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Title:
TREATMENT OF ENDOCRINE RESISTANT BREAST CANCER
Document Type and Number:
WIPO Patent Application WO/2011/128434
Kind Code:
A2
Abstract:
The invention relates to pyrimidylaminobenzamides of formula (I) and other suitable PDGF-R inhibitors, 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.

Inventors:
DOWSETT, Mitch (Department of Academic Biochemistry, Royal Marsden HospitalFulham Roa, London Greater London SWS 6JJ, GB)
GHAZOUI, Zara (Department of Academic Biochemistry, Royal Marden HospitalFulham Roa, London Greater London SW3 6JJ, GB)
MARTIN, Lesley-Ann (Breakthrough Breast Cancer Research Centre Institute of Cancer Research, Chester Beatty Laboratories237 Fulham Roa, London Greater London SWS 6JB, GB)
MUNDHENKE, Christoph (Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe Bereich Gynäkologische OnkologieArnold-Heller-Str., Haus 24 Kiel, 24105, DE)
WEIGEL, Marion (Breakthrough Breast Cancer Research Centre Institute of Cancer Research, Chester Beatty Laboratories237 Fulham Roa, London Greater London SWS 6JB, GB)
Application Number:
EP2011/056003
Publication Date:
October 20, 2011
Filing Date:
April 15, 2011
Export Citation:
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Assignee:
NOVARTIS AG (Lichtstrasse 35, Basel, CH-4056, CH)
INSTITUTE OF CANCER RESEARCH: ROYAL CANCER HOSPITAL (123 Old Brompton Road, London, Greater London SW7 3RP, GB)
UNIVERSITÄTSKLINIKUM SCHLESWIG-HOLSTEIN (Arnold-Heller-Str.3, Kiel, 24105, DE)
DOWSETT, Mitch (Department of Academic Biochemistry, Royal Marsden HospitalFulham Roa, London Greater London SWS 6JJ, GB)
GHAZOUI, Zara (Department of Academic Biochemistry, Royal Marden HospitalFulham Roa, London Greater London SW3 6JJ, GB)
MARTIN, Lesley-Ann (Breakthrough Breast Cancer Research Centre Institute of Cancer Research, Chester Beatty Laboratories237 Fulham Roa, London Greater London SWS 6JB, GB)
MUNDHENKE, Christoph (Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe Bereich Gynäkologische OnkologieArnold-Heller-Str., Haus 24 Kiel, 24105, DE)
WEIGEL, Marion (Breakthrough Breast Cancer Research Centre Institute of Cancer Research, Chester Beatty Laboratories237 Fulham Roa, London Greater London SWS 6JB, GB)
International Classes:
A61K31/506; A61K31/404; A61K31/4196; A61K31/4439; A61K31/445; A61K31/5685; A61K45/06; A61P35/00
Domestic Patent References:
2007-10-11
2004-01-15
2004-01-15
2007-02-08
2007-02-08
Foreign References:
EP0236940A21987-09-16
US4978672A1990-12-18
JPH0218112A1990-01-22
GB2177700A1987-01-28
Other References:
CHOW ET AL: "Evaluation of neoadjuvant inhibition of aromatase activity and signal transduction in breast cancer", CANCER LETTERS, NEW YORK, NY, US, vol. 262, no. 2, 14 January 2008 (2008-01-14), pages 232-238, XP022552580, ISSN: 0304-3835
B. ARUN, J. L. MURRAY, R. WALTERS, A. BREWSTER, E. RIVERA, V. VALERO, R. BAST, R. L. THERIAULT, M. GREEN, M. GREEN,: "The combination of letrozole and imatinib mesylate for metastatic breast cancer", PROGRAM/PROCEEDINGS - AMERICAN SOCIETY OF CLINICAL ONCOLOGY.ASCO, THE SOCIETY, US, 1 January 2009 (2009-01-01), page 214, XP009138741,
BRAMA MARINA ET AL: "Osteoblast-conditioned medium promotes proliferation and sensitizes breast cancer cells to imatinib treatment", ENDOCRINE-RELATED CANCER, vol. 14, no. 1, March 2007 (2007-03), pages 61-72, XP002600758, ISSN: 1351-0088
AHLGREN M THIRLWELL R O'REGAN C MORMONT L LEVESQUE R GASPO M WOLOJ A BELLO B MARTELL B LEYLAND-JONES P ET AL: "Sunitinib plus exemestane for the first-line treatment of hormone receptor-positive metastatic breast cancer: Results of an open-label study", PROGRAM/PROCEEDINGS - AMERICAN SOCIETY OF CLINICAL ONCOLOGY.ASCO, THE SOCIETY, US, [Online] 1 January 2009 (2009-01-01), XP009138666, ISSN: 1081-0641 [retrieved on 2010-09-13]
COXON ANGELA ET AL: "Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors.", CLINICAL CANCER RESEARCH : AN OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 1 JAN 2009 LNKD- PUBMED:19118038, vol. 15, no. 1, 1 January 2009 (2009-01-01), pages 110-118, XP002600759, ISSN: 1078-0432
WEIGEL M T ET AL: "Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling", CANCER LETTERS, NEW YORK, NY, US LNKD- DOI:10.1016/J.CANLET.2008.07.040, vol. 273, no. 1, 8 January 2009 (2009-01-08), pages 70-79, XP025685877, ISSN: 0304-3835 [retrieved on 2008-09-21]
BRUEGGEMEIER R W ET AL: "AROMATASE INHIBITORS IN THE TREATMENT OF BREAST CANCER", ENDOCRINE REVIEWS, BALTIMORE, MD, US, vol. 26, no. 3, 1 January 2005 (2005-01-01), pages 331-345, XP009059540,
CHU DAVID ET AL: "Novel therapies in breast cancer: what is new from ASCO 2008", JOURNAL OF HEMATOLOGY & ONCOLOGY, BIOMED CENTRAL LTD, LONDON UK, vol. 1, no. 1, 1 October 2008 (2008-10-01) , page 16, XP021045985, ISSN: 1756-8722, DOI: 10.1186/1756-8722-1-16
See also references of EP 2558098A2
Attorney, Agent or Firm:
ROTH, Peter R. (NOVARTIS PHARMA AG, Patent Department, Basel, CH-4002, CH)
Download PDF:
Claims:
What is claimed is:

1 . A combination comprising (a) a pyrimidylaminobenzamide of formula I

wherein

Py denotes 3-pyridyi,

Ri represents hydrogen, Iower alkyl, lower alkoxy-lower alkyl, aeyioxy-iower alkyl, carboxy- !ower alkyl , iower alkoxycarbonyi-iower alkyi, or phenyl-lower aiky!;

Ra represents hydrogen, lower alkyl, optiona!iy substituted by one or mere identical or different radicals R?„ eycloaikyi, benzcycioalkyl, heterocyclyl an any! group, or a mono- or bicyc!ic heteroary! 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:

R3 represents hydroxy, iower aikoxy, acyloxy, carboxy, iower aikoxycarbonyi, carbamoyl, N- mono- or N.N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycioalky!, heterocyc!yl, an aryl group, or a mono- or blcyclic heteroary! 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 represents hydrogen, Iower alkyl, or haiogen; or a pharmaceuticaS!y acceptable sail thereof, and

(b) at least one aromatase inhibitor,

for the treatment of estrogen receptor-positive breast cancer.

2. The combination according to cSaim 1 , wherein the pyrimidyiaminobenzamide of formuia i is 4-methyl-3-((4-(3-pyridinyl)-2-pyrfmidinyl]am!no]-rV-i5-{4-methy!-1H-imidazoi-1-yl)~3- (tnfluoromet i) phenyi] benzam ide. 3, The combinaiion according to claim 2, wherein 4-methyl~3-f[4-{3-pyridinyi)~2>- pyrimtdinyl]am!no]-A/-(5-(4-methyi-1H-imidazoi-1-yl)-3-{tnt1uoromethyl)phenyiJ benzamide is employed in the form of its hydrochloride monohydrate.

4, A combination comprising (a) axitinib (AG013738) or suniiinib (SUTE T™) and (b) at least one aromatase inhibitor for the treatment of estrogen receptor-positive breast cancer.

5, The combinaiion according to any one of claims 1 to 4, wherein the aromatase inhibitor is selected from the group consisting of exemestane and formestane, aminog!utethimide, vorozole, fadrozoie, anastrozole and !etrozoie.

8. The combination according to claim 5 comprising (a) 4-methyl-3-[[4-(3-pyridinyl)-2- pyrimid!nyl]amino3-W-[5-(4-methyl-1 H-imidazol- 1 -yf)-3-(trifiuoromethyi)pheny13 benzamide or a pharrnaceuticaiiy acceptable salt thereof and (b) letrozole for the treatment of estrogen receptor-positive breast cancer.

7. A combination comprising (a) 4~met l-3- H"(3-pyn€i^^

methyl-1 H-imidazol-1-yi)-3-{trifiuoromethyl)phenyi] benzamide or a pharmaceutically acceptable saSt thereof and (b) tamoxifen for the treatment of estrogen receptor-positive breast cancer.

8. A pyrimidyiaminobenzamide of formula I

wherein

Py denotes 3-pyridy!, Ri represents hydrogen, lower aikyi, lower aikoxy-lower aikyi, acyloxy-iower alkyi, earboxy- lower aikyi, iower aikoxycarbony!-lower alkyl, or phertyMower aikyi;

R2 represents hydrogen, Iower aikyi, optionally substituted by one or more identical or different radicals R3, cyc!oa!kyl, benzcycloalkyi, heterocyciyl, an aryi group, or a mono- or bicyclic heteroaryi 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 poiysubstituted;

R3 represents hydroxy, lower alkoxy, acyioxy, carboxy, lower aikoxycarbonyl carbamoyl, N- mono- or Ν,Ν-disubstiiuted carbamoyl, amino, mono- or disubstituted amino, cyc!oalkyl, heterocyciyl, an aryl group, or a mono- or bicyclic heteroaryi 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 poiysubstituted; and

R4 represents hydrogen, lower aikyi, or halogen; or of a pharmaceutically acceptable sail thereof,

for the treatment of estrogen receptor-positive breast cancer.

9, The pyrimidylaminobenzamide according to claim 1 , wherein the pyrimidyiamino- benzamsde of formula I is 4-methyl-3-[[4-{3-pyridinyl)-2-pyri

1 H-imidazol~1~yi)-3-{trifluoromethyl}pheny!3 benzamide, preferably in the form of its hydroc !oride rnonohydrate.

10. A combination according to any one of claims 1 to 7 or a pyrimidyiaminobenzamide according to any one of claims 8 to 9 for the treatment of estrogen receptor-positive breast cancer in patients, who have either de novo or acquired resistance to at least one aromatase inhibitor.

Description:
TREATMENT OF ENDOCRINE RESISTANT BREAST CANCER

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.

The majority of breast tumors at primary diagnosis are estrogen receptor positive (ER positive). Estrogen (E) 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. However, resistance remains a major clinical problem.

It was now surprisingl found that a pynmidy!aminobenzamlde of formula I alone or in combination with an aromatase inhibitor (AS) can be used for the treatment of ER-positive breast cancer, especially in patients who have either de novo or acquired resistanc to an Al.

The expression "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

AROMASIN™. Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON™, Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMA™. Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX™. Letrozoie can be

administered, e.g. , in the form as it is marketed, e.g. under the trademark FEMARA™ or FEMAR™. Letrozole has been specifically described in the European patent No. 0 238 940 pubiished on September 16, 1987, as well as in US patent No. 4,978,672 published on December 18, 1990, and Japanese Patent No, 2018112 ail in the name of the applicant. Am inog lutein imide can be administered, e.g., in the form as it is marketed, e.g under the trademark ORIMETEN™, in a broader sense, the present invention provides for a method of treating endocrine resistant breast cancer by treating patient in need thereof with compounds inhibiting the PDGF signaling pathway. Other suitable PDGF-R receptor inhibitors are axitinib

(AG013736), and sunitinib (SUTENT™).

Studies have been performed on the in vitro effect of 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. Furthermore, nilotinib in combination with tamoxifen re-sensitized tamoxifen resistant MCF7 ceSSs (TAMR cells) to the inhibitory effect of tamoxifen (Fig. 1).

To identify the molecular mechanisms associated with resistance to E-deprivation, the iemporal changes in gene expression during adaptation to long-term culture of MCF7 human breast cancer eeS!s in the absence of E2 (long-term estrogen deprivation, LIED) was assessed, a cellular assay modeling resistance to an Al. Analyses of canonical signaling pathways show that platelet-derived growth factor (PDGF)7Abl is significantly elevated as early as one-week post E-deprivation (p=1.94 E-04). Of note this becam the top adaptive pathway at the point of resistance (p=1.15 E-07). Thus, it was found that 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. Furthermore, temporal changes in gene expression associated with LTED identify PDGF/Abl as the major adaptive pathway.

Assessment of the level of protein expression and activation status in a panel of cell lines modelling both endocrine sensitive and resistant breast cancer showed PDGFRfi was elevated in both LTED and tamoxifen resistant ivtCF7 cells (TAMR cells ) compared to wt~ MCF7. Moreover, the level of receptor phosphorylation was increased in the resistant ceil lines. PDGFRp expression was also evident in S BR3 (ER-/ERBB2+) but not in BT474 (ER+/ERBB2+) ceils. Of note both LTED and TAMR cells were sensitive to the inhibitory effect of the PDGFR/Abl tyrosine kinase inhibitor niiotinib, in the presence or absence of E. In contrast wt-MCF7 ceils showed limited sensitivity in the presence of E. Both SK8R3 and BT474 ce!is were insensitive.

These data indicate 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. Furthermore, niiotinib in combination with tamoxifen resensstises TAMR cells fo the inhibitory effect of tamoxifen.

The data summarized above are complemented by findings that PDGFR expression is associated with poor response to an aromatase inhibitor (A!) in a short-term pre-surgical {window of opportunity) clinical study as shown in the Example.

Hence, the present invention relates in particular fo pyrimidy!aminobenzamides of formula i

wherein

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 Ν,Ν-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

Ai,

The terms "treatment" or "therapy" refer to the prophylactic or preferably therapeutic {including but not limited to palliative, curing, symptom-alleviating, symptom-reducing) treatment of the diseases disclosed herein.

For the purpose of the present invention, preference is given to pyrimidylaminobenzamides of formula I, wherein the radicals mutually independentl of each other have the following meanings:

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 . cycloaikyi, benzcycioaikyi, heterocycly!, an aryl group, or a mono- or bicyclic heteroary! 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 pofysubstituted; 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

"nilotinib".

The general terms used Hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, un!ess otherwise indicated;

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.

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. 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.

An 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. In a preferred embodiment, 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 id i no, guanicfsno, ureido, mercapto, suifo, lower alkylthio, phenyithio, phenyl-iower a!kylthio, lower alkylphenylthio, lower alkyisuifinyi, phenylsulfiny!, pheny!-iower alkylsulfinyi, lower aikySphenylsulfiny!, lower alkylsulfonyl, pheny!su!fonyi, phenyl-lower alkylsulfonyl, lower a!kylphenyfsulfonyi, halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, such as especially irifluoromethanesuifonyl, dihydroxybora {-ΒζΟΗ^), heterocyclyl, a mono- or bicyclic heteroaryi group and lower a!k lene dioxy bound at adjacent C-atoms of the ring, such as methylene dioxy, Aryl is more preferably phenyl, naphthy! or 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. trifluoromethyi; hydroxy-lower aikyi, e.g. hydroxymethy! or 2~hydroxy~2~propyi; lower aikoxy-iower alkyl; e.g. methoxymethyi or 2-methoxyet yl; iower a!koxycarbonyi-!ower alky!, 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; 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!.

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, Ν,Ν-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 carbamoyl; and phenyl-iower aikoxycarbonyl, wherein the phenyl radical is unsubsiituted or especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower aikylamino, , -di-lower aikylamino, hydroxy, cyano, carboxy, lower aikoxycarbonyl, lower aikanoyl, and carbamoyl; and is preferably N-lower aikylamino, such as N-methySamino, hydroxy-iower aikylamino, such as 2-hydroxyethy!amino or 2- hydroxypropyl, lower aikoxy lower alkyi, such as methoxy ethyl, phenyl-iower aikylamino, such as benzyiaminc, N,N-di -lower aikylamino, N-phenyl-lower alky!-N-lower aikylamino, N,N-di-lower aikylphenylamino, lower aikanoylamino, such as acetylamino, or a substituent selected from the group comprising benzoylamino and phenyl-iower alkoxycarbonylarnino, wherein the phenyl radical in each case is unsubsiituted or especially substituted by niiro or amino, or also by halogen, amino, N-lower aikylamino, M.N-di-lower aikylamino, hydroxy, cyano, carboxy, lower aikoxycarbonyl, lower aikanoyl, carbamoyl or aminocarbonyiamino. 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 .

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!. such as I H-imidazo!-1 -yl, pyrro!y!, 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

benzyloxycarbonyioxy.

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 methyl, lower aikoxy, such as meihoxy or ethoxy. or hydroxy.

Preferably 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. ietrazoiyl, furazany!, benzofd]pyrazolyi, thsenyi and furanyi. More preferably 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,

benzoidjpyrazolyi, thienyi, and furanyi. in one preferred embodiment of the invention 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. in another preferred embodiment, 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-tetrahydrofuranyl, or 2-methyl-1 ,3-dioxolan-2-yi,

Pyrimidyiaminobenzamides within the scope of formula i and the process for their manufacture are disclosed in WO 04/005281 published on January 15, 2004 which is hereby incorporated into the present application by reference.

Pharmaceutically acceptabie salts of pyrimidyiaminobenzamides of formuia t are especiaii those disclosed in WO2Q07/G 15871 . in one preferred embodiment 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. Preferably, 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.

Usually, 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.

The structure of the active agents identified by code nos., generic or trade names may b taken from the actual edition of the standard compendium "The Merck Index 8 or from databases, e.g. Patents International (e.g. SMS World Publications). The corresponding content thereof is hereby incorporated by reference.

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

COMBINATION OF THE INVENTION,

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.

Moreover, 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. Examples of 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.

Further aspects of the invention are

® compounds of formula 1 alone or in combination with an aromatase inhibitor (A!) for the manufacture, of pharmaceutical compositions for use in the treatment of ER-positive breast cancer,, especially in patients who have either de novo or acquired resistance to an Al,

« 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):

wherein

Py denotes 3-pyridyl,

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, Λί- 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; or

or a pharmaceutically acceptable salt of such a compound.

The person skilled in the pertinent art is fully enabled to select a relevant test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects. The pharmacological activity is, for example, demonstrated in well established in vitro and in vivo test procedures.

The following Example illustrates the invention described above, but is not, however, intended to limit the scope of the invention in any way. EXAMPLE 1

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.