TW201521792A - Tablet formulation of a PI3K[alpha] inhibitor - Google Patents

Abstract

Provided herein are pharmaceutical formulations comprising a PI3K[alpha] inhibitor, and methods of use thereof for treating cancer in a patient in need of such treatment.

Description

Tablet formulation of PI3Kα inhibitor

The present invention provides a pharmaceutical formulation comprising a PI3K alpha inhibitor, and a method of using the same for treating a patient in need of treatment for cancer.

According to the National Cancer Institute, 41% of existing men and women will be diagnosed with cancer at some point in their lifetime. This widespread disease has led to the need for improved anti-cancer therapies to treat malignant diseases.

One of the important drugs targets a group of proteins called kinases. Protein kinases are a large family of diverse enzymes that catalyze protein phosphorylation and play a key role in cell signal transduction. It may have a positive or negative regulatory effect, depending on its protein target. Protein kinases are involved in specific signal transduction pathways that regulate cell function, such as, but not limited to, metabolism, cell cycle progression, cell attachment, vascular function, apoptosis, and angiogenesis. Cell signal transduction dysfunction is associated with many diseases, and its greatest features include cancer and diabetes. The literature has examined in detail the regulation of cytokines on signal transduction and the correlation between signal molecules and proto-oncogenes and tumor suppressor genes. Similarly, the association between diabetes and related conditions, as well as protein kinase levels, has also been demonstrated. See, for example, Sridhar et al., Pharmaceutical Research , 17(11): 1345-1353 (2000). Viral infection and its associated conditions are also associated with the regulation of protein kinases. Park et al., Cell 101 (7), 777-787 (2000).

The phospholipid inositol 3-kinase (PI3K or PIK3CA) consists of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents a catalytic subunit, It phosphorylates Ptdlns, PtdIns4P and PtdIns(4,5)P2 using ATP. PTEN is a tumor suppressor that inhibits cell growth through multiple mechanisms and allows PIP3, the major product of PIK3C, to be dephosphorylated. Protein kinase B (AKT1, PKB), in turn, needs to be transported to the cell membrane using PIP3, where it is phosphorylated and activated by the upstream kinase. The effect of PTEN on cell death is mediated through the PIK3CA/AKT1 pathway.

PI3Kα has been involved in the regulation of cell architecture reorganization, apoptosis, vesicle trafficking, proliferation and differentiation. The number and performance of PIK3CA are associated with many malignant diseases, such as ovarian cancer (Campbell et al., Cancer Res 2004, 64, 7678-7681; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al. Human Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005, 97, 26-34), cervical cancer, breast cancer (Bachman et al., Cancer Biol Ther 2004, 3, 772-775; Li et al. Breast Cancer Res Treat) 2006, 96, 91-95; Saal et al., Cancer Res 2005, 65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224), colorectal cancer (Smuence et al., Science 2004, 304, 554; Velho et al., Eur J Cancer 2005, 41, 1649-1654), endometrial cancer (Oda et al., Cancer Res. 2005, 65, 10669-10673), gastric cancer (Byun et al., Int J Cancer 2003, 104, 318). -327; Lee et al., the Oncogene 2005,24,1477-1480), hepatocellular carcinoma (Lee et al., the Oncogene 2005,24,1477-1480), human small cell and non-small cell lung carcinoma (Tang et lung Cancer 2006, 51, 181-191; Massion et al., Am JRespir Crit Care Med 2004, 170, 1088-1094), thyroid carcinoma (Wu et al., J Clin Endocrinol Metab 2005, 90, 4688- 4693), acute myeloid leukemia (AML) (Sujobert et al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML) (Hickey and Cotter J Biol Chem 2006, 281, 2441-2450) and nerve glue Maternal tumors (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642).

Many PI3K inhibitors are currently undergoing clinical evaluation in cancer patients, details of which can be found on ClinicalTrials.gov. For example: 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one alone or Combination with other medical ingredients is in lymphoma or leukemia (for its test see NCT01410513 and NCT01403636), malignant neoplastic or solid tumors (see tests NCT01587040, NCT01390818, NCT00485719, NCT01596270 and NCT00777699), brain tumors (the test can be See NCT01240460 and NCT00704080) for evaluation of human clinical trials in patients with breast cancer (see test for NCT01082068).

Based on the established biological activity of this compound, an optimized version is needed to achieve maximum patient efficacy. There is therefore a continuing need for novel compositions and methods that specifically target the PI3K signal transduction pathway for the treatment of cancer.

In one aspect, provided herein is a pharmaceutical formulation comprising 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3- d] Pyrimidine-7(8 H )-one or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. In a specific embodiment, the 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8) The H )-ketone is in the form of a free base. In some embodiments, the hydrogel is selected from the group consisting of microcrystalline cellulose, methyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl Cellulose, hydroxypropyl methylcellulose, polyethylene oxide, colloid, acrylate polymer and methacrylate polymer. In another specific embodiment, the hydrogel is microcrystalline cellulose. In a specific embodiment, the diluent is selected from the group consisting of sugars, starches, vegetable oils, lactose monohydrates, calcium phosphates, dextrin, dextrose, maltitol, maltose, starch, and sucrose. With talc. In a particular embodiment, the diluent is starch and the starch is pregelatinized starch or sodium starch glycolate.

In a specific embodiment, provided herein is a pharmaceutical formulation comprising (by weight) 10-30% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole) -5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and They are 0.1 to 10.0% hydroxypropyl methylcellulose, cerium oxide and type A crospovidone, respectively.

In another specific embodiment, provided herein is a pharmaceutical formulation comprising (by weight) about 20% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole- 5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% Hydroxypropyl methylcellulose, about 1% cerium oxide and about 4% type A crospovidone.

In a specific embodiment, the pharmaceutical formulation provided above is in the form of a lozenge.

In another specific embodiment, the pharmaceutical formulation provided above is in the form of a film ingot.

In still another embodiment, the pharmaceutical formulation provided above is in the form of an immediate release tablet. The formulation may comprise about 20 mg, 30 mg, 55 mg or 90 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d Pyrimidine-7(8 H )-one or a pharmaceutically acceptable salt thereof.

In another aspect, a compressed solid dosage form comprising 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridin[2,3- d] Pyrimidine-7(8 H )-one or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. The dosage form may comprise (by weight) 10-30% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d Pyrimidine-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and 0.1 to 10.0% hydroxypropylmethyl fiber, respectively , cerium oxide and type A cross-linked povidone. In another example, the dosage form may comprise (by weight) about 20% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [ 2,3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hydroxypropyl methylcellulose About 1% cerium oxide and about 4% type A crospovidone. The dosage form may comprise from about 10 to 100 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 ( 8 H )-ketone or a pharmaceutically acceptable salt thereof or about 20 mg, 30 mg, 55 mg or 90 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5-yl) Pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof. In one embodiment, the dosage form is a tablet, and in another embodiment, it is a film ingot.

In another aspect, there is provided a compressed solid dosage form, comprising A) an active agent, comprising an effective amount of a 2-amino-8-ethyl-4-methyl -6- (1 H - pyrazol-5 a pyridyl[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof, and B) at least one pharmaceutically acceptable additive, wherein the active agent content exceeds the compressed solid The total weight of the dosage form is about 10% by weight. The dosage form may comprise (by weight) 10-30% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d Pyrimidine-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and 0.1 to 10.0% hydroxypropylmethyl fiber, respectively , cerium oxide and type A cross-linked povidone. In another example, the dosage form may comprise (by weight) about 20% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [ 2,3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hydroxypropyl methylcellulose About 1% cerium oxide and about 4% type A crospovidone.

In a specific embodiment, the active agent of the dosage form comprises at least 95% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [2, 3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof. In another embodiment, the active agent of the dosage form comprises at least 97% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [2 , 3-d] pyrimidine-7(8 H )-one or a pharmaceutically acceptable salt thereof, and another embodiment comprises at least 99% 2-amino-8-ethyl-4-methyl -6-( 1H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating cancer in an individual comprising administering to the individual in need thereof the pharmaceutical formulation and dosage form described above. In a specific embodiment, the cancer is a solid tumor or a lymphoma. In still another specific embodiment, the lymphoma is painless non-Hodge Gold's lymphoma, quilt cell lymphoma (MCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or diffuse large B-cell lymphoma (DLBCL).

In a specific embodiment, the cancer is a blood cancer. In still another specific embodiment, the hematological cancer is acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or chronic lymphocytic leukemia (CLL).

The treatment can include re-administering other anticancer agents. Non-limiting examples of such agents include bentamustine, rituximab, erlotinib, letrozole or temozolomide.

In another aspect, the kit provides a kit comprising 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [2,3 -d] pyrimidine -7 (8 H) - one or a pharmaceutically acceptable salt thereof of a pharmaceutical formulation. In one embodiment, the kit comprises 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 A pharmaceutical composition of (8 H )-ketone or a pharmaceutically acceptable salt thereof. In a specific embodiment, the kit comprises instructions for treating a patient suffering from cancer using the compound or a pharmaceutical composition thereof.

Other subject matter, features, and advantages will be apparent from the following detailed description. The detailed description and the examples are intended to be illustrative, and are in the In addition, the examples are illustrative of the principles of the invention, and are not intended to be illustrative of the invention.

Figure 1 shows the preparation of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one Synthesis reaction diagram.

Figure 2 shows the production of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )- A flow chart of a ketone as a film-coated lozenge of an active pharmaceutical ingredient (API).

Providing a compound comprising 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one ( Also referred to herein as "Compound I"), hydrogel polymers, and pharmaceutical formulations with diluents. Also provided is a 2-amino-8-ethyl-4-methyl-6-( 1H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one Compressed solid dosage form. The composition of the present invention suitable for treating cancer has superior to the past 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d] Features of the pyrimidine-7( 8H )-one formulation, including improved manufacturability.

Certain terms used herein are described below. The compounds of the invention are illustrated by standard nomenclature. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning

Structure of "2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one" The formula is as follows:

In the present application, 2-amino-8-ethyl-4-methyl-6-( 1H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7( 8H )- A ketone or a pharmaceutically acceptable salt or solvate thereof is referred to as "Compound I".

The compound 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one is PI3K ( A selective inhibitor of phospholipid creatinine 3-kinase, which has potent inhibitory activity against PI3K signal transduction in both in vitro and in vivo tumor modes. The synthesis and characterization of Compound I is described in U.S. Patent No. 8,044,062, the disclosure of which is incorporated herein in its entirety.

The "yield" of each reaction described herein is expressed as a percentage relative to the theoretical yield.

"Individuals" for the purposes of the present invention include humans and other animals, specifically mammals, and other organisms. These methods are therefore suitable for use in human medical and veterinary use. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment, the patient is a human.

The term "effective amount" or "pharmaceutically effective amount" or "medically effective amount" refers to an amount of the agent sufficient to provide the desired biological, medical, and/or prophylactic result. The result may be to reduce, alleviate, ameliorate, alleviate, delay and/or attenuate one or more symptoms, symptoms or causes of the disease or any other desired biological system changes. When referring to cancer, an effective amount thereof includes an amount sufficient to reduce the tumor and/or decrease the rate of tumor growth (e.g., inhibit tumor growth) or to prevent or delay other undesirable cell proliferation. In some embodiments, the effective amount is sufficient to delay the amount of development. In some embodiments, an effective amount is sufficient to prevent or delay the amount of relapse. An effective amount can be administered one or more times. An effective amount of a drug or composition can be: (i) reducing the number of cancer cells; (ii) reducing the tumor; (iii) inhibiting, delaying, slowing to some extent, preferably stopping the infiltration of cancer cells into peripheral organs; Inhibiting (ie, slowing down to some extent, preferably stopping) tumor metastasis; (v) inhibiting tumor growth; (vi) preventing or delaying the onset and/or recurrence of the tumor; and/or (vii) letting one or more The symptoms associated with cancer are alleviated to some extent. The amount can vary depending on factors such as the size and weight of the individual, the type of disease, or the particular compound employed. The amount can vary depending on the compound, the disease state and its severity, the age of the patient being treated, and the like. Those skilled in the art will be able to determine this effective amount based on their knowledge and the present disclosure.

A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the pharmacological activity of the desired parent compound. It is understood that pharmaceutically acceptable salts are non-toxic. Further suitable pharmaceutically acceptable salts can be found in "Remington's Pharmaceutical Sciences , 17th Edition, Mack Publishing Company, Easton, PA, 1985", the disclosure of which is incorporated herein by reference. , or "Bakery Salts ," by SMBerge et al., J. Pharm. Sci., 1977; 66: 1-19, the disclosures of which are hereby incorporated by reference.

Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as acetic acid, trifluoroacetic acid, and propionic acid. , hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4 -hydroxybenzhydryl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- Naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ylidene-1-carboxylic acid), 3-phenylpropionic acid , trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid and salicylic acid, etc. Wait. In a specific embodiment, 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8) is employed. H )-Ketone hydrochloride type or hydrochloride type.

Examples of pharmaceutically acceptable base addition salts include those formed by substitution of an acidic proton in a parent compound with a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, Manganese, aluminum salts, and so on. Preferred salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines (including naturally substituted amines), cyclic amines Salts with basic ion exchange resins. Examples of the organic base include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, and Cyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hexamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, Hydrazine, piperazine, piperidine, N -ethylpiperidine, trimethylolmethylamine, N -methylglucamine, polyamine resin, and the like. Examples of organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

"Treatment" or "treatment" of a disease, condition or symptom as used herein, unless otherwise indicated, means inhibiting a disease, a disease or a symptom, ie, halting its development; and alleviating the disease, disease or condition, even if the disease The lesion or symptom subsides. As is known in the art, it may be desirable to adjust the treatment based on systemic or local delivery, age, weight, general health, gender, diet, time of administration, drug interaction, and severity of the condition, and is readily acquainted by those skilled in the art. Use routine experiments to decide.

The terms "comprising" and "including", as used herein, are open and unrestricted, unless otherwise indicated.

The terms "a", "an", "the", "the", and <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; . When a compound, a salt, or the like is used in the plural form, it is intended to mean a singular compound, a salt, and the like.

The term "about" as used herein generally refers to a value that does not vary by more than 10%, 5%, or 1%. For example, the broadest meaning of "about 25 mg/kg" generally means that the value is 22.5-27.5 mg/kg, that is, 25 ± 2.5 mg/kg.

The term "oral dosage form" as used herein means any pharmaceutical composition that is intended to be administered to the gastrointestinal tract of a human or other mammal via the oral cavity of a human or other mammal. For the purposes of the present invention, the delivery pattern can be a compressed tablet dosage form.

The term "medical effect" as used herein refers to achieving the desired biological, medical, and/or prophylactic results. The result may be to reduce, ameliorate, alleviate, alleviate, delay and/or attenuate one or more symptoms, symptoms or causes of the disease, or any other desired biological system changes. When referring to cancer, the effect can be to shrink the tumor and/or reduce the rate of tumor growth (eg, inhibit tumor growth) or prevent or delay other undesirable cell proliferation. In some embodiments, this effect can be delayed development. In some embodiments, the effect can be delayed recurrence. In other aspects, the effect can be: (i) reducing the number of cancer cells; (ii) reducing the tumor; (iii) inhibiting, delaying, slowing to some extent, preferably stopping the infiltration of cancer cells into peripheral organs; (iv) inhibiting (ie, slowing down to some sort of Degree, preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) delay tumor onset and/or recurrence; and/or (vii) relieve one or more cancer-related symptoms to some extent.

Pharmaceutical formulation of Compound I

When the pharmaceutical formulation of Compound I is produced by fluidized bed granulation, a multi-factor test is performed to develop an optimum compression profile, injection force, aspect ratio (eg, lamination or capping and stamping) and stability. Sex (for example, impurities, analytical values, dissolved forms are determined after storage of the tablet at 50 ° C / 75% RH for 3 months). From these tests, 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8 H) was obtained. a pharmaceutical formulation of a ketone or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. In a specific embodiment, the 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8) The H )-ketone is in the form of a free base.

In some embodiments, the hydrogel is selected from the group consisting of microcrystalline cellulose, methyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxyl Propyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, colloid, acrylate polymer and methacrylate polymer. In another specific embodiment, the hydrogel is microcrystalline cellulose. In certain embodiments, the diluent is selected from the group consisting of sugars, starches, vegetable oils, lactose monohydrates, calcium phosphates, dextrin, dextrose, maltitol, maltose, starch, and sucrose. With talc. In a particular embodiment, the diluent is a starch such as pregelatinized starch or sodium starch glycolate.

In a specific embodiment, provided herein is a pharmaceutical formulation comprising (by weight) 10-30% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole- 5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and respectively It is 0.1 to 10.0% of hydroxypropylmethylcellulose, cerium oxide and type A crospovidone.

In another specific embodiment, provided herein is a pharmaceutical formulation comprising (by weight) about 20% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole- 5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% Hydroxypropyl methylcellulose, about 1% cerium oxide and about 4% type A crospovidone.

In another specific embodiment, the pharmaceutical formulations provided above are in a lozenge form. In another specific embodiment, the pharmaceutical formulation provided above is in the form of a film ingot. The formulation may comprise from about 10 mg to 100 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8 H )-ketone or a pharmaceutically acceptable salt thereof. The formulation may comprise about 20 mg, 30 mg, 55 mg or 90 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d Pyrimidine-7(8 H )-one or a pharmaceutically acceptable salt thereof.

In another aspect, a compressed solid dosage form that is readily ingested is provided. Specifically, a 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8 H) is provided. a compressed solid dosage form of a ketone or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. The dosage form may comprise (by weight) 10-30% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d Pyrimidine-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and 0.1 to 10.0% hydroxypropylmethyl fiber, respectively , cerium oxide and type A cross-linked povidone. In another example, the dosage form may comprise (by weight) about 20% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [ 2,3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hydroxypropyl methylcellulose About 1% cerium oxide and about 4% type A crospovidone. The dosage form may comprise from about 10 to 100 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 ( 8 H )-ketone or a pharmaceutically acceptable salt thereof or about 20 mg, 30 mg, 55 mg or 90 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5-yl) Pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof. In one embodiment, the dosage form is a tablet, and in another embodiment, a film ingot.

In another aspect, there is provided a compressed solid dosage form, comprising A) comprising an effective amount of a 2-amino-8-ethyl-4-methyl -6- (1 H - pyrazol-5-yl) pyridine And an active agent of [2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof, and B) at least one pharmaceutically acceptable additive, wherein the active agent is present in excess of the compressed solid The total weight of the dosage form is about 10% by weight. The dosage form may comprise (by weight) 10-30% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d Pyrimidine-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and 0.1 to 10.0% hydroxypropylmethyl fiber, respectively , cerium oxide and type A cross-linked povidone. In another example, the dosage form may comprise (by weight) about 20% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [ 2,3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hydroxypropyl methylcellulose About 1% cerium oxide and about 4% type A crospovidone.

In a specific embodiment, the active agent of the dosage form comprises at least 95% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [2, 3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof. In another embodiment, the active agent of the dosage form comprises at least 97% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [2 , 3-d] pyrimidine-7(8 H )-one or a pharmaceutically acceptable salt thereof, and in another embodiment, it comprises at least 99% 2-amino-8-ethyl-4- Methyl-6-( 1H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof.

In another specific embodiment, the pharmaceutical formulation provided above is in the form of an immediate release lozenge. "Immediate release" means that the dosage form releases the active ingredient immediately upon contact with the gastric fluid and completely dissolves in about one hour.

In some embodiments, the pharmaceutical composition comprising Compound I can be in the form of a film-coated tablet, as detailed in Table 1.

_a When referring to the Pharmacopeia, it is indicated by the current version of the Pharmacopoeia. _b Excluded during manufacturing. _c comes from plants. _d Opadry® II 33G92256 yellow contains 40% hydroxypropyl methylcellulose 6mPa.s (Ph.Eur.-USP-JP), 21% lactose monohydrate (Ph.Eur.-NF-JP), 16.87% titanium dioxide (Ph. Eur.-USP-JP), 8.13% yellow iron oxide (NF-JP), 8% polyethylene glycol (macrogol) 3350 (Ph. Eur.-NF), 6% triacetin (Ph. Eur.-USP-JP).

Method for preparing a pharmaceutical formulation comprising Compound I

Preparation of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one (Compound I The composite diagram is shown in Figure 1.

2 provides a flow diagram of a method of making a film-coated lozenge comprising Compound I, including process control. According to the flow chart, the manufacturing steps of the film-coated tablets are as follows:

1. Weigh all components.

2. Add microcrystalline cellulose to the mixer and mix for about 2 minutes at about 7r/min.

3. Add compound I, pregelatinized starch, half of the type A crospovidone and anhydrous colloidal vermiculite to a mixer containing cellulose, and mix all the components at about 7r/min for about 15 minutes.

4. The mixture obtained in step 3 was sieved through a 1 mm mesh screen.

5. Preparation of binder solution: Hydroxypropyl methylcellulose 6 mPa.s was added to pure water and stirred for about 45 minutes. The concentration was set at 9.5%.

6. Add the mixture to a fluid bed granulator. The binder solution was added to the mixture at a flow rate of about 100 g/min and the inlet air temperature was about 65 ° C to allow the wet mixture to form granules. The binder solution solution line is washed with water until proper drying weight loss is obtained.

7. The wet granules are dried using an inlet air temperature of about 65 ° C until the loss on drying is similar to that achieved by the dry mixture.

8. The resulting granules were sieved on a 1 mm mesh screen.

9. The other half of the type A crospovidone, colloidal anhydrous vermiculite and magnesium stearate were sieved through a 1 mm mesh screen.

10. Add the other half of the type A cross-linked povidone, colloidal anhydrous vermiculite and stearic acid to the calibrated granules, and mix for about 20 minutes at about 7 r/min to obtain a homogeneous mixture.

11. Take the lubricated pellets on a rotary compressor, assemble 6R6 punching holes for 20mg concentration, assemble 5,4R8, 4 punch holes for 55mg, or punch 9,9R9,9 punching holes for 90mg concentration, the nominal concentration of 20mg The nominal mass of 100 mg, the nominal mass of 55 mg concentration is 275 mg or 90 mg, and the nominal mass is 450 mg.

12. In a mixing tank, a film coat suspension was prepared using pure water and Opadry II 33G92256 yellow.

13. The tablet obtained in step 11 is placed in a coated pan with an inlet air temperature of about 65 °C. The coating suspension was sprayed onto the tablet until it reached 104 mg for 20 mg of the tablet, 288.75 mg of the 55 mg tablet, or 472.5 mg of the 90 mg tablet.

In order to ensure the consistency, quality, concentration and purity of the drug, the analysis process and the conformity standard test by the drug are shown in Table 2.

Method for treating cancer using a pharmaceutical formulation of Compound I

One aspect of the invention provides a method of treating cancer in a subject, comprising administering to the individual an effective amount of a pharmaceutical formulation comprising Compound I: 2-amino-8-ethyl-4-methyl- 6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one, hydrogel polymer, and diluent.

"Cancer" refers to a cell proliferative disorder, including but not limited to: heart: sarcoma (vascular aneurysm, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibroids, lipomas and malformations; Lung: bronchial carcinoma (squamous cells, undifferentiated small cells, undifferentiated large cells, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoma, Mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (pancreatic ductal adenocarcinoma, insulinoma, Glucagonoma, gastrinoma, carcinoid tumor, intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, Lipoma, Neurofibromatosis, fibroids, large intestine (adenocarcinoma, tubular adenoma, villus adenoma, hamartoma, leiomyomas); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor) ) [kidney cell tumor], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, metastatic epithelial carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (sperm Cell tumor, malformoma, embryonal carcinoma, malformed carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroid, fibroadenoma, adenoma-like tumor, lipoma); liver: hepatoma ( Hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Irvine Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor chordoma, skeletal chondroma (osteochondral osteochondral), benign chondroma, chondroblastoma, Cartilage myxoid fibroma, osteoid osteoma and giant cell tumor; nerve System: cranial bone (osteoma, hemangioma, granuloma, xanthoma, malformation osteitis), meninges (meningioma, meningioma, glioma), brain (stellate cell tumor, medulloblastoma, glial) Tumor, ependymoma, germ cell tumor [pineal tumor], polymorphic glioblastoma, oligodendrocyte glioma, Schwannoma, retinoblastoma, congenital tumor , spine (neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, poor differentiation of precancerous cervical), ovary (ovarian cancer] Benign serous cystadenoma, mucinous cystadenocarcinoma, unclassified carcinoma], granular layer of ovarian follicular cell tumor, Sertoli Leydig cell tumor, asexual embryonal tumor, malignant malformoma), genital (scale) Cell carcinoma, intraepithelial neoplasia, adenocarcinoma, fibrosarcoma, melanoma), vaginal (clear cell carcinoma, squamous cell carcinoma, grape sarcoma [embryo rhabdomyosarcoma], fallopian tube (cancer)); Blood: blood (myeloid leukemia [acute and chronic], Lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma] Skin; malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's Sarcoma, sputum metaplasia, lipoma, hemangioma, cutaneous fibroids, crab disease, dryness; and adrenal gland: neuroblastoma. Thus, a "cancer cell" as provided herein includes a cell that has been replaced by one or more of the above conditions.

In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a lymphoma, such as: painless non-Hodgkin's lymphoma, quilt cell lymphoma (MCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL) Or diffuse large B-cell lymphoma (DLBCL).

In certain embodiments, the cancer is breast cancer, non-small cell lung cancer, melanoma, colorectal cancer, glioblastoma, astrocytoma, or glioma. In another specific embodiment, the cancer is breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, lymphoma, lung cancer, small cell lung cancer, non-small cells Lung cancer, melanoma, ovarian cancer, cervical cancer, pancreatic cancer, blood cancer, prostate adenocarcinoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML) or thyroid carcinoma.

In certain embodiments, the cancer is a blood cancer, such as acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or chronic lymphocytic leukemia (CLL).

This treatment may include additional administration of other anticancer agents. Non-limiting examples of such agents include bentamustine, rituximab, erlotinib, letrozole or temozolomide.

In certain embodiments of the method, the pharmaceutical formulation comprises Compound I formulated into a tablet. In particular, in one embodiment, the tablet is an immediate release film coating tablet. Formulations of Compound I can be formulated to contain any desired amount of Compound I. In a particular embodiment, the tablet is formulated to comprise 20 mg or 30 mg of 20% w/w Compound I (either as a free base or a pharmaceutically acceptable salt thereof). In another embodiment, the tablet is formulated to contain 55 or 90 mg of 20% w/w Compound I (either as a free base or a pharmaceutically acceptable salt thereof). Specific embodiment In particular embodiments, the tablet is formulated as a free base form comprising 20 mg or 30 mg of 20% w/w Compound I. In another embodiment, the tablet is formulated as a free base form comprising 55 or 90 mg of 20% w/w Compound I.

Dosing method

Administration of a pharmaceutical formulation comprising Compound I can be carried out via any acceptable mode of administration or agent for similar uses. The administration method may be a solid, semi-solid, lyophilized powder or a liquid dosage form, such as, for example, a tablet, a suppository, a pill, a soft elastic and hard capsule, a powder, a solution, a suspension or an aerosol, etc., in particular, A unit dosage form suitable for simple administration of an accurate dose, for example: oral, nasal, parenteral (intravenous, intramuscular, or subcutaneous), topical, transdermal, transvaginal, intravesical, cerebral Intra or rectal administration. In a preferred embodiment, the tablet is administered orally in a lozenge form.

In the pharmaceutical compositions disclosed herein, the effective amount of Compound I administered will vary with a variety of factors, including the activity of the particular compound employed, the metabolic stability and the duration of action of the compound, age, weight, general health, Gender, diet, mode of administration and timing, rate of excretion, combination of drugs, severity of the particular disease state, and ongoing therapy in the patient. Compound I can be administered to a patient in a dosage range of from about 0.1 to about 2,000 mg per day.

The precise dosage for children will generally decrease with the child's smaller size and weight, and the dosage will be adjusted depending on body size and weight and other factors. For example, the dosage will again vary with other factors including the needs of the child, the severity of the condition being treated, and the pharmacological activity of the compound used. Those skilled in the art are familiar with how to determine the optimal dosage for a particular child. If formulated as a fixed dose, such combination products may employ other pharmaceutically active agents (groups) of the compounds of the invention within the above dosage range and within the approved dosage range. If it is not suitable to use the combination formulation, the compound I can also be used sequentially with known pharmaceutically acceptable agents (groups).

Set

In another embodiment, a kit is provided comprising a compound I: 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [ A pharmaceutical formulation of 2,3-d]pyrimidin-7( 8H )-one. In one example, the kit comprises the compound I: 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d] A pharmaceutical composition of pyrimidine-7( 8H )-one. In a specific embodiment, the kit comprises instructions for treating a patient suffering from cancer using the compound or a pharmaceutical composition thereof.

Claims (37)

A pharmaceutical formulation comprising 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8 H a ketone or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. The pharmaceutical formulation according to claim 1, wherein the 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d The pyrimidine-7(8 H )-one is in the form of a free base. The pharmaceutical formulation according to claim 1 or 2, wherein the hydrogel is selected from the group consisting of microcrystalline cellulose, methyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidine Ketone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene oxide, colloid, acrylate polymer and methacrylate polymer. The pharmaceutical formulation according to claim 1 or 2, wherein the hydrogel is microcrystalline cellulose. The pharmaceutical formulation according to claim 1 or 2, wherein the diluent is selected from the group consisting of a saccharide, a starch, a vegetable oil, a lactose monohydrate, a calcium phosphate, a dextrin, a dextrose, Maltitol, maltose, starch, sucrose and talc. The pharmaceutical formulation according to claim 1 or 2 wherein the diluent is starch and the starch is pregelatinized starch or sodium starch glycolate. A pharmaceutical formulation according to claim 1 or 2, which comprises (by weight) 10-30% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole- 5-yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and respectively It is 0.1 to 10.0% of hydroxypropylmethylcellulose, cerium oxide and type A crospovidone. A pharmaceutical formulation according to claim 1 or 2, which comprises (by weight) about 20% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5) -yl)pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hydroxyl Propyl methylcellulose, about 1% cerium oxide and about 4% type A crospovidone. The pharmaceutical formulation according to claim 8 wherein the microcrystalline cellulose has a density rating of pH 302 and a particle size of 90 μm. The pharmaceutical formulation according to any one of claims 1 to 9, wherein the pharmaceutical formulation is in a tablet form. The pharmaceutical formulation according to claim 10, wherein the pharmaceutical formulation is in the form of a film ingot. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the pharmaceutical formulation is in the form of an immediate release tablet. The pharmaceutical formulation according to any one of claims 1 to 12, wherein the formulation comprises about 20 mg, 30 mg, 55 mg or 90 mg of 2-amino-8-ethyl-4-methyl-6- ( 1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof. The pharmaceutical formulation according to any one of claims 1 to 13, wherein the formulation provides a medical effect. A compressed solid dosage form comprising 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7 (8 H a ketone or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. According to the dosage form of claim 15 of the patent application, which comprises (by weight) 10-30% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5-yl) Pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and 0.1 to 10.0 respectively % hydroxypropyl methylcellulose, cerium oxide and type A crospovidone. According to the dosage form of claim 15 comprising about 20% by weight of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridine And [2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hydroxypropylmethyl Cellulose, about 1% cerium oxide and about 4% type A crospovidone. A dosage form according to claim 15 wherein the dosage form comprises from about 10 to 100 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [ 2,3-d]pyrimidin-7(8 H )-one or a pharmaceutically acceptable salt thereof. A dosage form according to claim 15 wherein the dosage form comprises about 20 mg, 30 mg, 55 mg or 90 mg of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5-yl) Pyrido[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof. The dosage form according to any one of claims 15 to 19, wherein the dosage form is a tablet. The dosage form according to any one of claims 15 to 20, wherein the dosage form is a film ingot. A compressed solid dosage form comprising A) an active agent comprising an effective amount of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridinium [2, 3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof, and B) at least one pharmaceutically acceptable additive, wherein the active agent is present in an amount greater than the total weight of the compressed solid dosage form 10% by weight. According to the dosage form of claim 22, which comprises (by weight) 10-30% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5-yl) pyrido [2,3-d] pyrimidin -7 (8 H) - one acceptable salts or pharmaceutically; 55-65% microcrystalline cellulose; 5-15% pregelatinized starch and were from 0.1 to 10.0 % hydroxypropyl methylcellulose, cerium oxide and type A crospovidone. According to the dosage form of claim 22, it comprises (by weight) about 20% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazol-5-yl)pyridine And [2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hydroxypropylmethyl Cellulose, about 1% cerium oxide and about 4% type A crospovidone. The dosage form according to any one of claims 22 to 24, wherein the active agent comprises at least 95% 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5 Pyridyl[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof. The dosage form according to any one of claims 22 to 24, wherein the active agent comprises at least 97% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5 Pyridyl[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof. The dosage form according to any one of claims 22 to 24, wherein the active agent comprises at least 99% of 2-amino-8-ethyl-4-methyl-6-(1 H -pyrazole-5 Pyridyl[2,3-d]pyrimidin-7( 8H )-one or a pharmaceutically acceptable salt thereof. A method of treating cancer in a subject in need thereof, comprising administering to the individual a pharmaceutical formulation according to any one of claims 1 to 14. A method of treating cancer in an individual in need thereof, comprising administering to the individual a dosage form according to any one of claims 15 to 27. The method of claim 28 or 29, wherein the cancer is a solid tumor. The method of claim 28 or 29, wherein the cancer is a lymphoma. According to the method of claim 31, wherein the lymphoma is painless non-Hodgkin's lymphoma, quilt cell lymphoma (MCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL) Or diffuse large B-cell lymphoma (DLBCL). The method of claim 28 or 29, wherein the cancer is breast cancer, non-small cell lung cancer, melanoma, colorectal cancer, glioblastoma, or glioma. The method of claim 28 or 29, wherein the cancer is a blood cancer. The method according to claim 34, wherein the blood cancer is acute myeloid leukemia (AML), chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia (CLL). The method of any one of claims 28 to 35, wherein the treatment comprises Invest in other anticancer agents. According to the method of claim 36, wherein the anticancer agent is bentamustine, rituximab, erlotinib, letrozole or temozolomide ( Temozolomide).