EP2558098A2 - Traitement d'un cancer du sein résistant à l'endocrine - Google Patents

Traitement d'un cancer du sein résistant à l'endocrine

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Publication number
EP2558098A2
EP2558098A2 EP11716500A EP11716500A EP2558098A2 EP 2558098 A2 EP2558098 A2 EP 2558098A2 EP 11716500 A EP11716500 A EP 11716500A EP 11716500 A EP11716500 A EP 11716500A EP 2558098 A2 EP2558098 A2 EP 2558098A2
Authority
EP
European Patent Office
Prior art keywords
mono
iower
zero
breast cancer
group
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.)
Withdrawn
Application number
EP11716500A
Other languages
German (de)
English (en)
Inventor
Mitch Dowsett
Zara Ghazoui
Lesley-Ann Martin
Christoph Mundhenke
Marion Weigel
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.)
Novartis AG
Schleswiger Tauwerkfabrik Oellerking GmbH and Co KG
Universitatsklinikum Schleswig Holstein UKSH
Institute of Cancer Research
Original Assignee
Novartis AG
Schleswiger Tauwerkfabrik Oellerking GmbH and Co KG
Universitatsklinikum Schleswig Holstein UKSH
Institute of Cancer Research
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 Novartis AG, Schleswiger Tauwerkfabrik Oellerking GmbH and Co KG, Universitatsklinikum Schleswig Holstein UKSH, Institute of Cancer Research filed Critical Novartis AG
Priority to EP11716500A priority Critical patent/EP2558098A2/fr
Publication of EP2558098A2 publication Critical patent/EP2558098A2/fr
Withdrawn legal-status Critical Current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
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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 invention relates to a pyrsmidyiaminobenzamide of formula I as defined below alone or in combination with at least one aromatase inhibitor for the treatment of endocrine resistant breast cancer and to a method of treating warm-blooded animals including humans suffering from endocrine resistant breast cancer by administering to a said animal in need of such treatment an effective dose of a pyrimidylaminobenzamide of formula I alone or in combination with an aromatase inhibitor.
  • Estrogen mediates its effects by binding to the ER.
  • E-bound ER associates classically with estrogen response elements (EREs) on target genes controlling proliferation and cell survival.
  • ER ability to regulate gene transcription is also influenced by the activity of co-regulatory proteins such as AI B1 , Therapies targeting the estrogenic stimulation of tumor growth have been a major success in reducing mortality from ER-positive breast cancer.
  • resistance remains a major clinical problem.
  • aromatase inhibitor or "Ai” as used herein relates to compounds which inhibit the estrogen production, i.e the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially exemestane and formestane and, in particular, non-steroids, such as amsnoglutethimide, vorozole, fadrozole, anastrozo!e and, especially, !etrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark
  • Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARONTM
  • Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMATM
  • Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEXTM.
  • Letrozoie can be
  • niiotinib in breast cancer cell Sines modeling endocrine sensitive and resistant disease.
  • the pyrtmtdy!aminobenzamide nilotinib, an inhibitor of PDGF-R and Bcr-AbL inhibits proliferation of these ceil lines in a concentration dependent manner.
  • nilotinib in combination with tamoxifen re-sensitized tamoxifen resistant MCF7 ceSSs (TAMR cells) to the inhibitory effect of tamoxifen (Fig. 1).
  • the PDGF/Abi canonical pathway is a major adaptive pathway allowing escape from the suppression of proliferation seen with oestrogen deprivation.
  • PDGFR and Abl are elevated at the protein level in both the tamoxifen resistant and LTED cell lines.
  • temporal changes in gene expression associated with LTED identify PDGF/Abl as the major adaptive pathway.
  • thai PDGFRp is associated with the endocrine resistant phenotype.
  • Assessment using ER/ERE linked reporter assays shows that niiotinib suppresses ER- mediated transcription and inhibits expression of two endogenous E-regulated genes TFF1 and PGR Chromatin immune-precipitation indicates that niiotinib reduces the recruitment of AiB1 and CBP to the TFF1 promoter.
  • niiotinib in combination with tamoxifen resensstises TAMR cells fo the inhibitory effect of tamoxifen.
  • the present invention relates in particular fo pyrimidy!aminobenzamides of formula i
  • Py denotes 3-pyridyi, represents hydrogen, iower aikyi, lower a!koxy-lower aikyi, acyloxy-lower a!ky!, carboxy- iower aikyi, lower alkoxycarbonyi-lower aikyi, or phenyl-iower aikyi;
  • R 2 represents hydrogen, iower aikyi, optionally substituted by one or more identical o different radicais R 3l cycloalkyl, benzcycloaikyi, heterocycly!, an aryi group, or a mono- or bicyclic heieroary! group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or poly substituted;
  • R 3 represents hydroxy, lower aSkoxy, acy!oxy > carboxy, lower aikoxycarbonyl, carbamoyl, N- mono- or ⁇ , ⁇ -disubstituied carbamoyl, amino, mono- or disubstituied amino, cycloaikyi, heterocyciy!, an aryl group, or a mono- or bicyciic heieroaryi group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or po!ysubstituted; and
  • R 4 represents hydrogen, lower alkyl, or halogen; or of a pharmaceutically acceptable salt thereof, aione or in combination with at least one aromatase inhibitor for the treatment of ER-positive breast cancer, especially i patients who have either de novo or acquired resistance to an
  • treatment refers to the prophylactic or preferably therapeutic ⁇ including but not limited to palliative, curing, symptom-alleviating, symptom-reducing) treatment of the diseases disclosed herein.
  • R represents hydrogen, iower a!kyl, iower a!koxy-lower aikyi, acyloxy-lower aikyi, carboxy- iower alkyl, iower alkoxycarbonyl-lower aikyi, or poenyl-lower alkyl: more preferably hydrogen;
  • Rj represents hydrogen, iower aikyi, optionally substituted by one or more identical or different radicals R 3 .
  • R 3 represents hydroxy, lower aikoxy, acyioxy, carboxy, lower alkoxycarbonyl, carbamoyl, U- mono- or N.N-disubstiiuted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyc!yi, an aryi group, or a mono- or bscyciie heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and
  • R4 represents lower alkyl especially methyl.
  • a preferred pyrimidyiaminobenzamide is 4-m:ethyl-3-[[4 ⁇ (3 ⁇ pyridinyl) ⁇ 2-pyrimidiny!]amino] ⁇ W- [5-(4-methyl-1 H-imidazol-1 -yl)-3- ⁇ trifluorometh l)phenyl] benzamide, also known as
  • the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
  • lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower a!kyi is butyl, such as n-bufyl, sec-butyl, isobuty!, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methy!.
  • Preferably lower alkyl is methyl, propyl or tert-butyl.
  • Lower acyl is preferably formyl or lower alky!carbony!, in particular acetyl.
  • aryi group is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical.
  • aryi is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, f!uorenyl or phenanthfenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower aikyi, substituted Sower alkyl, lower alkenyl, Sower alkynyi, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, aikanoyi, benzoyl, carbamoyl, N-mono ⁇ or N,N-disubstituied carbamoyl, am
  • tetrahydronaphthyl which in each case is either unsubstituied or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine,, or bromine; hydroxy; hydroxy etherified by lower aikyi, e.g, by methyl, by halogen-lower aikyi, e.g. trifluoromethyi, or by phenyl; lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy, iower aSkyl, e.g. methyl o propyl; halogen-lower aikyi, e.g.
  • methoxy- carbonylmethyl lower alkynyi, suc as 1-propynyl; esterified carboxy, especially lower aikoxycarbonyl, e g, methoxy carbonyi, n-propoxy carbonyi or iso-propoxy carbonyi; N-roono- subsiituted carbamoyl, in particular carbamoyl monosubstituted by lower aikyi, e.g. methyl, rvpropyi or iso-propyi; amino; lower aikylamino, e.g. methylam ' ino; di-lower aikylamino, e.g.
  • dimethylamino or diethylamino dimethylamino or diethylamino; lower alkylene-amino, e.g. pyrroiidino or piperidino; iower oxaaikyiene-amino, e.g. morpholino, lower azaalkylene-amino, e.g. piperazino, acyiamino, e.g. acetylamino or benzoylamino; Iower a!kySsuifonyi, e.g. methy!sulfony!; suffamoyi; or phenySsulfony!.
  • lower alkylene-amino e.g. pyrroiidino or piperidino
  • iower oxaaikyiene-amino e.g. morpholino
  • lower azaalkylene-amino e.g. piperazin
  • a cycloalkyi group is preferably cyclopropyi, cyciopentyi, cyciohexyS or cycioheptyi, and may be unsubstituied or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, Iower aikoxy, such as methoxy or ethoxy, or hydroxy, and further by oxo or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.
  • Substituted alkyl is aikyi as last defined, especially lower aikyi, preferably methyl; where one or more, especially up to three, substituents may be present, primarily from the group selected from halogen, especia!!y fluorine, amino, N-lower aikylamino, ⁇ , ⁇ -dMower a!kyiamino, N-lower aikanoylamino, hydroxy, cyano, carboxy. lower aikoxycarbonyl, and phenyl-iower aikoxycarbonyl Triffuarornethyi is especially preferred.
  • Mono- or disubstituted amino is especiaiiy amino substituted by one or two radicals selected independentiy of one another from lower alkyi, such as methyl; hydroxy-iower alkyi, such as 2-hydroxyeihyl; lower aikoxy lower alkyi, such as meihoxy ethyl; phenyl-iower alkyi, such as benzyl or 2-phenyiethyl; lower aikanoyl, such as acetyl; benzoyi; substituted benzoyl, wherein the phenyl radical is especiaiiy substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, H-iower aSkySamtno, M ; N-dl-iower aikylamino, hydroxy, cyano, carboxy, lower aikoxycarbonyl, lower aikanoyl, and
  • Pisubstiiuted amino is also Sower alkySene-amino, e.g. pyrrolidine, 2-oxopyrrolidino or piperidino; lower oxaaikylene-amino, e.g. morphoiino, or lower azaalkyiene-amino, e.g. piperazino or N-substituted piperazino, such as N-methyipiperazino or - methoxycarbonyl piperazi no .
  • alkySene-amino e.g. pyrrolidine, 2-oxopyrrolidino or piperidino
  • lower oxaaikylene-amino e.g. morphoiino
  • lower azaalkyiene-amino e.g. piperazino or N-substituted piperazino, such as N-methyipiperazino or - methoxycarbonyl piperazi no
  • Halogen is especially fluorine, chlorine, bromine, or iodine, especiaiiy fluorine, chlorine, or bromine.
  • Etherified hydroxy is especiaiiy Ce-Caalkyloxy, such as n-decyioxy, lower aikoxy ⁇ preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-iower aikoxy, such as benzyloxy, phenyloxy, halogen-lower aikoxy, suc as trifluoromethoxy, 2,2.2-trifluoroethoxy or 1 , 1 ,2,2-teirafluoroethoxy, or lower ajkoxy which is substituted by mono- or bicyciic hetero- aryi comprising one or two nitrogen atoms, preferabiy Sower aikoxy which is substituted by imidazoiy!.
  • aikoxy such as benzyloxy, phenyloxy, halogen-lower aikoxy, suc as trifluoromethoxy, 2,2.2-tri
  • benzimidazolyi such as 1 -benzimidazoiyl, pyridyi, especially 2-, 3- or 4-pyridyl, pyrimldinyL especialiy 2-pyrimidinyi, pyrazinyl, isoqutnoliny!, especially 3-isoquinolinyl, quinoiinyl, indolyl or thiazoiy!.
  • Esterified hydroxy is especially lower alkanoyloxy, benzoy!oxy, tower a!koxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyioxy, such as
  • Esterified carboxy is especially lower alkoxycarbonyi, such as tert-butoxycarbonyl, iso ⁇ propoxycarbonyi, methoxycarbonyl or ethoxycarbonyi, phenyl-lower alkoxycarbonyi, or phenyloxycarbonyl.
  • Aikanoyl is primarily a!kylcarbonyL especialiy lower alkanoyi, e.g. acetyl.
  • N- ono- or N.N-disubstituted carbamoyl is especialiy substituted by one or two substituents independently selected from lower aikyi, phenyl-lower aikyl and hydroxy-tower alkyl, or lower aikyiene, oxa-lower aikyiene or aza-iower aikyiene optionally substituted at the terminal nitrogen atom.
  • a mono- or bicyciic heteroaryi group comprising zero, one, two or three ring nitrogen atoms and zero or one oxyge atom and zero or one sulfur atom, which groups in each cas are unsubstituted or mono- or poSysubstituted, refers to a heterocyclic moiety thai is unsaturated in the ring binding the heteroaryi radical to the rest of the molecule in formula i and is preferabiy a ring, where in the binding ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroaiom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring preferably has 5 to 12, more preferably 5 or 8 ring atoms; and which may be unsubstituted or substituted by one or more, especialiy one or two, substitutents seiected from the group defined above as subsiituienis for aryi, most preferabl by lower alkyl, such as
  • the mono- or bicyciic heteroaryi group is seiected from 2H-pyrroiyl, pyrroiyi, imidazoiyi, benzimidazolyi, pyrazolyl, indazolyl, purinyi, pyridyi, pyrazinyl, pyrimidinyi, pyridazinyl, 4H ⁇ quinoiiziny1, isoquinoly!, quinolyi, phthalazinyl, naphthyridinyi, quinoxalyl, quinazolinyl, quinnoiinyi, pteridinyi, indolizinyl, 3H-indoiyl, indolyS, isoindolyl, oxazolyl, isoxazoiyl, thiazolyi, isothiazoiyl, triazolyl.
  • the mono- or bicycSic heteroaryl group is selected from the group consisting of pyrroiyi, imidazoiyi, such as 1 H-imidazoi ⁇ 1 ⁇ yi, benziniidazolyi, such as 1 - benzimidazoiyi, indazolyl, especiaiiy 5-indazolyi, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyL especiaiiy 3-isoquinaltnyl, quinolinyL especiaiiy 4- or 8-quinolinyL indo!yi, especially 3-indolyi thiazaiyl,
  • the pyridyi radical is substituted by hydroxy in ortho position to the nitrogen atom and hence exists at least pariiaSiy in the form of the corresponding tautomer which is pyridin ⁇ (1 H)2-one.
  • the pyrimidinyl radical is substituted by hydroxy both in position 2 and 4 and hence exists in several tautomeric forms, e.g. as pyrimidine- ⁇ 1 H, 3H)2,4-dione.
  • Heterocyc!yS is especially a five, six or seven-membered heterocyclic system with one or two heieroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especiaiiy by lower alky I, such as methyl, phenyi-iower aikyi, such as benzyl, oxo, or heteroaryl, such as 2- piperazinyl; heterocyclyl is especially 2- or 3 ⁇ pyrroiidiny!, 2-oxo-5-pyrrolidinyi, piperidinyL N- benzyl-4-piperidinyl, -!ower alkyl-4-piperidinyi, N-lower alky!-piperazinyL morphoSinyl, -e.g. 2- or 3-morpholinyl, 2-oxo-1 H-azepin-3 ⁇ yl, 2-tetrahydr
  • niioiinib is employed in the form of its hydrochioride monohydraie.
  • WO2007/015870 discloses certain polymorphs of ni latin ib and pharmaceutically acceptable saits thereof usefui for the present invention.
  • the pyrimidyiaminobenzamides of formuia i can be administered by an route including oraiiy, parenteraily, e.g., Intraperitoneal ly, intravenously, intramuscularly, subcutaneousSy, infratumoraiiy, or rectaiJy, or enterally.
  • the pyrimidyiaminobenzamides of formula I is administered orally, preferably at a daily dosage of 50-2000 mg.
  • a preferred oral daily dosage of rsilotinib is 200 - 1200 mg, e.g. 800 mg, administered as a single dose or divided into multiple doses, such as twice daily dosing.
  • a small dose is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
  • the upper limit of dosage is that imposed by side effects and can be determined by trial fo the host being treated.
  • a combination which comprises (a) a pyrimjdylaminobenzamides of formula 1 as defined herein and (b) at Ieast one aromaiase inhibitor, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier, will be referred to hereinafter as a
  • a further benefit is that lower doses of the active ingredients of the COMBINATION OF THE INVENTION can be used, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish th incidence of side- effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the present invention in particular pertains to a COMBINATION OF THE INVENTION which comprises (a) ni!ofinib in. a dosage range of 100 to 800 mg/day, preferably 200, 250, 300, 350 or 400 mg/day, and (b) letrozole in a dosage range of 0.5, 1 0. 1 ,5, 2.0, 2.5, 3,0, 3.5 or 4.0 mg/day.
  • the present invention provides a commercial package comprising as active ingredients COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential use alone or in combination with at least one aromaiase inhibitor for the treatment of ER -positive breast cancer, especially in patients who have either de novo or acquired resistance to an Al.
  • Fadrozoie may be administered orally to a human in a dosage range varying from 0.5 to 10 mg/day, preferably from 1 to 2.5 mg/day.
  • Letrozo!e may be administered craiiy to a human in a dosage range varying from 0.5 to 5 mg/day, preferabiy from 0.5 to 4 mg/day, most preferably from 1 to 2.5 mg/day.
  • dosage range varying from 0.5 to 5 mg/day, preferabiy from 0.5 to 4 mg/day, most preferably from 1 to 2.5 mg/day.
  • compositions containing letrozole are well known in the art, e.g> Physicians' Desk Reference Copyright ⁇ 2001 (Medical Economics Company Snc).
  • Anastrozoie may be administered orally to a human in a dosage range varying from 0.25 to 10 mg/day, preferably from 0.5 to 2.5 mg/day.
  • Exemesfane may be administered orally to a human in a dosage range varying from 5 to 200 mg/day, preferably from 10 to 25 mg/day, or parenieraiiy from 50 to 500 mg/day, preferabiy from 100 to 250 mg/day, li the drug shall be administered in a separate pharmaceutical composition, it can be administered in the form disclosed in GB 2, 77,700.
  • Formestane may be administered parenieraiiy to a human in a dosage range varying from 100 to 500 mg/day, preferabiy from 250 to 300 mg/day.
  • a method of treating warm-blooded animals including humans suffering from ER- positive breast cancer, especially in patients who have either de novo or acquired resistance to an Al by administering to a said animal in need of such treatment an effective dose of a PDGF-R inhibitors alone or in combination with an aromatase inhibitor (Al), more specifically to a method of treating or preventing estrogen receptor-positive breast cancer comprising administering a pyrimidylaminobenzamide derivatives of formula (I):
  • R represents hydrogen, Sower aikyi, Sower alkoxy-lower alkyl, acyloxy-lower alkyl, earboxy- iower aikyi, iower aikoxycarbonyl-lower aikyi, or phenyMower alkyl;
  • R 2 represents hydrogen, Sower aikyi, optionally substituted by one or more identical or different radicals
  • R 3 cycioalkyl, benzcyeloaikyi, heterocyciy!, an aryi group, or a mono- or bicyclic heieroaryl group comprising 0-, 1-, 2- or 3- ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, w ch groups in each case are unsubstituted or mono- or poiy-subststuted; and
  • R 3 represents hydroxy, lower a!koxy. acyloxy, carboxy, lower aikoxycarbonyl, carbamoyl, ⁇ - mono- or MM-di-substituied carbamoyl, amino, mono- or di-substituted amino, cycloaSkyS, heterocyciyl, an aryi group, or a mono- or bs-cycSsc heieroaryl grou comprising 0-, 1 -, 2- or 3-rsng nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 suifur atom, which groups in each case are unsubstituted or mono- or poiy-substituted;
  • R 4 represents hydrogen, Sower aikyl or halogen
  • Ciinica! data from 81 postmenopausal patients treated with an Al in the neoadjuvant setting, showed increases in PDGFRp and PDGF expression after two weeks (1.25 foid, p 0.003 and 1.43 fold, p ⁇ 4.4E-06). Low PDGFR at pre-treatment was associated with a better response.

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Abstract

La présente invention concerne des pyrimidylaminobenzamides de formule (I) et d'autres inhibiteurs des récepteurs PDGF-R adéquats, seuls ou associés avec au moins un inhibiteur de l'aromatase, utilisés pour traiter le cancer du sein hormono-résistant; l'invention concerne également un procédé de traitement des animaux à sang chaud, notamment les êtres humains, souffrant du cancer du sein hormono-résistant en administrant audit animal le nécessitant une dose efficace d'un pyrimidylaminobenzamide de formule (I), seul ou associé à un inhibiteur de l'aromatase.
EP11716500A 2010-04-16 2011-04-15 Traitement d'un cancer du sein résistant à l'endocrine Withdrawn EP2558098A2 (fr)

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EP10160113 2010-04-16
EP11716500A EP2558098A2 (fr) 2010-04-16 2011-04-15 Traitement d'un cancer du sein résistant à l'endocrine
PCT/EP2011/056003 WO2011128434A2 (fr) 2010-04-16 2011-04-15 Traitement du cancer du sein hormono-résistant

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EP3373967B9 (fr) 2015-11-10 2023-10-04 Paracrine Therapeutics AB Traitement d'un cancer du sein négatif pour er à l'aide d'un inhibiteur du pdgf-cc et d'un anti- strogène

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GB8517360D0 (en) 1985-07-09 1985-08-14 Erba Farmitalia Substituted androsta-1,4-diene-3,17-diones
US4978672A (en) 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
US4749713A (en) 1986-03-07 1988-06-07 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
JP2710053B2 (ja) 1988-07-05 1998-02-10 スズキ株式会社 自動車の車体構造
GB0215676D0 (en) * 2002-07-05 2002-08-14 Novartis Ag Organic compounds
GT200600315A (es) 2005-07-20 2007-03-19 Formas cristalinas de 4-metilo-n-[3-(4-metilo-imidazol-1-ilo)-5-trifluorometilo-fenilo]-3-(4-pyridina-3-ilo-pirimidina-2-iloamino)-benzamida
GT200600316A (es) 2005-07-20 2007-04-02 Sales de 4-metilo-n-(3-(4-metilo-imidazol-1-ilo)-5-trifluorometilo-fenilo)-3-(4-piridina-3-ilo-pirimidina-2-iloamino)- benzamida.
KR20080109068A (ko) * 2006-04-05 2008-12-16 노파르티스 아게 암을 치료하기 위한 ｂｃｒ-ａｂｌ/ｃ-ｋｉｔ/ｐｄｇｆ-ｒ ｔｋ 억제제를 포함하는 조합물

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ANONYMOUS: "Abstract 2920: Experimental and clinical studies reveal the PDGF/Abl pathway as a novel therapeutic target in endocrine-resistant breast cancer -- Weigel et al. 70 (1008): 2920 -- Cancer Research", 15 April 2010 (2010-04-15), XP055099414, Retrieved from the Internet <URL:http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/70/8_MeetingAbstracts/2920> [retrieved on 20140130] *
HUAJUN ZHAO ET AL: "Enhanced resistance to tamoxifen by the c-ABL proto-oncogene in breast cancer", NEOPLASIA (NEW YORK, N.Y.), 1 March 2010 (2010-03-01), Canada, pages 214 - 223, XP055099078, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/20234815> DOI: 10.1593/neo.91576 *
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See also references of WO2011128434A2 *

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