TW201642865A - Use of 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine for treating gastric cancers - Google Patents

Abstract

The present invention relates to the use of 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (compound A), more particularly (+)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (compound A'), for treating gastric cancer, preferably gastric cancers in which cells have an amplification of the C-MYC gene.

Description

4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5-tri-2- The use of amines in the treatment of gastric cancer

The present invention relates to 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5- three 2-Amine (Compound A), more specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) Methyl]phenyl}-1,3,5-three 2-Amine (Compound A ' ) is used for the treatment of gastric cancer, preferably gastric cancer in which the cells have C-MYC gene amplification.

The family of cyclin-dependent kinase (CDK) proteins consists of members that are key regulators of the cell division cycle (cell cycle CDK), members involved in the regulation of gene transcription (transcriptional CDK), and members with other functions. CDK needs to be associated with a regulatory cyclin subunit to activate. The cell cycle CDK CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK4/cyclin D, and CDK6/cyclin D are sequentially activated to drive cells into and through the cell division cycle. Transcription of CDK CDK9/cyclin T and CDK7/cyclin H via phosphorylation of the carboxy terminal domain (CTD) regulates the activity of RNA polymerase II. The positive transcription factor b (P-TEFb) is a heterodimer of CDK9 and one of the four cyclin partners cyclin T1, cyclin K, cyclin T2a or T2b.

However, CDK9 (NCBI GenBank Gene ID 1025) exclusively involves transcriptional regulation, CDK7 is additionally involved in cell cycle regulation as a CDK activating kinase (CAK).

The gene transcription system of RNA polymerase II is initiated by assembly of the pre-initiation complex at the promoter region and phosphorylation of SerD and Ser7 of CTD by CDK7/cyclin H. For most genes, RNA polymerase II stops mRNA transcription after it moves 20-40 nucleotides along the DNA template. The proximal pause of this promoter of RNA polymerase II is mediated by a negative elongation factor and it is thought to regulate the primary control mechanisms responsible for the rapid induction of genes for various stimuli (Cho et al., Cell Cycle 2010, 9, 1697). P-TEFb is critically involved in overcoming the near-suspension of the promoter of RNA polymerase II and the transition to a productive elongation state by phosphorylation of Ser2 of CTD and by phosphorylation and inactivation of a negative elongation factor.

The activity of P-TEFb itself is regulated by several mechanisms. About half of the cells P-TEFb are present in the 7SK nuclear small RNA (7SK snRNA), La-related protein 7 (LARP7/PIP7S) and hexamethylene diacetamide-inducible protein 1/2 (HEXIM1/2, He, etc. Human, Mol. Cell 2008, 29, 588) in an inactive complex. The remaining half of P-TEFb is present in the active complex containing the bromodomain protein Brd4 (Yang et al, Mol. Cell 2005, 19, 535). Brd4 recruits P-TEFb to the chromatin region where gene transcription is prepared by interacting with the acetylated tissue protein. P-TEFb maintains a functional balance by alternately interacting with its positive and negative regulators: P-TEFb, which binds to the 7SK snRNA complex, represents the release of active P-TEFb from its cellular transcription and cell proliferation requirements. Library (Zhou and Yik, Microbiol. Mol. Biol. Rev. 2006, 70, 646). Furthermore, the activity of P-TEFb is regulated by post-translational modifications including phosphorylation/dephosphorylation, ubiquitination, and acetamidine (reviewed in Cho et al., Cell Cycle 2010, 9, 1697).

The dysregulated CDK9 kinase activity of P-TEFb heterodimers is associated with a variety of human pathological environments such as hyperproliferative diseases (e.g., cancer), viral-induced infectious diseases, or cardiovascular diseases.

It is believed that cancer is over-mediated by imbalance between proliferation and cell death (apoptosis) Proliferative disorder. High levels of anti-apoptotic Bcl-2-family proteins are found in a variety of human tumors and result in prolonged survival and therapeutic resistance of tumor cells. Inhibition of P-TEFb kinase activity has been shown to reduce the transcriptional activity of RNA polymerase II, resulting in a decrease in short-lived anti-apoptotic proteins, particularly Mcl-1 and XIAP, and the ability of tumor cells to undergo apoptosis. A variety of other proteins associated with the transformed tumor phenotype (eg, Myc, NF-kB reactive gene transcript, mitotic kinase) are short-lived proteins or are encoded by short-lived transcripts, such short-lived transcript pairs by P-TEFb Inhibition-mediated reduction of RNA polymerase II activity sensitivity (reviewed in Wang and Fischer, Trends Pharmacol. Sci. 2008, 29, 302).

Many viruses rely on the transcriptional machinery of the host cell to transcribe their own genome. In the case of HIV-1, RNA polymerase II is recruited to the promoter region within the viral LTR. The viral transcriptional activator (Tat) protein binds to the nascent viral transcript and overcomes the promoter proximal RNA polymerase II pause by recruiting P-TEFb, which in turn promotes transcriptional elongation. In addition, the Tat protein increases the fraction of active P-TEFb by replacing the P-TEFb inhibitory protein HEXIM1/2 in the 7SK snRNA complex. Recent data have shown that inhibition of kinase activity of P-TEFb is sufficient to block HIV-1 replication at concentrations of kinase inhibitors that are non-cytotoxic to host cells (reviewed in Wang and Fischer, Trends Pharmacol. Sci. 2008, 29, 302). Similarly, for other viruses, P-TEFb has been reported to be recruited by viral proteins such as B-cell cancer-associated Epstein-Barr virus, in which nuclear antigen EBNA2 protein and P- TEFb interaction (Bark-Jones et al., Oncogene 2006, 25, 1775); and human T lymphoblastic virus type 1 (HTLV-1), in which transcriptional activator Tax recruits P-TEFb (Zhou et al., J. Virol) .2006, 80, 4481).

Cardiac hypertrophy (ie, cardiac adaptive response to mechanical overload and stress (hemodynamic stress, such as hypertension, myocardial infarction)) can lead to heart failure and death for a long time. Cardiac hypertrophy is shown to be associated with increased transcriptional activity and RNA polymerase II CTD phosphorylation in cardiomyocytes. P-TEFb was found to be activated by dissociation from the inactive 7SK snRNA/HEXIM1/2 complex. These findings indicate that pharmacological inhibition of P-TEFb kinase activity can be used as a therapeutic approach to treat heart Hypertrophy (reviewed in Dey et al., Cell Cycle 2007, 6, 1856).

In summary, multiple lines of evidence indicate selective inhibition of CDK9 kinase activity by P-TEFb heterodimer (=CDK9 and one of the four cyclin partners cyclin T1, cyclin K, cyclin T2a or T2b) Represents new ways to treat diseases such as cancer, viral diseases and/or heart diseases. CDK9 is a family of at least 13 closely related kinases in which a subset of the cell cycle CDK performs a variety of roles in regulating cell proliferation. Therefore, co-suppression of cell cycle CDK (eg, CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK4/cyclin D, CDK6/cyclin D) and CDK9 is expected to affect normal proliferative tissues, such as the intestine. Mucosa, lymph and hematopoietic organs and reproductive organs. In order to maximize the therapeutic margin of CDK9 kinase inhibitors, molecules with high selectivity for CDK9 are required.

In summary, CDK inhibitors and CDK9 inhibitors are described in a number of different publications: in summary, both WO2008129070 and WO2008129071 describe 2,4-substituted aminopyrimidines as CDK inhibitors. It also claims that some of these compounds can be used as selective CDK9 inhibitors (WO2008129070) and CDK5 inhibitors (WO2008129071), respectively, but do not present specific CDK9 IC50 (WO2008129070) or CDK5 IC50 (WO200812971) data.

WO2008129080 discloses 4,6 substituted aminopyrimidines and shows that these compounds show inhibitory effects on protein kinase activity of various protein kinases such as CDK1, CDK2, CDK4, CDK5, CDK6 and CDK9, among which CDK9 inhibition is preferred (example) 80).

EP1218360 B1 describes three as kinase inhibitors Derivatives, but did not reveal potent or selective CDK9 inhibitors.

WO2008079933 discloses aminopyridines and aminopyrimidine derivatives and their use as inhibitors of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9.

WO2011012661 describes aminopyridine derivatives which are useful as CDK inhibitors.

Wang et al. (Chemistry & Biology 2010, 17, 1111-1121) describe 2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK inhibitors which show anticancer activity in animal models.

WO2004009562 discloses the replaced three Kinase inhibitor. CDK1 and CDK4 test data were presented for the selected compounds, but no CDK9 data.

WO2004072063 describes heteroaryl (pyrimidine, three a substituted pyrrole that acts as an inhibitor of a protein kinase such as ERK2, GSK3, PKA or CDK2.

WO2010009155 reveals three And a pyrimidine derivative which acts as an inhibitor of the tissue protein deacetylase and/or cyclin dependent kinase (CDK). The CDK2 test data is presented for the selected compounds.

WO2003037346 (corresponding to US7618968B2, US7291616B2, US2008064700A1, US2003153570A1) is related to aryl three And uses thereof, including inhibition of lysophosphatidyltransferase beta (LPAAT-beta) activity and/or proliferation of cells such as tumor cells.

WO2008025556 describes carbamoyl sulfoximide having a pyrimidine nucleus which is useful as a kinase inhibitor. No CDK9 data was presented.

WO2002066481 describes pyrimidine derivatives as cyclin-dependent kinase inhibitors, without mentioning CDK9 and not presenting CDK9 data.

WO2008109943 relates to phenylaminopyrimidine compounds and their use as kinase inhibitors, in particular as JAK2 kinase inhibitors. Particular examples focus on compounds having a pyrimidine nucleus.

WO2009032861 describes substituted pyrimidinylamines as JNK kinase inhibitors. Particular examples focus on compounds having a pyrimidine nucleus.

WO2011046970 relates to an aminopyrimidine compound as an inhibitor of TBKL and/or IKK ε. Particular examples focus on compounds having a pyrimidine nucleus.

WO2012160034 A compound of the invention. It reveals that compounds inhibit HeLa cells (cervical cancer), HeLa/MaTu/ADR cells (cervical cancer), NCI-H460 cells (non-small cell lung cancer), DU145 cells (hormone-dependent human prostate cancer), Caco-2 cells Cell proliferation of (colorectal cancer) and B16F10 cells (melanoma).

Object of the present invention is improved gastric cancer, preferably wherein the treatment of gastric cancer cells have gene amplification of the C-MYC.

Treatment of gastric cancer

Gastric cancer is an invasive disease and is the second leading cause of cancer-related mortality worldwide (Jemal A et al, Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69-90). Dietary improvement and the reduction of H. pylori infection due to the use of antibiotics have led to a steady decline in the incidence and mortality of gastric cancer, but the prognosis of gastric cancer patients in Western countries is still poor (Lordick F.Unmet needs) And challenges in gastric cancer: The way forward. Can Treat Rev 2014;40:692-700). This is in stark contrast to the overall five-year survival rate of patients with gastric cancer in Japan, which has resulted in 70% of patients surviving in the regular screening of early diagnosis in Japan (European Union Network of Excellence (EUNE) for Gastric Cancer Steering Group. Gastric Cancer in Europe. Br J Surg 2008; 95: 406-408). Unfortunately, early gastric cancer rarely presents symptoms that cannot be explained by other factors and therefore cannot be diagnosed until it has progressed to the late metastatic stage.

A single curative treatment for locally advanced gastric cancer is surgical resection, in which tumor removal combined with extensive lymph node dissection and long-term follow-up results in increased efficacy. Pre-operative chemotherapy consisting of epirubicin, cisplatin, and capecitabine (or other platinum/fluoropyrimidine combinations) has also been shown to be beneficial in improving overall survival and It has been widely used as a standard care in Europe (Waddell et al, Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Radiotherapy and Oncology 2014; 110:189- 194). In the absence of surgery, recurrence, or metastatic cancer, chemotherapy and optimal supportive care provide enhanced quality of life and improved patient outcomes. However, the response to first-line chemotherapeutic agents is still poor.

Trastuzumab (anti-HER2 (epidermal growth factor receptor kinase 2) antibody), which results in enhanced overall survival in combination with cisplatin and fluoropyrimidine, was approved by the FDA in 2010 for the treatment of HER2 overexpression metastasis Patients with gastric cancer. Importantly, how the advancement of trastuzumab in the molecular characterization of tumors can be translated into excellent examples of successful and targetable therapeutics (Bang YJ et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2) -positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial, Lancet 2010; 376 (9742): 687-697).

C-MYC amplification in gastric cancer

In gastric cancer, genomic aberrations are usually repeated, including TP53, PIK3CA, ErbB2, ErbB3, KRAS, MET, and MYC (Yang W et al., Targeted therapy for gastric cancer: Molecular pathways and ongoing investigations. Biochimica et Biophysica Acta 2014; 1846: 232-7).

The dysregulated MYC manifests itself as the basis for the pathogenesis of many human tumors and appears to be the intersection of many important pathways and processes involved in the induction of carcinogenesis (Fletcher S et al., Small-molecule inhibitors of the Myc oncoprotein. Biochim. Biophys. Acta 2014). The C-MYC gene is an important member of the MYC proto-oncogene family and several studies have demonstrated a link between C-MYC expression and gastric cancer. C-MYC has been shown to have more than 40% of gastric cancer (Milne AN et al, Early onset gastric cancer: on the road to unravelling gastric carcinogenesis. Curr Mol Med 2007; 7 (1): 15-28) and intestinal type and diffuse Type gastric adenocarcinoma is described (Calcagno DQ et al, Interrelationship between chromosome 8 aneuploidy, C-MYC amplification and increased expression in individuals from northern Brazil with gastric adenocarcinoma. World J Gastroenterol 2006; 12(38): 6207-6211). Higher C-MYC performance is also associated with metastasis (Kozma L et al, C-MYC amplification and cluster analysis in human gastric carcinoma. Anticancer Res 2001; 21(1B): 707-710; Onoda N et al., Overexpression of C -MYC messenger RNA in primary and metastatic lesions of carcinoma of the stomach. J Am Coll Surg 1996;182(1): 55-59) and associated with poor prognosis (Han S et al, C-MYC expression is related with Cell proliferation and associated with poor clinical outcome in human gastric cancer. J Korean Med Sci 1999; 14(5): 526-530; De SouzaC et al, MYC Deregulation in Gastric Cancer and Its Clinicopathological Implications. Plos One 2013;8(5 ):e64420).

In summary, the evidence indicates that increased C-MYC-based amplification may be important instigator gastric cancer and a disease progression (Instigator), this is due to this transcription factor may be a fundamental role in regulating cell proliferation and apoptosis in the sum.

Detection of C-MYC gene amplification

Gene amplification (also known as gene duplication or chromosomal replication) is a cellular process in which multiple copies of a gene are produced. The genes on each of the copies can be transcribed and translated, which results in overproduction of mRNA and protein corresponding to the amplified gene. Gene amplification is an important feature of many advanced cancers and has prognostic and therapeutic implications in clinical cancer treatment (Myllykangas S, Knuutila S. Manifestation, mechanisms and mysteries of gene amplifications. Cancer Lett 2006; 232(1): 79-89) .

A variety of methods are available for detecting gene amplification in clinical samples. In these methods, clinical trials usually use conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) to determine patient testing. Copy number change in the sample (Myllykangas S, Knuutila S. Manifestation, mechanisms and mysteries of gene amplifications. Cancer Lett 2006; 232(1): 79-89). Although there are no standard methods for detecting C-MYC amplification, all of the techniques mentioned above as well as multiplex attachment-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), Single nucleotide polymorphism (SNP) arrays and traditional Southern and slot printing methods are already in use and strongly supported by several publications (Deming SL et al., C-myc amplification in breast cancer: a meta- Analysis of its occurrence and prognostic relevance.Br J Cancer 2000;83(12):1688-1695;Setoodeh R et al,Double-hit mantle cell lymphoma with MYC gene rearrangement or amplification:a report of four cases and review of the literature .Int J Clin Exp Pathol 2013;6(2):155-67;Balko JM et al,Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifier actionable therapeutic targets.Cancer Discov 2014;4(2) :232-45; Kim S et al, High-throughput sequencing and copy number variation detection using formalin fixed embedded tissue in metastatic gastric c ancer.PLoS One 2014;9(11):e111693;Minca EC et al, Genomic microarray analysis on formalin-fixed paraffin-embedded material for uveal melanoma prognostication.Cancer Genet 2014;207(7-8):306-15;Poddighe PJ et al, Genomic amplification of MYC as double minutes in a patient with APL-like leukemia, Mol Cytogenet 2014;7(1):67; Vogt N et al, Amplicon rearrangements during the extrachromosomal and intrachromosomal amplification process in a glioma.Nucleic Acids Res 2014;42(21):13194-205; Baykara O et al, Amplification of chromosome 8 genes in lung cancer. J Cancer 2015;6(3):270-5;Ooi A et al.,Semi-comprehensive analysis of Gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Mod Pathol 2015:doi:10.1038/modpathol.2015.33;Verbeke SL et al, Array CGH analysis identifies two distinct subgroups of primary angiosarcoma of bone.Genes Chromosomes Cancer 2015; 54(2): 72-81).

The compound 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5- has been found. three a 2-amine (Compound A, Formula (I)) or one of its physiologically acceptable salts or mirror image isomers,

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three 2-amine (Compound A ') or a pharmaceutically one who acts on the particular tumor type in the not previously covered physiologically, i.e. gastric cancer, gastric preferably wherein cells have gene amplification of the C-MYC.

4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5-tri 2-Amine (Compound A) is an anilinopyrimidine derivative substituted with a selected sulfonimide which can be separated into two stereoisomers, namely: (+)-4-(4-fluoro-2 -methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5-three 2-Amine (Compound A') and (-)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl] Phenyl}-1,3,5-three 2-Amine (Compound A").

Compound A' is preferred and is used as BAY1143572 in clinical studies.

In the case of the reference to the compound A below, it is thus meant that the pure stereoisomers A' and A" are And any mixture of the two.

The present invention relates to 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5- three -2-amine (Compound A) or one of its physiologically acceptable or mirror image isomers, more specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N -{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5-three Use of a 2-amine (Compound A ' ) or one of its physiologically acceptable salts for the treatment and/or prevention of gastric cancer, preferably gastric cancer in which the cells have C-MYC gene amplification.

Preferred are the compounds A 'for the treatment and / or prevention of gastric cancer cells with the use of gene amplification of C-MYC.

Methods for detecting such amplification include, but are not limited to, conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), Multiple ligation-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern blotting, and slit printing.

This application further relates to 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3, 5-three -2-amine or one of its physiologically acceptable or mirror image isomers, more specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3- [(S-Methylsulfonimide)methyl]phenyl}-1,3,5-three 2-amine or a physiologically acceptable salt of one of those uses, for the manufacture of treatment of gastric cancer, the agent preferably having a gastric cancer cells wherein the gene amplification of C-MYC.

Another aspect of the invention is 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]benzene of formula (I) Base}-1,3,5-three a 2-amine (Compound A) or one of its physiologically acceptable salts or mirror image isomers,

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three One of a 2-amine or a physiologically acceptable salt thereof

Use in the manufacture of a medicament for treating cancer in an individual, wherein the medicament is manufactured for the treatment of gastric cancer.

Preferred are compounds A 'in the manufacture of a medicament the treatment of gastric cancer cells wherein the gene amplification of C-MYC in the.

Methods for detecting this amplification include (but are not limited to) Conventional cytogenetics (chromosome banding), chromosome comparison gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), multiple ligation-dependent probe amplification (MLPA), PCR-based Methods (such as quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern printing and slit printing.

The present application further provides 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1 of the formula I, 3,5-three 2-amine

(Compound A) or one of its physiologically acceptable salts or mirror image isomers,

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three Use of a 2-amine (Compound A ' ) or one of its physiologically acceptable salts for the treatment of gastric cancer, preferably a gastric cancer in which the cell has a C-MYC gene amplification.

Preferred are compounds A 'have utility for the treatment of gastric cancer cells wherein the gene amplification of C-MYC.

Methods for detecting such amplification include, but are not limited to, conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), Multiple ligation-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern blotting, and slit printing.

The present invention is also directed to 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1 of the formula I, 3,5-three a 2-amine (Compound A) or one of its physiologically acceptable salts or mirror image isomers,

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three Use of a 2-amine (Compound A ' ) or one of its physiologically acceptable salts for use in a method of treating and/or preventing gastric cancer, preferably wherein the cells have C-MYC gene-amplified gastric cancer .

Preferred is the use of Compound A ' for the treatment and/or prevention of a method in which a cell has a C-MYC gene-amplified gastric cancer.

Methods for detecting this amplification include (but are not limited to) Conventional cytogenetics (chromosome banding), chromosome comparison gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), multiple ligation-dependent probe amplification (MLPA), PCR-based Methods (such as quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern printing and slit printing.

Another aspect of the invention is 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]benzene of formula (I) Base}-1,3,5-three More specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[2-amine or one of its physiologically acceptable salts or mirror image isomers (S-methylsulfonimide)methyl]phenyl}-1,3,5-three 2-amine (Compound A ') or a physiologically acceptable salt of one of those uses, for the treatment of diagnosed with C-MYC amplification method to a human patient of gastric cancer characterized in that the method of The method comprises the steps of: a) analyzing a tumor sample from a patient, and b) determining whether the C-MYC gene is amplified, and c) administering a C-MYC amplification as defined in step b; 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3 , 5-three -2-amine or one of its physiologically acceptable or mirror image isomers, more specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3- [(S-Methylsulfonimide)methyl]phenyl}-1,3,5-three One of the 2-amines (Compound A ' ) or a physiologically acceptable salt thereof.

Another aspect of the present invention like lines of treatment for gastric cancer, comprising the steps of: a) analyzing a sample of a tumor from a patient, and b) determining whether the amplified C-MYC gene, and c) if step b as Defining that the C-MYC gene is amplified, a therapeutically effective amount of 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) of formula I is administered. Methyl]phenyl}-1,3,5-three -2-amine (Compound A) or one of its physiologically acceptable or mirror image isomers, preferably (+)-4-(4-fluoro-2-methoxyphenyl)-N-{ 3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5-three One of the 2-amines (Compound A ' ) or a physiologically acceptable salt thereof.

Another aspect of the invention is a method of treating and/or preventing gastric cancer, preferably a gastric cancer in which the cell has a C-MYC gene amplification, which method uses an effective amount of 4-(4-fluoro-2-methyl) of formula I Oxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5-three -2-amine (Compound A) or one of its physiologically acceptable salts or mirror image isomers

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three The 2-amine (Compound A ' ) or one of its physiologically acceptable salts is used.

A preferred method of treatment is the use of an effective amount of Compound A ' to treat and/or prevent gastric cancer in which the cells have C-MYC gene amplification.

Methods for detecting such amplification include, but are not limited to, conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), Multiple ligation-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern blotting, and slit printing.

The application further provides a pharmaceutical composition comprising 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl} -1,3,5-three -2-amine or one of its physiologically acceptable or mirror image isomers, more specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3- [(S-Methylsulfonimide)methyl]phenyl}-1,3,5-three 2-amine or a physiologically acceptable salt of one of those, for the treatment of cancer, preferably wherein the gene amplification in gastric cancer cells have C-MYC.

The invention also relates to a pharmaceutical composition comprising 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl] of formula I] Phenyl}-1,3,5-three a 2-amine (Compound A) or one of its physiologically acceptable salts or mirror image isomers,

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three One of the 2-amines (Compound A ' ) or a physiologically acceptable salt thereof

And at least one inert, non-toxic, pharmaceutically suitable adjuvant for the treatment and/or prevention of gastric cancer, preferably gastric cancer wherein the cells have C-MYC gene amplification.

A preferred pharmaceutical composition is a pharmaceutical composition comprising Compound A ' for use in the treatment of gastric cancer in which the cells have a C-MYC gene amplification.

Methods for detecting such amplification include, but are not limited to, conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), Multiple ligation-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern blotting, and slit printing.

The application further provides 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5 -three 2-amine, more specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]benzene Base}-1,3,5-three -2-amine (compound A ' )

In combination with at least one other active ingredient, it is used to treat gastric cancer, preferably gastric cancer in which the cells have C-MYC gene amplification.

The invention also relates to a pharmaceutical combination comprising 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]benzene of formula I Base}-1,3,5-three a 2-amine (Compound A) or one of its physiologically acceptable salts or mirror image isomers,

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three 2-amine (Compound A ') or a physiologically acceptable salt of one of those, and at least one or more other active ingredients, for the treatment and / or prevention of cancer, preferably wherein cells C-MYC gene Amplified gastric cancer.

A preferred pharmaceutical combination comprises a pharmaceutical combination of Compound A ' for use in the treatment of gastric cancer in which the cells have a C-MYC gene amplification.

Methods for detecting such amplification include, but are not limited to, conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), Multiple ligation-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern blotting, and slit printing.

Another aspect of the invention is for use in a method of identifying a patient who is responsive to the use of a CDK9 inhibitor for the treatment of gastric cancer, wherein the CDK9 inhibitor is Compound A and wherein the method comprises detecting a tissue sample from a patient Amplification of C-MYC gene in tumor cells.

Preferred are used to identify lines tend CDK9 inhibitor is advantageously used in the process of gastric cancer patients with treatment of the reaction, CDK9 inhibitor compound wherein A 'and wherein the method comprises detecting in a sample from a tissue of the patient's tumor cells C-MYC gene amplification and in which patients were identified as treating gastric cancer with a CDK9 inhibitor, the tumor cells of such patients have C-MYC gene amplification.

Another aspect of the invention is the identification of 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) of the formula (I). Methyl]phenyl}-1,3,5-three -2-amine or one of its physiologically acceptable salts or mirror image isomers

More specifically, (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1, 3,5-three One of the 2-amines (Compound A ' ) or a physiologically acceptable salt thereof

A method for treating a patient responsive to gastric cancer, wherein the method comprises detecting C-MYC amplification in tumor cells from a tissue sample from a patient and wherein the patients are identified as treating gastric cancer using a CDK9 inhibitor, the patients the tumor cells C-MYC gene amplification.

Methods for detecting such amplification include, but are not limited to, conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), Multiple ligation-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern blotting, and slit printing.

Another aspect of the present invention predicts whether a patient is using 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide)-based group of formula (I). )methyl]phenyl}-1,3,5-three -2-amine or one of its physiologically acceptable or mirror image isomers, more specifically (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3- [(S-Methylsulfonimide)methyl]phenyl}-1,3,5-three A method of treating a response of one of the 2-amines (Compound A ' ) or one of its physiologically acceptable salts, wherein the method comprises detecting C-MYC amplification in tumor cells from a tissue sample from a patient .

Methods for detecting such amplification include, but are not limited to, conventional cytogenetics (chromosome banding), chromosome comparative gene hybridization (CGH), fluorescence in situ hybridization (FISH), next generation sequencing (NGS), Multiple ligation-dependent probe amplification (MLPA), PCR-based methods (eg, quantitative PCR (qPCR) and digital PCR), single nucleotide polymorphism (SNP) arrays, Southern blotting, and slit printing.

The use of a physiologically tolerable salt of Compound A should likewise be considered to be encompassed by the present invention.

The physiologically safe salt of Compound A encompasses acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as the following acid salts: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid , benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

The physiologically safe salt of Compound A also covers salts of conventional bases, such as, by way of example and preferably, alkali metal salts (for example, sodium and potassium salts), alkaline earth metal salts (for example, calcium and magnesium salts); and derived from ammonia. Or an ammonium salt of an organic amine having 1 to 16 C atoms, such as the following as an example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, three Ethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methyl Hexahydropyridine.

The invention further provides a medicament comprising Compound A and at least one or more additional active ingredients for use in the treatment of gastric cancer, preferably gastric cancer wherein the cells have C-MYC gene amplification.

Compound A can have systemic and/or local activity. For this purpose, it can be administered in a suitable manner, for example, orally, parenterally, via the pulmonary route, nasally, sublingually, translingually, buccally, transrectally, transvaginally, transdermally, transdermally, via Conjunctiva, ocular or in the form of an implant or stent.

For such administration routes, the compound A of the present invention can be administered in a suitable administration form.

Suitable for oral administration of a compound A according to the invention and which comprises a compound A of the invention in a crystalline and/or amorphous and/or dissolved form, according to the prior art, for example, a tablet (uncoated or coated lozenges, for example, a coating having a tolerant gastric juice or delayed dissolution or insolubilization and controlled release of a compound of the invention), a tablet that rapidly disintegrates in the oral cavity, or a film/flake, film/frozen Drying agents, capsules (such as hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be achieved without the absorption step (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or including absorption (eg intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal) . Formulations suitable for parenteral administration are, in particular, solutions for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Examples of other routes of administration are pharmaceutical forms for inhalation [especially powder inhalers, nebulizers], nasal drops, solutions, sprays; tablets, films to be administered through the tongue, sublingually or buccally /Flakes or capsules, suppositories; preparations for eyes and ears, eye washes, eye inserts, ear drops, ear powders, ear washes, ear tampon; vaginal capsules, aqueous suspensions (lotions, oscillating) Mixture (mixturae agitandae), lipophilic suspension, ointment, cream, transdermal therapeutic system (eg patch), milk, paste, foam, spread, implant or stent.

Compound A can be converted to the administered form as described. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable adjuvants. Such adjuvants include, inter alia

̇ fillers and excipients (eg cellulose, microcrystalline cellulose such as Avicel®, lactose, mannitol, starch, calcium phosphate such as Di-Cafos®),

Ointment base (such as petroleum glue, paraffin, triglyceride, wax, wool wax, wool wax, lanolin, hydrophilic ointment, polyethylene glycol),

基质 Substrate for suppositories (eg polyethylene glycol, cocoa butter, stearin)

̇ solvent (eg water, ethanol, isopropanol, glycerol, propylene glycol, medium chain length triglyceride fatty oil, liquid polyethylene glycol, paraffin),

a surfactant, emulsifier, dispersant or wetting agent (such as sodium lauryl sulfate, lecithin, phospholipids, fatty alcohols such as Lanette®, sorbitan fatty acid esters such as Span®, such as Tween®, etc. Polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid glycerides such as Cremophor®, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerin fatty acid esters, poloxamers such as Pluronic® Poloxamer)),

̇ buffer and acids and bases (such as phosphate, carbonate, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine)

Isotonic agent (eg glucose, sodium chloride),

Ruthenium sorbent (eg high dispersion ruthenium dioxide)

̇ tackifiers, gel formers, thickeners and/or binders (eg polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose) Sodium, starch, carbomer, polyacrylic acid such as Carbopol®, alginate, gelatin,

̇ disintegrating agent (for example, modified starch, sodium carboxymethylcellulose, sodium starch glycolate such as Explotab®, crosslinked polyvinylpyrrolidone, croscarmellose sodium such as AcDiSol®) ,

̇ flow regulators, lubricants, glidants and mold release agents (eg magnesium stearate, stearic acid, talc, highly dispersed cerium oxide such as Aerosil®),

̇ coating materials (such as sugar, shellac) and film forming agents for rapid or modified dissolution of membranes or diffusion membranes (for example, polyvinylpyrrolidone such as Kollidon®, polyvinyl alcohol, hydroxypropyl Methylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polycondensation such as Eudragit® Methacrylate),

Capsule material (eg gelatin, hydroxypropyl methylcellulose),

Neodymium synthetic polymers (eg polylactic acid, polyglycolide, polyacrylates, polymethacrylates such as Eudragit®, polyvinylpyrrolidone such as Kollidon®, polyvinyl alcohol, polyvinyl acetate, polyoxidation Ethylene, polyethylene glycol and copolymers thereof and block copolymers),

̇ plasticizer (such as polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, dibutyl phthalate),

̇ penetration enhancer,

Ruthenium stabilizers (eg antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

̇ preservatives (eg, parabens, sorbic acid, sodium thioglycolate, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

̇ coloring agents (such as inorganic pigments such as iron oxide, titanium dioxide),

A seasoning, sweetener, odor and/or odor masking agent.

Furthermore, the invention relates to medicaments comprising at least one compound of the invention, usually together with one or more inert, non-toxic pharmaceutically suitable adjuvants, and for their use for the above mentioned purposes.

Dosage and treatment plan

Dosage and treatment regimens can and must vary depending on the type of cancer and the target of the treatment.

The daily dosage system is usually between 20 mg and 850 mg and can be divided into a plurality of identical or different dosage units, preferably 2 dosage units, which can be taken simultaneously or according to a certain schedule. use.

In particular, the daily dosage is between 30 mg and 500 mg and can be divided into a plurality of identical or different dosage units, preferably 2 dosage units, which can be administered simultaneously or according to a schedule.

Preferably, the daily dosage is between 20 mg and 400 mg and can be divided into a plurality of identical or different dosage units, preferably 2 dosage units, which can be administered simultaneously or according to a schedule.

More specifically, the daily dosage is between 40 mg and 300 mg and can be divided into a plurality of identical or different dosage units, preferably two, which can be taken simultaneously or according to a schedule.

More preferably, the daily dosage range is between 20 mg and 200 mg and can be divided into a plurality of identical or different dosage units, preferably two, which can be administered simultaneously or according to a schedule.

Even better daily dosages are between 50 mg and 180 mg and can be divided into a plurality of identical or different dosage units, preferably two, which can be taken simultaneously or according to a schedule.

This applies to both monotherapy and combination therapy with other anti-hyperproliferative, cytostatic or cytotoxic substances, which may require a reduced dose.

Treatment can be performed in a regularly repeated cycle. The treatment cycle can have a varying duration, such as 21 days or 28 days, wherein the dosage is administered continuously or intermittently. Preferably, the length is 28 days, wherein the dosage is administered continuously or intermittently.

A continuous schedule involves daily dosing, for example, 21 daily doses in a 21 day cycle or 28 daily doses in a 28 day cycle. A preferred continuous schedule is 28 daily doses in a 28 day cycle.

The intermittent schedule relates to the treatment period, followed by a non-treatment period, such as in a 21 day period or a 28 day period. The preferred cycle duration for the intermittent schedule is 28 days.

The treatment period can be repeated more than once in a given treatment cycle.

The treatment period can be, for example, from 1 day to 21 days, more preferably from 3 days to 14 days.

Even better intermittent schedules involve treatment for 3 days followed by non-treatment for 4 days, repeated weekly in this manner, completing a 28-day treatment period.

The treatment is successful when at least the disease is stable and the adverse effects are at an easy to treat but at least acceptable level. Thus, the number of treatment cycles applied can vary from patient to patient depending on the response to treatment and tolerance.

The treatment is successful when at least the disease is stable and the adverse effects are at an easy to treat but at least acceptable level.

Compound A can be used alone or in combination with one or more other pharmacologically effective substances, provided that the combination does not cause undesirable and unacceptable adverse effects. Accordingly, the invention further provides a medicament comprising a compound A of the invention and one or more additional active ingredients, in particular for the treatment and/or prevention of the diseases mentioned above.

For example, Compound A can be used in combination with a known anti-hyperproliferation, cytostatic or cytotoxic substance to treat cancer. It is especially preferred that the compound A of the invention is combined with other substances used in cancer therapy or with radiation therapy.

Examples of suitable active ingredients for combination purposes include: albumin-bound paclitaxel, afinitor, aldesleukin, alendronic acid, alfofone , alitretinoin, allopurinol, aloprim, alooxi, hexamethylene melamine, aminoglutethimide, amifostine ), amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, arsenic Aromasin, 5-azacytidine, azathioprine, BCG or tessing BCG (tice-BCG), bestatin, betamethasone acetate, betamethasone sodium phosphate , bexarotene, bleomycin sulfate, bromouridine, bortezomib, busulfan, calcitonin, alemtuzum, cape Hebin, carboplatin, casodex, cefesone, sir interleukin (celmol) Eukin), cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine Dakaba (dacarbazine), dactinomycin, daunoxome, decadron, dexamethasone phosphate, delestrogen, denileukin diftitox , depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, deoxyfluorouridine, more flexible Doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, Epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, sodium citrate, acetylene Estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, non Filgrastim, finasteride, fligrastim, fluorouridine, fluconazole, fludarabine, monophosphorus 5-fluorodeoxyuridine, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, and formoterol ( Fotemustine), fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin (goserelin), granisetron hydrochloride, histrelin, hycamtin, hydrocortone, erythro-hydroxydecyl adenine, hydroxyurea, tey Ibrizumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon alpha 2, interferon alpha 2 alpha, interferon alpha 2 beta, interferon alpha nl, interferon alpha n3, interferon beta, interference Γ1a, interleukin 2, intron A, iressa, irinotecan, kytril, lapatinib, lentinan sulfate, letrozole, Formazan tetrahydrofolate, leuprolide, leuprolide acetate, levamisole, levulinic acid Salt, levothroid, levoxyl, lomustine, lonidamine, marinol, nitrogen mustard, mecobalamin, acetic acid Medroxyprogesterone, megestrol acetate, melphalan, menest, 6-巯嘌呤, mesna, methotrexate, metvix, Miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, modrenal, mes Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC -631570, OCT-43, octreotide, ondansetron hydrochloride, orapred, oxaliplatin, paclitaxel, pediapred , pegaspargase, pegasys, pentostatin, picibanil, pilocarpine hyd Rochloride), pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone ), premarin, procarbazine, procrit, raltitrexed, RDEA119, rebif, etidium phosphonate-186 (rhenium- 186 etidronate), rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, division Semustine, sizofiran, sobuzoxane, solu-medrol, streptozocin, strontium chloride-89, Cinsrod (synthroid), tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide Temozolomide), teniposide, propionate, testred, thioguanine, thiotepa, thyrotropin, tularophosphonate Acid (tiludronic acid), topotecan (topotecan), toremifene, tositumomab, trastuzumab, treosulfan, retinoic acid , trexall, trimethyl melamine, trimetrexate, triptorelin acetate, triptorelin, UFT, uridine, valrubicin Valrubicin), vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, simkad Zinecard), net statin (zinostatin stimalamer), zofran (zofran); ABI-007, acolbifene, actimmune, affinitak, amine Base pterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), carcinoma Avastin, CCI-779, CDC-501, celebrex, cetuximab, cristatol, cyproterone acetate Decitabine, DN-101, doxorubicin MTC, dSLIM, dutasteride, edotecarin, eflornithine, isa Exatecan, fenretinide, histamine dihydrochloride, histrine hydrogel implant, 鈥-166DOTMP, ibandronic acid, interferon γ, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, liab Libra, lonafarnib, miproxifen, minodronate, MS-209, liposome MTP-PE, MX-6, nafarelin , nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, polyglutamate paclitaxel (paclitaxel polyglutamate), pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifene, leopard frog (ranpirnase), 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha 1, thiazole Tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, transMID-107R, valspodar, vapreotide Vapreotide), vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid, and combinations thereof.

In a preferred embodiment, Compound A of the present invention can be combined with the following active ingredients: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldileukin, arba Alemtuzumab, alitu A, hexamethylene melamine, amine luminamide, amrubicin, amsacrine, anastrozole, agrabin, arsenic trioxide, aspartate, aza Azacitidine, basiliximab, BAY 80-6946, belototecan, bendamustine, bevacizumab, bexarotene, ratio Bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium leucovorin , capecitabine, carboplatin, carmofur, carmustine, catummaxomab, celecoxib, sir interleukin, cetuximab , chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronate, crocola (Clofarabine), Kerry he enzyme (crisantaspase), cyclophosphamide, cyproterone, cytarabine, dacarbazine , dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, dinisin 2 Denosumab, demullin, dibrospidium chloride, docetaxel, deoxyfluorouridine, doxorubicin, doxorubicin + estrone, eculus Monoclonal antibody (eculizumab), edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin , epithioanthrol, afaberetin, betaitrein, iriplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, elixir Everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, formoterol, fulvestrant, nitric acid Record, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutathione (glutoxim), goserelin, histamine dihydrochloride , histamine, hydroxyurea, I-125 particles, ibandronic acid, temimumab, idarubicin, ifosfamide, imatinib, imiquimod, Iprosulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide (lenalidomide), lenograstim, lentinan, letrozole, leuprolide, levamisole, lisuride, lobaplatin, lomustine, lonidamine, horse Masoprocol, medroxyprogesterone, megestrol acetate, melphalan, mepitiostane, guanidine, methotrexate, methoxsaren, amidoxime Ester, methyl ketone, mifamurtide, miltefosine, miribatin, mitobronitol, mitoguazone, mitophorol, silk Myomycin, mitoxantrone, mitoxantrone, nedaplatin, nerarabine, nilotinib, nilutamide, nimotuzumab Nimustine, nicotinamide, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel , palifermin, palladium-103 particles, pamidronic acid, panitumumab, pazopanib, pembellase, PEG-ipitapolin (Methoxy PEG-beta epoetin), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine , pentastatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, pucamycin, polyamine Sugar (poliglusam), estradiol polyphosphate, polysaccharide-K, porphyrin sodium, pralatrexate, prednistatin, procarbazine, quinagolide, radium chloride-223 , raloxifene, raltitrexed, ranimustine, razoxane, refametinib, regorafenib, risedronate Ronic acid), rituximab, romidepsin, romiposttim, saxstatin, sipuleucel-T, zozolam, sobuzo , sodium glycididazole, sorafenib, streptozotocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tazo Namin, teicoferrin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus ), teniposide, fluorenone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thioguanine, tocilizumab, topotem Kang, toremifene, tosimizumab, trobectedin, trastuzumab, troxulfan, retinoic acid, trolostane, triptorelin, ko Trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vaprefen, vemurafenib, vinblastine, vincristine, Changchun Xin, vinflunine, vinorelbine, vorinostat, vorozole, 钇-90 glass microspheres, zostatin, net statin, zoledron Acid, zorubicin.

Compound A is also expected to be combined with biotherapeutic agents, such as antibodies, such as cancer, rituxan, erbitux, herceptin, cetuximab. Anti-) and recombinant proteins.

Compound A can also be combined with other therapeutic agents that fight angiogenesis to achieve positive effects, for example, with cancer, axitinib, repiginib, centrein, sorafenib. Or a combination of sunitinib. Combination with proteasome and mTOR inhibitors as well as anti-hormone and steroid metabolic enzyme inhibitors is particularly useful because of its advantageous side-effect profile.

In general, the combination of Compound A with other cell growth inhibitory or cytotoxic agents allows the following objectives to be achieved: ̇ In terms of slowing tumor growth, reducing its size, or even completely eliminating it compared to treatment with individual active ingredients Improved efficacy; 可能性 the possibility of using a chemotherapeutic agent that is lower than the dose in the case of monotherapy; ̇ the possibility of achieving more tolerable therapy with fewer side effects than individual administration; The possibility of a wide range of neoplastic diseases; ̇ achieving a higher response rate to therapy; 更长 longer patient survival time compared to current standard therapies.

Furthermore, the compound A of the present invention can also be used in combination with radiation therapy and/or surgery.

Instance 1. Preparation of Compound A

Compound A ' was prepared according to the procedure set forth in Example 4 of WO 2012/160034.

2. Proliferation analysis

^#incubated with the substance for 72 hours

3. In vivo experiment

The aim of this realization was to evaluate the in vivo efficacy and tolerability of Compound A ' in two gastric cancer models of monotherapy and combination with paclitaxel or cisplatin in subcutaneously implanted NMRI nu/nu mice.

3.1 Abbreviations and abbreviations

3.2 Design

The study included two in vivo efficacy experiments using female NMRI nu/nu mice with C-MYC amplified subcutaneous gastric cancer xenografts. Compound A ' was evaluated in a single dose and in combination therapy with paclitaxel and cisplatin at a dose level. The anti-tumor activity and tolerance of all groups were evaluated using a vehicle control group as a reference.

3.3 Experimental procedure 3.3.1. Specific animal information

Mouse strain, sex: NMRI nu/nu, female

Animal Supply: Harlan

Total number of mice

Performance test (implantation/randomization): 280/120

Approx. weeks of age at the time of transplantation: 5-7 weeks

About the age of the week when randomized: 7.5-13 weeks

Captive conditions

Animals are housed in individual ventilated cages. Animals were monitored twice daily. All materials are autoclaved prior to use. Feel free to provide food and water.

3.3.2 Cancer Information 3.3.2.1 Characterization of test tumors

The patient-derived GXF 251 tumor model used in this study was obtained from a cancer patient sample. GXA SCH LX is a cell line-derived cancer model (Oncotest, Freiburg, Germany). These gastric cancer xenografts all exhibit C-MYC amplification.

3.3.2.2 Tumor transplantation

Gastric cancer tumor fragments were obtained from successive generations of xenografts in nude mice and placed in PBS containing 10% penicillin/streptomycin. Tumor fragments (one fragment per animal; 3-4 mm margin length) were then subcutaneously implanted into the ventral flank of NMRI nu/nu receptor mice under isoflurane anesthesia.

3.3.3 Randomization

Animals and tumor implants were monitored daily until the maximum number of implants showed clear signs of solid tumor growth. At randomization, the volume of the growing tumor is initially determined. According to the study protocol, taking into account the value and the average tumor volume than the groups of about 100-120mm ^3, having a volume of ³ 50-250mm, preferably 80-200mm partitioned experimental group of animals the tumor ³ . Record and maintain the results of randomization and experimental data. Unrandomized animals are euthanized. The date of randomization was designated as day 0 of the experiment.

3.3.4. Test reagents

Vehicle Compound A ' : 80% (m/V) PEG400 in water for injection

Media agents paclitaxel and cisplatin: 0.9% saline

Compound A ' : a dosing solution (2.5 mg/ml) was prepared once a week by diluting Compound A ' powder in a vehicle at 0.25% (w/v); the drug solution was stored at 4 ° C; the drug volume was 10 ml/kg.

Pacific paclitaxel: 1.6 ml of the storage solution was mixed with 6.4 ml of vehicle to obtain a drug solution.

Cisplatin: 1.6 mg of cisplatin was suspended in 8 ml of vehicle to obtain a drug solution.

3.3.5. Observation and calculation 3.3.5.1 Mortality

Mortality checks are performed daily during routine monitoring.

3.3.5.2 Weight

Mice were weighed twice a week. The relative body weight (expressed in %) of individual mice is calculated by multiplying the individual body weight (BW _X ) on Day _X by the individual body weight (BW ₀ ) on Day ₀ by 100 as follows:

Similarly, the median relative weight of the group is calculated, considering only the weight of the mice that live on the day in question.

3.3.5.3 Tumor volume

Tumor volume was determined by two-dimensional measurement on the day of randomization (Day 0) and then twice a week (i.e., on the same day the mice were weighed) using a caliper. The tumor volume was calculated according to the following formula: tumor volume = (a × b ² ) × 0.5

Where a represents the largest tumor diameter and b represents the orthogonal tumor diameter.

The relative volume (RTV) of individual tumors on day x was calculated by dividing the absolute individual tumor volume (T _x ) on day _x by the absolute individual tumor volume (T ₀ ) of the same tumor on day ₀ multiplied by 100%. : RTV _x [%]=(T _x /T ₀ )×100

3.3.5.4 Antitumor activity

Antitumor activity was assessed as the maximum tumor volume inhibition relative to the vehicle control group.

3.3.5.5 Tumor suppression, test/control value expressed in %

Tumor inhibition (T/C%) for a specific date was calculated by multiplying the ratio of the median RTV of the test group relative to the control group by 100.

The minimum (or optimal) T/C% value recorded for a particular test group during the experiment indicates the maximum anti-tumor activity of each treatment. The T/C value is calculated if at least 4 randomized animals in a group are alive on the day of the discussion.

3.3.5.6 Effectiveness criteria

The group best T/C value (%) is used for activity rating as follows:

3.4 Results 3.4.1 Compound A 'having the mouse xenograft anti-tumor efficacy

Compound A ' was evaluated in a single gastric cancer model in combination with paclitaxel or cisplatin in two subcutaneously implanted NMRI nu/nu mice at a dose level. Two gastric cancer xenograft models GXA SCH LX and GXF 251 exhibited C-MYC amplification.

In the GXA SCH LX tumor model, compound A ' , paclitaxel, or cisplatin monotherapy showed moderate antitumor activity with a maximum T/C value of 44.6%, 36.2%, and 39.7%, respectively. Compound A 'Pacific paclitaxel or cisplatin in combination with an increase of the antitumor efficacy of the respective monotherapies, such that the optimum T / C values of 22.0% (high activity) and 27.7% (moderate activity), respectively.

Compared to respective vehicle control group, GXA SCH LX of tumor growth by Compound A 'and the combination treatment significantly reduced, such as by non-parametric Kruskal - Wallis test (non-parametric Kruskal-Wallis test ), followed by Dunn's post-test.

In the GFX 251 tumor model, Compound A ' monotherapy produced border antitumor activity with an optimal T/C value of 59.9%, whereas paclitaxel or cisplatin as a single agent did not show antitumor efficacy. However, the combination of Compound A ' with paclitaxel or cisplatin increased the anti-tumor efficacy of each monotherapy, resulting in optimal TC values of 18.0% (high activity) and 38.1% (medium activity), respectively.

Compared with the vehicle control group and the respective separate paclitaxel or cisplatin monotherapy, GFX 251 of Tumor Growth by Compound A 'combination treatment significantly reduced, such as by Kruskal - Wallis test, followed by Deng Tested after the test.

Taken together, these data indicate that Compound A ' has significant and significant anti-tumor activity in combination with paclitaxel or cisplatin in patients with gastric cancer showing C-MYC amplification.

3.4.2. Survival and weight changes

The median BWL of the no or intermediate group was observed to be as high as 7.9% in the tumor models GXA SCH LX and GXF 251. The group receiving the control vehicle, cisplatin or paclitaxel monotherapy showed a 100% survival rate. The group receiving Compound A ' single or combination treatment exhibited a survival rate in the range of 80-90%, except that the animals receiving the combination of Compound A ' and Pacific Paclitaxel in the model GXASCHLX showed a 70% survival rate.

In summary, Compound A ' showed an acceptable tolerability profile in two mice with C-MYC amplified gastric cancer xenografts.

3.5. Summary and conclusion

In vivo efficacy and tolerance of Bayer Healthcare's study compound Compound A ' was evaluated in a single and in combination therapy with paclitaxel or cisplatin in two subcutaneously transplanted gastric cancer xenograft models. Two gastric cancer xenografts GXA SCH LX and GXF 251 exhibiting C-MYC amplification were subcutaneously implanted into female NMRI nu/nu mice. An amount of one dose (25mg / kg / day) once oral administration of Compound A 'and a subcutaneous tumor was established by initial treatment i.e. daily. The vehicle treated control group was included in each experiment. The group size was 10 mice per group. The anti-tumor activity (tumor growth inhibition) and tolerance of all groups were evaluated using a vehicle control group as a reference.

In tumor model GXA SCH LX, Compound A ', paclitaxel or cisplatin monotherapy showed moderate anti-tumor activity, wherein the minimum T / C values of 44.6%, 36.2% and 39.7%, respectively. Moderate antitumor activity was also observed in both GXA SCH LX and GFX 251 gastric cancer models using Compound A ' in combination with cisplatin, with minimum T/C values of 27.7% and 38.1%, respectively. High antitumor activity was observed in both GXA SCH LX and GFX 251 gastric cancer models using Compound A ' and paclitaxel, with minimum T/C values of 22% and 18%, respectively. In all of these cases, tumor growth was significantly attenuated by the combination of Compound A ' with paclitaxel or cisplatin compared to the respective vehicle control group (Kruskal-Wallis test, followed by Dunn test). The median BWL of the no- or medium-group was observed to be as high as 7.9% in the GXA SCH LX and GXF 251 tumor models. Taken together, these data indicate that Compound A ' has significant and significant anti-tumor activity in combination with paclitaxel or cisplatin in patients with gastric cancer that preferably has C-MYC amplification.

Claims (33)

4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3, of formula (I), 5-three Use of a 2-amine or one of its physiologically acceptable salts or mirror image isomers, It is used in the manufacture of a medicament for treating cancer in an individual, wherein the medicament is manufactured for the treatment of gastric cancer. The use of a compound of formula (I) according to any one of claims 1 wherein the mirror image isomer (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[( S-methylsulfonimide fluorenyl)methyl]phenyl}-1,3,5-three One of a 2-amine or a physiologically acceptable salt thereof. The use of claim 1 or 2, wherein the system to be treated has detected a C-MYC expander in a tissue sample from the individual containing tumor cells. The requested item 3 of use, wherein the C-MYC-based amplification is detected by the following: conventional cytogenetics, chromosome comparative genome hybridization, fluorescent in situ hybridization, next-generation sequencing, multiplex ligation-dependent probe amplification , quantitative PCR or digital PCR, single nucleotide polymorphic array, Southern printing or slit printing. A method for identifying a patient who tends to respond favorably to a CDK9 inhibitor, such as a compound of formula I, claim 1 or claim 2, and wherein the method comprises detecting a patient from the patient C-MYC amplification in tumor cells in tissue samples, and wherein the patients were identified as treating gastric cancer with a CDK9 inhibitor, the tumor cells of such patients having the C-MYC gene amplification. As used in claim 5, the patient is preferred to advantageously 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) of formula (I). Methyl]phenyl}-1,3,5-three a method of treating a gastric cancer by reacting one of a 2-amine or a physiologically acceptable salt thereof or a mirror image isomer, wherein the method comprises detecting C-MYC expansion in tumor cells in a tissue sample from the patient Increased, and wherein the patients were identified as using 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide)-based formula (I) Base]phenyl}-1,3,5-three -2-amines treat gastric cancer, and tumor cells of such patients have the C-MYC gene amplification. The method of the requested item 6, wherein the C-MYC-based amplification is detected by the following: conventional cytogenetics, chromosome comparative genome hybridization, fluorescent in situ hybridization, next-generation sequencing, multiplex ligation-dependent probe amplification , quantitative PCR or digital PCR, single nucleotide polymorphic array, Southern printing or slit printing. A compound of formula I 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5- three a 2-amine or one of its physiologically acceptable salts or mirror image isomers, It is used to treat gastric cancer. The compound of claim 8, wherein the mirror image isomer (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) is used. )methyl]phenyl}-1,3,5-three One of a 2-amine or a physiologically acceptable salt thereof. A compound according to claim 8 or 9, wherein the system to be treated is derived from a tissue sample of the individual containing tumor cells in which the C-MYC amplification has been detected. The request of the compound of item 10, wherein the C-MYC-based amplification is detected by the following: conventional cytogenetics, chromosome comparative genome hybridization, fluorescent in situ hybridization, next-generation sequencing, multiplex ligation-dependent probe amplification , quantitative PCR or digital PCR, single nucleotide polymorphic array, Southern printing or slit printing. A compound of formula I 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5- three a 2-amine or one of its physiologically acceptable salts or mirror image isomers, It is used in a method for treating and/or preventing gastric cancer. The compound of claim 12, wherein the mirror image isomer (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonate) is used. Iminomethyl)methyl]phenyl}-1,3,5-three One of a 2-amine or a physiologically acceptable salt thereof. The compound of the requested item 12 or 13, wherein a system of the subject to be treated from the tissue containing the tumor cells of the sample was detected by amplification of the C-MYC. 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3, of formula (I), 5-three a method for treating a human patient diagnosed with gastric cancer characterized by C-MYC amplification, wherein the method comprises a method for treating a human patient diagnosed with gastric cancer characterized by C-MYC amplification, the method comprising: The following steps: a) analyzing a tumor sample from the patient, and b) determining whether the C-MYC gene is amplified, and c) administering a C-MYC amplification as defined in step b, the administration is effective 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3 , 5-three -2-Amine or one of its physiologically acceptable salts or mirror image isomers. A method of treating gastric cancer comprising the steps of: a) analyzing a tumor sample from the patient, and b) determining whether C-MYC is amplified, and c) if C-MYC is amplified as defined in step b And administering a therapeutically effective amount of 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimido)methyl]phenyl} of formula I -1,3,5-three -2-amine or one of its physiologically acceptable salts or mirror image isomers The method of claim 16, wherein (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) is administered in step c) Methyl]phenyl}-1,3,5-three One of a 2-amine or a physiologically acceptable salt thereof. 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidomethyl)methyl]phenyl}-1,3,5- three Use of a 2-amine or one of its physiologically acceptable salts or mirror image isomers, It is used to treat and/or prevent gastric cancer. The use of a compound of the formula (I) according to claim 18, wherein the mirror image isomer (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methyl) is used. Sulfonimidomethyl)methyl]phenyl}-1,3,5-three One of a 2-amine or a physiologically acceptable salt thereof. The use of claim 18 or 19, wherein the system to be treated is derived from a tissue sample of the individual containing tumor cells that has been detected in the C-MYC . The use of claim 20, wherein the C-MYC amplification is detected by conventional cytogenetics, chromosome comparative gene hybridization, fluorescent in situ hybridization, next generation sequencing, multiple ligation-dependent probe amplification , quantitative PCR or digital PCR, single nucleotide polymorphic array, Southern printing or slit printing. A pharmaceutical combination comprising 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide)-based group of formula I as defined in claim 1 Methyl]phenyl}-1,3,5-three a 2-amine or one of its physiologically acceptable salts or mirror image isomers, And at least one or more additional active ingredients for use in the treatment and/or prevention of gastric cancer. A pharmaceutical composition comprising 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide)-based group of formula I as defined in claim 1 )methyl]phenyl}-1,3,5-three a 2-amine or one of its physiologically acceptable salts or mirror image isomers, And at least one inert, non-toxic, pharmaceutically suitable adjuvant for the treatment and/or prevention of gastric cancer. The pharmaceutical combination or pharmaceutical composition of claim 22 or 23 which comprises (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) Mercapto)methyl]phenyl}-1,3,5-three One of a 2-amine or a physiologically acceptable salt thereof. The requested item 22 to 24 or a pharmaceutical composition according to any one of the pharmaceutical composition, wherein one of the systems to be treated from the subject a sample of tissue containing the tumor cells have been detected by amplification of C-MYC. The pharmaceutical composition or pharmaceutical composition of claim 25, wherein the C-MYC amplification is detected by the following: conventional cytogenetics, chromosome comparative gene hybridization, fluorescent in situ hybridization, next generation sequencing, multiple connection dependence Probe amplification, such as quantitative PCR or digital PCR, single nucleotide polymorphic arrays, Southern blotting or slit printing. A pharmaceutical composition or a pharmaceutical composition according to any one of claims 22 to 26 for use in the treatment and/or prevention of gastric cancer. A method for treating and/or preventing gastric cancer using an effective amount of 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) )methyl]phenyl}-1,3,5-three -2-amine or one of its physiologically acceptable salts or mirror image isomers The method of treatment of claim 28, wherein the mirror image isomer (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimide) is used. Methyl]phenyl}-1,3,5-three One of a 2-amine or a physiologically acceptable salt thereof. The method of treatment of claim 28 or 29, wherein the system to be treated is derived from a tissue sample of the individual containing the tumor cell and the C-MYC amplification has been detected. The method of claim 30, wherein the C-MYC amplification is detected by the following methods: conventional cytogenetics, chromosome comparative gene hybridization, fluorescent in situ hybridization, next generation sequencing, multiple connection dependent probe amplification Increased, quantified PCR or digital PCR, single nucleotide polymorphic arrays, Southern blotting or slit printing. A method for predicting whether a patient is using 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimido)methyl]phenyl} of formula (I) -1,3,5-three A method of treating a reaction with a 2-amine or one of its physiologically acceptable salts or mirror image isomers, wherein the method comprises detecting C-MYC amplification of tumor cells in a tissue sample from the patient. The method of claim 32, wherein the C-MYC amplification is detected by conventional cytogenetics, chromosome comparative gene hybridization, fluorescent in situ hybridization, next generation sequencing, multiple ligation-dependent probe amplification , quantitative PCR or digital PCR, single nucleotide polymorphic array, Southern printing or slit printing.