JP2013525296A - Treatment of endocrine therapy-resistant breast cancer - Google Patents

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 treating endocrine therapy resistant breast cancer, and A method of treating warm-blooded animals, including humans suffering from endocrine therapy-resistant breast cancer, wherein said animal in need of such treatment is treated with a pyrimidyl of formula I alone or in combination with an aromatase inhibitor It relates to a method by administering an effective amount of aminobenzamide.

Description

  The present invention suffered from a pyrimidylaminobenzamide of formula I as defined below and endocrine therapy resistant breast cancer, alone or in combination with at least one aromatase inhibitor, for treating endocrine therapy resistant breast cancer. A method of treating warm-blooded animals, including humans, by administering an effective dose of a pyrimidylaminobenzamide of formula I alone or in combination with an aromatase inhibitor to said animals in need of such treatment About.

  The majority of breast tumors are estrogen receptor positive (ER positive) in the primary diagnosis. Estrogen (E) exerts its action by binding to ER. E-linked ER is classically associated with the estrogen response element (ERE) of the target gene that controls proliferation and cell survival. The ability of ER to regulate gene transcription is also affected by the activity of co-regulatory proteins such as AIB1. Treatments targeting estrogen stimulation of tumor growth have been very successful in reducing mortality of ER-positive breast cancer. However, resistance remains a major clinical problem.

  Surprisingly now, patients with ER-positive breast cancer, particularly either congenital or acquired resistance to AI, with pyrimidylaminobenzamide of formula I alone or in combination with an aromatase inhibitor (AI) It was found that it can be used for the treatment of

  The term “aromatase inhibitor” or “AI”, as used herein, relates to compounds which inhibit the production of estrogens, ie, 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 aminoglutethimide, borozole, fadrozole, anastrozole, especially letrozole. For example, exemestane can be administered, eg, in the form as it is marketed, eg under the trademark AROMASIN. For example, formestane can be administered, eg, in the form as it is marketed, eg under the trademark LENTARON. For example, fadrozole can be administered, eg, in the form as it is marketed, eg under the trademark AFEMA. For example, anastrozole can be administered, eg, in the form as it is marketed, eg under the trademark ARIMIDEX. For example, letrozole can be administered, eg, in the form as it is marketed, eg under the trademark FEMARA or the trademark FEMAR. Letrozole is disclosed in European Patent No. 0236940 issued September 16, 1987 and US Pat. No. 4,978,672 issued December 18, 1990 and Japanese Patent No. 2018112, all in the name of the applicant. It is specifically described. For example, aminoglutethimide can be administered, eg, in the form as it is marketed, eg under the trademark ORIMETEN.

  In a broad sense, the present invention provides a method of treating endocrine therapy-resistant breast cancer by treating a patient in need of such treatment with a compound that inhibits the PDGF signaling pathway. Other suitable PDGF-R receptor inhibitors are axitinib (AG013736) and sunitinib (SUTENT ™).

  We have studied the in vitro effects of nilotinib in breast cancer cell lines that model endocrine therapy sensitive and resistant diseases. Pyrimidylaminobenzamido nilotinib, an inhibitor of PDGF-R and Bcr-Abl, inhibits the growth of these cell lines in a concentration-dependent manner. Furthermore, nilotinib, when combined with tamoxifen, made tamoxifen-resistant MCF7 cells (TAMR cells) sensitive again to the inhibitory action of tamoxifen (FIG. 1).

  To identify the molecular mechanisms associated with resistance to E-blocking, a long-term culture of MCF7 human breast cancer cells in the absence of E2 (long-term estrogen blocking, LTED), a cellular assay that models resistance to AI. The time course of gene expression during adaptation was evaluated. Analysis of the canonical signaling pathway shows that platelet-derived growth factor (PDGF) / Abl is markedly elevated as early as 1 week after E-blocking (P = 1.94 E-04). ). It should be noted that this was the highest adaptive pathway at the time of resistance (p = 1.15 E-07). Thus, the classical PDGF / Abl pathway was found to be the main adaptive pathway that allows avoidance from the growth inhibition seen with estrogen blockade. PDGFR and AbI are elevated at the protein level in both tamoxifen-resistant and LTED cell lines. Furthermore, PDGF / Abl is identified as the main adaptive transmission pathway from the time course of gene expression related to LTED.

  An assessment of the level of protein expression and activation status in a panel of cell lines modeled both endocrine therapy-sensitive and resistant breast cancers compared to wt-MCF7 in LTED and Tamoxifen-resistant MCF7 cells (TAMR cells). Both showed an increase in PDGFRβ. Furthermore, the level of receptor phosphorylation was elevated in resistant cell lines. PDGFRβ expression was also evident in SKBR3 (ER− / ERBB2 +) but not in BT474 (ER + / ERBB2 +) cells. Of note, both LTED and TAMR cells were sensitive to the inhibitory action of the PDGFR / Abl tyrosine kinase inhibitor nilotinib in the presence or absence of E. In contrast, wt-MCF7 cells showed limited sensitivity in the presence of E. Both SKBR3 and BT474 cells were insensitive.

  These data indicate that PDGFRβ is associated with an endocrine therapy resistant phenotype. Evaluation using an ER / ERE binding reporter assay indicates that nilotinib represses ER-mediated transcription and inhibits expression of both endogenous E regulatory genes TFF1 and PGR. Chromatin immunoprecipitation shows that nilotinib reduces the recruitment of AIB1 and CBP to the TFF1 promoter. Furthermore, nilotinib, when combined with tamoxifen, resensitizes TAMR cells to the inhibitory action of tamoxifen.

  The data summarized above are supplemented by the finding that PDGFR expression is associated with a weak response to aromatase inhibitors (AI) in short-term preoperative (opportunity of treatment) clinical trials, as shown in the Examples.

  Thus, the present invention specifically relates to formula I, in particular, alone or in combination with at least one aromatase inhibitor for treating ER positive breast cancer in patients with either congenital or acquired resistance to AI.

［式中、
Ｐｙは、３−ピリジルを表し、
Ｒ_１は、水素、低級アルキル、低級アルコキシ−低級アルキル、アシルオキシ−低級アルキル、カルボキシ−低級アルキル、低級アルコキシカルボニル−低級アルキル、またはフェニル−低級アルキルを表し、
Ｒ_２は、水素、１個もしくは複数の同一もしくは異なる基Ｒ_３で場合によって置換されている低級アルキル、シクロアルキル、ベンズシクロアルキル、ヘテロシクリル、アリール基、または、０、１、２、もしくは３個の環窒素原子および０もしくは１個の酸素原子および０もしくは１個の硫黄原子を含む単環式もしくは二環式ヘテロアリール基であり、これらの基は、各場合、非置換であるか、一または多置換されており、
Ｒ_３は、ヒドロキシ、低級アルコキシ、アシルオキシ、カルボキシ、低級アルコキシカルボニル、カルバモイル、Ｎ−モノもしくはＮ，Ｎ−二置換カルバモイル、アミノ、一もしくは二置換アミノ、シクロアルキル、ヘテロシクリル、アリール基、または、０、１、２、もしくは３個の環窒素原子および０もしくは１個の酸素原子および０もしくは１個の硫黄原子を含む単環式もしくは二環式ヘテロアリール基であり、これらの基は、各場合、非置換であるか、一または多置換されており、
Ｒ_４は、水素、低級アルキル、またはハロゲンを表す］のピリミジルアミノベンズアミドまたは薬学的に許容されるその塩に関する。

[Where:
Py represents 3-pyridyl,
R ₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl,
R ₂ is hydrogen, a lower alkyl, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group, or 0, 1, 2, or 3 optionally substituted with one or more identical or different groups R ₃ A monocyclic or bicyclic heteroaryl group containing a ring nitrogen atom and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which in each case are unsubstituted or Or multi-substituted,
R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, or 0 , 1, 2 or 3 ring nitrogen atoms and monocyclic or bicyclic heteroaryl groups containing 0 or 1 oxygen atom and 0 or 1 sulfur atom, each group in each case , Unsubstituted or mono- or polysubstituted,
R ₄ represents hydrogen, lower alkyl, or halogen], and relates to pyrimidylaminobenzamide or a pharmaceutically acceptable salt thereof.

  The term “treatment” or “treatment” refers to a prophylactic or preferably therapeutic (such as, but not limited to, alleviation, therapy, symptom relief, symptom reduction) treatment of a disease disclosed herein.

It is a figure which shows the effect | action of nilotinib with respect to cell proliferation.

For the purposes of the present invention, pyrimidylaminobenzamides of the formula I are preferred, in which the groups, independently of one another, have the following meanings:
R ₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl, more preferably hydrogen,
R ₂ is hydrogen, a lower alkyl, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group, or 0, 1, 2, or 3 optionally substituted with one or more identical or different groups R ₃ A monocyclic or bicyclic heteroaryl group containing a ring nitrogen atom and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which in each case are unsubstituted or Or multi-substituted,
R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, or 0 , 1, 2 or 3 ring nitrogen atoms and monocyclic or bicyclic heteroaryl groups containing 0 or 1 oxygen atom and 0 or 1 sulfur atom, each group in each case , Unsubstituted or mono- or polysubstituted,
R ₄ represents lower alkyl, especially methyl.

  A preferred pyrimidylaminobenzamide is 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl), also known as “nilotinib”. -1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide.

  The general terms mentioned above or below preferably have the following meanings in the context of this disclosure, unless otherwise indicated.

  The prefix “lower” refers to a group having up to 7 carbon atoms, including 7 in particular, up to 4 carbon atoms including 4 which may be linear or one or more One of the branched chains having a branch.

  Similarly, when a plural form is used for a compound, salt, etc., a single compound, salt, etc. are meant.

  Lower alkyl is preferably alkyl having a minimum of 1 to 7 including 1 and a maximum of 7 including preferably 1 to a maximum of 4 including 1 to 4, preferably linear or branched, preferably , Lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl, or methyl. Preferred lower alkyl is methyl, propyl, or tert-butyl.

  Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl.

An aryl group is an aromatic group that is attached to a molecule through a bond located at the aromatic ring carbon atom of the group. In a preferred embodiment, aryl is an aromatic group having 6-14 carbon atoms, in particular phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, which is unsubstituted or, in particular, amino, Mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N- Mono- or N, N-disubstituted carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, lower alkylsulfinyl, phenyl Rusulfinyl, phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkyl mercapto, halogen-lower alkylsulfonyl, such as, in particular, trifluoromethane 1 selected from sulfonyl, dihydroxybora (—B (OH) ₂ ), heterocyclyl, monocyclic or bicyclic heteroaryl groups, and lower alkylenedioxy bonded to the adjacent C atom of the ring, for example, methylenedioxy Is substituted with one or more, preferably up to 3, in particular with 1 or 2 substituents. Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, these groups being in each case unsubstituted or halogen, in particular fluorine, chlorine or bromine; hydroxy; lower alkyl, for example Hydroxy, etherified with methyl, halogen-lower alkyl such as trifluoromethyl, or phenyl; lower alkylenedioxy bonded to two adjacent C atoms, such as methylenedioxy, lower alkyl, such as methyl or Propyl; halogen-lower alkyl, such as trifluoromethyl; hydroxy-lower alkyl, such as hydroxymethyl, or 2-hydroxy-2-propyl; lower alkoxy-lower alkyl; such as methoxymethyl, or 2-methoxyethyl; A Coxycarbonyl-lower alkyl, such as methoxy-carbonylmethyl; lower alkynyl, such as 1-propynyl; esterified carboxy, particularly lower alkoxycarbonyl, such as methoxycarbonyl, n-propoxycarbonyl, or iso-propoxycarbonyl; N Monosubstituted carbamoyl, especially carbamoyl monosubstituted by lower alkyl, eg methyl, n-propyl or isopropyl; amino; lower alkylamino, eg methylamino; di-lower alkylamino, eg dimethylamino or diethylamino; Lower alkylene-amino, such as pyrrolidino, or piperidino; lower oxaalkylene-amino, such as morpholino, lower azaalkylene-amino, such as piperazino, acylamino , For example, acetylamino or benzoylamino; lower alkylsulfonyl, e.g., methylsulfonyl; sulfamoyl; by one or two substituents selected from the group comprising or phenylsulfonyl, are independently substituted.

  The cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, which is unsubstituted or defined as one or more, in particular one or two, substituents for aryl as described above Substituents selected from the group, most preferably in lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and also oxo, and in benzcyclopentyl or benzcyclohexyl, etc. As such, it may be condensed with a benzo ring.

  Substituted alkyl is alkyl as defined immediately above, in particular lower alkyl, preferably methyl, where one or more, in particular up to 3, predominantly halogen, in particular fluorine, amino, N-lower alkyl. There may be substituents from the group selected from amino, N, N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is particularly preferred.

  Mono- or disubstituted amino is in particular lower alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; lower alkoxy lower alkyl, such as methoxyethyl; phenyl-lower alkyl, such as benzyl or 2-phenyl. Ethyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl (phenyl groups are in particular nitro, amino, halogen, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl 1 or more, preferably 1 or 2 substituents selected from lower alkanoyl and carbamoyl; and phenyl-lower alkoxycarbonyl (the phenyl group is unsubstituted, Or In particular, one or more selected from nitro, amino, halogen, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl, preferably Is substituted by one or two groups selected independently of each other from one to two substituents, preferably N-lower alkylamino, for example N -Methylamino, hydroxy-lower alkylamino, such as 2-hydroxy-ethylamino, or 2-hydroxypropyl, lower alkoxy lower alkyl, such as methoxyethyl, phenyl-lower alkylamino, such as benzylamino, N, N- Di-lower alkylamino, N-phen Ru-lower alkyl-N-lower alkylamino, N, N-di-lower alkylphenylamino, lower alkanoylamino, eg acetylamino, or selected from the group comprising benzoylamino and phenyl-lower alkoxycarbonylamino Substituents (phenyl groups are in each case unsubstituted or, in particular, nitro or amino, or likewise halogen, amino, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy , Cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, or aminocarbonylamino). Disubstituted amino is also lower alkylene-amino, such as pyrrolidino, 2-oxopyrrolidino, or piperidino; lower oxaalkylene-amino, such as morpholino, or lower azaalkylene-amino, such as piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.

  Halogen is in particular fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.

Etherified hydroxy is in particular C ₈ -C ₂₀ alkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, Phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy, or 1,1,2,2-tetrafluoroethoxy, or a single atom containing one or two nitrogen atoms Cyclic or bicyclic heteroaryl, preferably imidazolyl, such as 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, in particular 2-, 3- or 4-pyridyl, Pyrimidinyl, especially - pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, lower alkoxy substituted indolyl, or the thiazolyl.

  Esterified hydroxy is in particular lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.

  Esterified carboxy is in particular lower alkoxycarbonyl, such as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl or phenyloxycarbonyl.

  Alkanoyl is mainly alkylcarbonyl, in particular lower alkanoyl, for example acetyl.

  N-mono or N, N-disubstituted carbamoyl is in particular optionally substituted at the position of lower alkyl, phenyl-lower alkyl, and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene, or terminal nitrogen atoms. Substituted by one or two substituents independently selected from aza-lower alkylene.

  A monocyclic or bicyclic heteroaryl group containing 0, 1, 2 or 3 ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom (these groups in each case Unsubstituted or mono- or polysubstituted) means a heterocyclic moiety that is unsaturated in the ring connecting the heteroaryl group to the rest of the molecule of formula I, preferably a ring. Wherein, in the linked ring or, in some cases, in the linked ring, at least one carbon atom is replaced with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; The linking ring here preferably has 5 to 12, more preferably 5 to 6 ring atoms and is unsubstituted or one or more, in particular one or two. Ally in above Substituents of selected from the groups defined as substituents, and most preferably, lower alkyl, e.g., methyl, lower alkoxy, such as methoxy or ethoxy, or may be substituted by hydroxy. Monocyclic or bicyclic heteroaryl groups are preferably 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, Selected from naphthyridinyl, quinoxalyl, quinazolinyl, quinolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolyl, tetrazolyl, furazanyl, benzo [d] pyrazolyl, thienyl, and furanyl. Monocyclic or bicyclic heteroaryl groups are more preferably pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, imidazolyl, especially 5-indazolyl, pyridyl, In particular, 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl , Benzo [d] pyrazolyl, thienyl, and furanyl. In one preferred embodiment of the invention, the pyridyl group is substituted by hydroxy in the ortho position relative to the nitrogen atom, so that at least in the corresponding tautomeric form which is pyridine- (1H) 2-one. Partially exists. In other preferred embodiments, the pyrimidinyl group is substituted by hydroxy at both the 2 and 4 positions so that it exists as several tautomers, eg, pyrimidine- (1H, 3H) 2,4-dione To do.

  Heterocyclyl is a 5-, 6- or 7-membered heterocyclic ring system having 1 or 2 heteroatoms, particularly selected from the group comprising nitrogen, oxygen, and sulfur, and is unsaturated or wholly or partially May be saturated and unsubstituted, or in particular substituted by lower alkyl, eg methyl, phenyl-lower alkyl, eg benzyl, oxo, or heteroaryl, eg 2-piperazinyl , Heterocyclyl is in particular 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, for example 2- or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2 Tetrahydrofuranyl, or 2-methyl-1,3-dioxolan-2-yl.

  Pyrimidylaminobenzamides within the scope of formula I and their preparation are disclosed in WO 04/005281, published on 15 January 2004, which is incorporated herein by reference. .

  Pharmaceutically acceptable salts of the pyrimidylaminobenzamide of the formula I are in particular those disclosed in WO 2007/015871. In one preferred embodiment, nilotinib is used in the form of its hydrochloride monohydrate. WO 2007/015870 discloses certain polymorphs of nilotinib and pharmaceutically acceptable salts thereof are useful in the present invention.

  The pyrimidylaminobenzamide of Formula I can be administered by any route including oral, parenteral, eg, intraperitoneal, intravenous, intramuscular, subcutaneous, intratumoral, or rectal, or enteral. The pyrimidylaminobenzamide of formula I is preferably administered orally, preferably at a daily dose of 50 to 2000 mg. A preferred oral daily dose of nilotinib is 200-1200 mg, eg, 800 mg, administered in multiple doses, such as a single dose or twice a day.

  Usually, a low dose is administered initially and the dose is gradually increased until the optimal dose for the host under treatment is determined. The upper dose limit is determined by side effects and can be determined by testing the host to be treated.

  The structure of the active agent is specified by a code number, and the generic name or trade name can be obtained from a practical version of the standard dictionary “Merck Index” or from a database such as an international patent (for example, IMS World Publications). The corresponding content is incorporated herein by reference.

  Comprising (a) a pyrimidylaminobenzamide of the formula I as defined in this application and (b) at least one aromatase inhibitor, in which the active ingredient is in each case in free form or pharmaceutical A combination that is present in the form of an acceptable salt and optionally has at least one pharmaceutically acceptable carrier is hereinafter referred to as a “combination of the invention”.

  A further advantage is that the active ingredients of the “combination of the invention” can be used at low doses, for example, in many cases not only need lower doses but also be administered less frequently, Or it can be used to reduce the incidence of side effects. This is in accordance with the needs and requirements of patients undergoing treatment.

  In particular, the present invention provides (a) nilotinib with a dose in the range of 100-800 mg / day, preferably 200, 250, 300, 350, or 400 mg / day, and (b) a dose of 0.5, 1.0 , 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 mg / day of letrozole.

  Furthermore, the present invention relates to a “combination of the present invention” as an active ingredient and, in particular, for treating ER positive breast cancer in patients with either congenital or acquired resistance to AI, alone or at least 1 Commercial packaging with instructions for use at the same time, separately or sequentially in combination with a seed aromatase inhibitor is also provided.

  Fadrozole can be administered orally to humans in a dose range of 0.5 to 10 mg / day, preferably 1 to 2.5 mg / day.

  Letrozole can be administered orally to humans in a dosage range of 0.5-5 mg / day, preferably 0.5-4 mg / day, most preferably 1-2.5 mg / day. Examples of compositions containing letrozole are well known in the art, for example, Physicians' Desk Reference Copyright (Copyright) 2001 (Medical Economics Company Inc).

  Anastrozole can be administered orally to humans in a dose range of 0.25 to 10 mg / day, preferably 0.5 to 2.5 mg / day.

  Exemestane can be administered to humans in a dosage range of 5-200 mg / day, preferably 10-25 mg / day, or parenterally, 50-500 mg / day, preferably 100-250 mg / day. . If the drug must be administered as a separate pharmaceutical composition, it can be administered in the form disclosed in GB 2,177,700.

  Formestane can be administered parenterally to humans in a dose range of 100-500 mg / day, preferably 250-300 mg / day.

A further aspect of the invention is:
-A compound of formula I, alone or in combination with an aromatase inhibitor (AI), for the manufacture of a pharmaceutical composition for use in the treatment of ER-positive breast cancer, particularly in patients with congenital or acquired resistance to AI,
A method of treating warm-blooded animals, including humans suffering from ER-positive breast cancer, in particular patients with congenital or acquired resistance to AI, said animal in need of such treatment alone Or a method by administering an effective dose of a PDGF-R inhibitor in combination with an aromatase inhibitor (AI), more specifically formula (I):

［式中、
Ｐｙは、３−ピリジルを表し、
Ｒ_１は、水素、低級アルキル、低級アルコキシ−低級アルキル、アシルオキシ−低級アルキル、カルボキシ−低級アルキル、低級アルコキシカルボニル−低級アルキル、またはフェニル−低級アルキルを表し、
Ｒ_２は、水素、１個もしくは複数の同一もしくは異なる基Ｒ_３で場合によって置換されている低級アルキル、シクロアルキル、ベンズシクロアルキル、ヘテロシクリル、アリール基、または、０、１、２、もしくは３個の環窒素原子および０もしくは１個の酸素原子および０もしくは１個の硫黄原子を含む単環式もしくは二環式ヘテロアリール基であり、これらの基は、各場合、非置換であるか、一または多置換されており、
Ｒ_３は、ヒドロキシ、低級アルコキシ、アシルオキシ、カルボキシ、低級アルコキシカルボニル、カルバモイル、Ｎ−モノもしくはＮ，Ｎ−ジ−置換カルバモイル、アミノ、一もしくは二置換アミノ、シクロアルキル、ヘテロシクリル、アリール基、または、０、１、２、もしくは３個の環窒素原子および０もしくは１個の酸素原子および０もしくは１個の硫黄原子を含む単環式もしくは二環式ヘテロアリール基であり、これらの基は、各場合、非置換であるか、一または多置換されており、
Ｒ_４は、水素、低級アルキル、またはハロゲンを表す］のピリミジルアミノベンズアミド誘導体、または薬学的に許容されるそのような化合物の塩を投与することを含む、エストロゲン受容体陽性乳癌の処置または予防方法
である。

[Where:
Py represents 3-pyridyl,
R ₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl,
R ₂ is hydrogen, a lower alkyl, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group, or 0, 1, 2, or 3 optionally substituted with one or more identical or different groups R ₃ A monocyclic or bicyclic heteroaryl group containing a ring nitrogen atom and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which in each case are unsubstituted or Or multi-substituted,
R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono or N, N-di-substituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyl, heterocyclyl, aryl group, or Monocyclic or bicyclic heteroaryl groups containing 0, 1, 2 or 3 ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom; Are unsubstituted or mono- or polysubstituted,
Treatment of estrogen receptor positive breast cancer comprising administering a pyrimidylaminobenzamide derivative of R ₄ represents hydrogen, lower alkyl, or halogen, or a pharmaceutically acceptable salt of such a compound, or It is a preventive method.

  Those skilled in the art are well able to select an appropriate test model and demonstrate the therapeutic indications and beneficial effects indicated above and below. Pharmacological activity is demonstrated, for example, in well-established in vivo and in vitro test procedures.

The following examples are illustrative of the invention described above, but are not intended to limit the scope of the invention in any way.

  Clinical data for 81 postmenopausal patients treated with AI in the new adjuvant setting were increased PDGFRβ and PDGF expression after 2 weeks (1.25 fold, p = 0.003 and 1.43 fold, p = 4.4E-06). Low PDGFRβ before treatment was associated with a better response.

Claims (10)

For treating estrogen receptor positive breast cancer,
(A) Formula I

[Where:
Py represents 3-pyridyl,
R ₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl,
R ₂ is hydrogen, a lower alkyl, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group, or 0, 1, 2, or 3 optionally substituted with one or more identical or different groups R ₃ A monocyclic or bicyclic heteroaryl group containing a ring nitrogen atom and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which in each case are unsubstituted or Or multi-substituted,
R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, or 0 , 1, 2 or 3 ring nitrogen atoms and monocyclic or bicyclic heteroaryl groups containing 0 or 1 oxygen atom and 0 or 1 sulfur atom, each group in each case , Unsubstituted or mono- or polysubstituted,
R ₄ represents hydrogen, lower alkyl, or halogen], or a pharmaceutically acceptable salt thereof;
(B) A combination comprising at least one aromatase inhibitor.   The pyrimidylaminobenzamide of formula I is 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl). 2. The combination of claim 1 which is) -3- (trifluoromethyl) phenyl] benzamide.   4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl The combination according to claim 2, wherein benzamide is used in the form of its hydrochloride monohydrate. For treating estrogen receptor positive breast cancer,
(A) axitinib (AG013736) or sunitinib (SUTENT ™);
(B) A combination comprising at least one aromatase inhibitor.   5. A combination according to any one of claims 1-4, wherein the aromatase inhibitor is selected from the group consisting of exemestane and formestane, aminoglutethimide, borozole, fadrozole, anastrozole, and letrozole. For treating estrogen receptor positive breast cancer,
(A) 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoro Methyl) phenyl] benzamide, or a pharmaceutically acceptable salt thereof,
6. The combination of claim 5 comprising (b) letrozole. For treating estrogen receptor positive breast cancer,
(A) 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoro Methyl) phenyl] benzamide, or a pharmaceutically acceptable salt thereof,
(B) A combination comprising tamoxifen. Estrogen receptor positive reaction for treating breast cancer,
Formula I

[Where:
Py represents 3-pyridyl,
R ₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl,
R ₂ is hydrogen, one or a plurality, lower alkyl optionally substituted with the same or a different group _{R 3,} cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or 0, 1, 2 or 3, Monocyclic or bicyclic heteroaryl groups containing 1 ring nitrogen atom and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which in each case are unsubstituted or One or multiple substitutions,
R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, or 0 , 1, 2 or 3 ring nitrogen atoms and monocyclic or bicyclic heteroaryl groups containing 0 or 1 oxygen atom and 0 or 1 sulfur atom, each group in each case , Unsubstituted or mono- or polysubstituted,
R ₄ represents hydrogen, lower alkyl, or halogen], or a pharmaceutically acceptable salt thereof.   The pyrimidylaminobenzamide of formula I is 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl). Pyrimidylaminobenzamide according to claim 1, which is) -3- (trifluoromethyl) phenyl] benzamide, preferably in the form of its hydrochloride monohydrate.   8. A combination according to any one of claims 1 to 7, for treating estrogen receptor positive breast cancer in a patient having either congenital or acquired resistance to at least one aromatase inhibitor, or claim Item 10. The pyrimidylaminobenzamide according to any one of Items 8 to 9.

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