene et l'inhibition de l'aromatase WO2001089516A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP01937066A EP1292297A1 (fr) 2000-05-23 2001-05-22 Combinaison pharmaceutique de bicalutamide et d'anastrozole permettant d'obtenir un effet anti-androgene et l'inhibition de l'aromatase
AU2001262834A AU2001262834A1 (en) 2000-05-23 2001-05-22 Pharmaceutical combination of bicalutamide and anastrozole for providing an anti-androgenic effect and aromatase inhibition
JP2001585760A JP2003534279A (ja) 2000-05-23 2001-05-22 抗アンドロゲン作用およびアロマターゼ阻害を与えるためのビカルタミドおよびアナストロゾールの医薬組合せ
US10/276,112 US20030114519A1 (en) 2000-05-23 2001-05-22 Pharmaceutical combination of bicalutamide and anastrozole for providing an anti-androgenic effect and aromatase inhibition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0012293.7A GB0012293D0 (en) 2000-05-23 2000-05-23 Pharmaceutical combination
GB0012293.7 2000-05-23

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WO2001089516A1 true WO2001089516A1 (fr) 2001-11-29

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EP (1) EP1292297A1 (fr)
JP (1) JP2003534279A (fr)
AU (1) AU2001262834A1 (fr)
GB (1) GB0012293D0 (fr)
WO (1) WO2001089516A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102988313A (zh) * 2011-09-14 2013-03-27 北京以岭生物工程技术有限公司 一种阿那曲唑分散片及其制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2500062E (pt) 2007-11-13 2015-10-12 Curadis Gmbh Esteroides c-19 para utilizações terapêuticas específicas

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2102287A (en) * 1981-05-22 1983-02-02 Schering Ag Use of aromatase-inhibitors with antiandrogens for treatment of prostatic hyperplasia.
EP0100172A1 (fr) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Dérivés d'amides
EP0296749A1 (fr) * 1987-06-16 1988-12-28 Zeneca Limited Composés hétérocycliques renfermant un groupe aralkyle substitué
US4895715A (en) * 1988-04-14 1990-01-23 Schering Corporation Method of treating gynecomastia
WO1995019770A1 (fr) * 1994-01-21 1995-07-27 Sepracor, Inc. Procedes et compositions de traitement de maladies dependantes des androgenes a l'aide de r-(-)-casodex optiquement pur
WO2001049294A1 (fr) * 1999-12-30 2001-07-12 Pharmacia Italia S.P.A. Produit pour le traitement de la gynecomastie

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2102287A (en) * 1981-05-22 1983-02-02 Schering Ag Use of aromatase-inhibitors with antiandrogens for treatment of prostatic hyperplasia.
EP0100172A1 (fr) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Dérivés d'amides
EP0296749A1 (fr) * 1987-06-16 1988-12-28 Zeneca Limited Composés hétérocycliques renfermant un groupe aralkyle substitué
US4895715A (en) * 1988-04-14 1990-01-23 Schering Corporation Method of treating gynecomastia
WO1995019770A1 (fr) * 1994-01-21 1995-07-27 Sepracor, Inc. Procedes et compositions de traitement de maladies dependantes des androgenes a l'aide de r-(-)-casodex optiquement pur
WO2001049294A1 (fr) * 1999-12-30 2001-07-12 Pharmacia Italia S.P.A. Produit pour le traitement de la gynecomastie

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JEROME P. RICHIE: "Anti-androgens and other hormonal therapies for prostate cancer", UROLOGY, vol. 54, no. 6A, 1999, pages 15 - 18, XP002946332 *
R.C. COOMBES ET AL.: "Aromatase inhibitors and their use in the sequential setting", ENDOCRINE-RELATED CANCER, vol. 6, 1999, pages 259 - 263, XP002946334 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102988313A (zh) * 2011-09-14 2013-03-27 北京以岭生物工程技术有限公司 一种阿那曲唑分散片及其制备方法

Also Published As

Publication number Publication date
GB0012293D0 (en) 2000-07-12
JP2003534279A (ja) 2003-11-18
EP1292297A1 (fr) 2003-03-19
AU2001262834A1 (en) 2001-12-03

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