Tablets containing mesylate of thienopyrimidine derivative, preparation method therefor, and use thereof

Abstract

Provided are tablets containing the mesylate of a thienopyrimidine derivative, a preparation method therefor, and use thereof. The preparation of the tablets comprises wet granulation and dry granulation, wherein components for the wet granulation include: 350-355 parts by weight of the mesylate of the thienopyrimidine derivative, 85-90 parts by weight of filler 1, 165-170 parts by weight of filler 2, 15-20 parts by weight of disintegrant 1, 15-20 parts by weight of a binder,150-155 parts by weight of filler 3, 40-45 parts by weight of disintegrant 2, and 4-5 parts by weight of a lubricant. Provided is use of the tablets and the preparation method therefor in the preparation of a drug for treating diseases caused by abnormal cell proliferation caused by EGFR overexpression.

Description

A tablet containing thiophene pyrimidine derivative mesylate, its preparation method and application Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a tablet containing thiophene pyrimidine derivative methanesulfonate, its preparation method, and its application. Background Technology

[0002] Epidermal growth factor receptor (EGFR, Erbb1) is involved in the proliferation of both normal and malignant tumor cells. EGFR overexpression has been found to be associated with cancers such as lung cancer, breast cancer, head and neck cancer, and bladder cancer.

[0003] The EGFR family comprises four receptor tyrosine kinases: EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Tyrosine kinases play a role in signal transduction. They bind ligands to the receptor's ligand-binding domain extracellularly, forming active homodimers or heterodimers, leading to autophosphorylation of EGFR and activation of stopping proteins (Greulich H. Chen, PLoS Med, 2005, 2, e313; Olayioye MA, EMBO J, 2000, 19, 3159-3167). These signals promote cellular processes such as proliferation, protein synthesis, angiogenesis, cell growth, and survival.

[0004] EGFR overexpression is present in approximately 70% of cancer patients (Seymour, LK, Curr Drug Targets, 2001, 2, 117-133). EGFR tyrosine kinase has become a therapeutic target, and several drugs have been developed to inhibit kinase activity and block its signal transduction pathway as ATP competitors, such as the FDA-approved Tarceva, Irressa, and Gilotrif (all 4-amino-quinazoline inhibitors). These drugs have been widely used in patients with EGFR-overexpressing non-small cell lung cancer (NSCLC), including wild-type and active mutation patients (W. Pao, Nat. Rev. Cancer, 2010, 10, 760-774; R. Rosell, Lancet Oncol, 2012, 13, 239-246; NULin, Breast Cancer Res, 2004, 6, 204-210).

[0005] Two common active mutations were found in patients: L858R and E746-A750 deletion. Mechanistic studies suggest that the clinical activity of Tarceva and Iressa in patients with active mutations may be a result of the combined effects of the enhanced binding affinity of the inhibitor to the mutant kinase and the addiction of mutant cells to proto-oncogenes (JA. Engelman, Science, 2007, 316, 1039-1043).

[0006] However, these first- and second-generation inhibitors with a 4-amino-quinazoline core structure are not effective in approximately 50% of patients with relapsed and acquired resistance diseases such as NSCLC. Acquired resistance is caused by mutations in the T790M gate residue (LV. Sequist, Sci Transl Med, 2011, 3, 75ra26; S. Kobayashi, N Engl J Med, 2005, 352, 786-792; W. Pao, PLoS Med, 2005, 2, 373; JA. Engelman, SeminRespir Crit Care Med, 2005, 26, 314-322). This mutation (the second mutation) increases the binding affinity of ATP for EGFR tyrosine kinase and affects the thermodynamic and kinetic binding properties of these formulations (CH. Yun, Proc Natl Acad Sci USA, 2008, 105, 2070-2075; Cancer Cell, 2007, 11, 217-227; M. Azam, Nat Struct Mol Biol, 2008, 15, 1109-1118; TA. Carter, Proc Natl Acad Sci USA, 2005, 102, 11011-11016). The larger methionine side chain in the choke region prevents those drug molecules from interacting with the ATP binding pocket at clinically effective concentrations.

[0007] Second-generation covalent EGFR inhibitors, such as the FDA-approved afatinib and the clinical-tested compound HKI-272, are effective in patients with the T790M mutation. However, the use of afatinib in patients with active mutations is limited due to dose-limiting toxicity that causes inhibition of wild-type EGFR.

[0008] Pyrimidine derivatives, represented by osimertinib, are third-generation EGFR-TKIs that are effective and selective inhibitors of mutant epidermal growth factor receptor (EGFR) tyrosine kinases without affecting wild-type EGFR, thus reducing side effects.

[0009] The thiophene pyrimidine derivative mentioned in this invention, as a third-generation EGFR-TKI, also exhibits strong inhibitory activity against EGFR-19del and L858R, two EGFR-sensitive gene mutations. It also shows strong inhibitory activity against EGFR19del / T790M and EGFRL858R / T790M, two drug-resistant dual-gene mutations resulting from resistance to first- and second-generation EGFR inhibitors. Furthermore, this thiophene pyrimidine derivative demonstrates good selectivity for the aforementioned tumor mutation genes and EGFR wild-type. Therefore, this thiophene pyrimidine derivative exhibits good inhibitory activity against tumors with the aforementioned sensitive / resistant gene mutations, demonstrating a good tumor-suppressive effect; secondly, its low activity against EGFR wild-type reduces the side effects of the compound, alleviating patient suffering and improving patient compliance. Animal pharmacokinetic studies have shown that this thiophene pyrimidine derivative is orally absorbed, exhibiting varying bioavailability across different animal species and sexes, ranging from 40% to 60%. The thiophene pyrimidine derivative is distributed in tissues greater than in plasma, with the highest distribution observed in lung tissue.

[0010] Therefore, this thiophene pyrimidine derivative exhibits good tumor-suppressive activity, low side effects, and ideal pharmacokinetic performance. Based on these factors, there is an urgent need to develop stable, orally effective formulations of thiophene pyrimidine derivatives suitable for preclinical animal studies and human administration during clinical trials. Summary of the Invention

[0011] To address the shortcomings of existing technologies, this invention, as a novel thiophene pyrimidine derivative, aims to provide a tablet containing a thiophene pyrimidine derivative mesylate, its preparation method, and its application. In drug development, there is a need to develop stable, orally effective formulations of thiophene pyrimidine derivatives suitable for preclinical animal studies and human administration during clinical trials for oral medications. This invention, through research and development of thiophene pyrimidine derivatives protected by patents (US10829495B2 / CN108289895B), screens and prepares the tablet containing the thiophene pyrimidine derivative mesylate.

[0012] This invention relates to crystalline compounds of thiophene pyrimidine derivative methanesulfonate, which is being proposed for the first time.

[0013] This invention provides a tablet containing thiophene pyrimidine derivative methanesulfonate, wherein the tablet is wet-granulated, and the composition and content of the tablet include: 350-355 parts by weight of thiophene pyrimidine derivative methanesulfonate, 185-90 parts by weight of filler, 2165-170 parts by weight of filler, 115-20 parts by weight of disintegrant, and 15-20 parts by weight of binder; 3150-155 parts by weight of filler, 40-45 parts by weight of disintegrant, and 4-5 parts by weight of lubricant.

[0014] Specifically, the filler 1 is selected from one or more of lactose monohydrate, mannitol, microcrystalline cellulose 101, pregelatinized starch, etc.; preferably, it is microcrystalline cellulose 101.

[0015] Specifically, the filler 2 is selected from one or more of lactose monohydrate 200, mannitol, microcrystalline cellulose 200, pregelatinized starch, etc.; preferably, it is lactose monohydrate 200.

[0016] Specifically, the disintegrant 1 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, sodium carboxymethyl starch, etc.; preferably, it is croscarmellose sodium;

[0017] Specifically, the adhesive is selected from one or more of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose E5, and povidone K30; preferably, it is hydroxypropyl cellulose.

[0018] Specifically, the filler 3 is selected from one or more of lactose monohydrate, mannitol, microcrystalline cellulose 101, pregelatinized starch, etc.; preferably, it is microcrystalline cellulose 101.

[0019] Specifically, the disintegrant 2 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, sodium carboxymethyl starch, etc.; preferably, it is croscarmellose sodium;

[0020] Specifically, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, etc.; preferably, it is magnesium stearate.

[0021] Preferably, the tablet (wet granulation) comprises: 351.9 parts by weight of thiophene pyrimidine derivative methanesulfonate, 10189.1 parts by weight of filler 1 microcrystalline cellulose, 200168 parts by weight of filler 2 lactose monohydrate, 16.8 parts by weight of disintegrant 1 croscarmellose sodium, 16.8 parts by weight of binder hydroxypropyl cellulose; 151.2 parts by weight of filler 3 microcrystalline cellulose, 42 parts by weight of disintegrant 2 croscarmellose sodium, and 4.2 parts by weight of lubricant magnesium stearate.

[0022] Specifically, the filler 3, disintegrant 2, and lubricant are added externally.

[0023] Specifically, the tablets also include a coating.

[0024] The coating includes blue opal coating powder; the blue opal coating powder is composed of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and indigo aluminum lake.

[0025] The present invention also provides a tablet containing thiophene pyrimidine derivative methanesulfonate, wherein the tablet is dry granulated, and the composition and content of the tablet include: 350-355 parts by weight of thiophene pyrimidine derivative methanesulfonate, 1160-165 parts by weight of filler, 2170-175 parts by weight of filler, 115-20 parts by weight of disintegrant, and 4-6 parts by weight of lubricant; 3170-175 parts by weight of filler and 275-80 parts by weight of disintegrant.

[0026] Specifically, the filler 1 is selected from one or more of lactose monohydrate 316, mannitol, microcrystalline cellulose 200, pregelatinized starch, etc.; preferably, it is microcrystalline cellulose 200.

[0027] Specifically, the filler 2 is selected from one or more of lactose monohydrate 316, mannitol, microcrystalline cellulose 200, pregelatinized starch, etc.; preferably, it is lactose monohydrate 316.

[0028] Specifically, the disintegrant 1 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, sodium carboxymethyl starch, etc.; preferably, it is croscarmellose sodium;

[0029] Specifically, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, etc.; preferably, it is magnesium stearate.

[0030] Specifically, the filler 3 is selected from one or more of lactose monohydrate 316, mannitol, microcrystalline cellulose 200, pregelatinized starch, etc.; preferably, it is microcrystalline cellulose 200.

[0031] Specifically, the disintegrant 2 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, sodium carboxymethyl starch, etc.; preferably, it is croscarmellose sodium.

[0032] Preferably, the composition and content of the tablet (dry granulation) include: 351.9 parts by weight of thiophene pyrimidine derivative methanesulfonate, 200 parts by weight of filler 1 microcrystalline cellulose, 161.7 parts by weight of filler 2 lactose monohydrate, 316 parts by weight of filler 1 sodium croscarmellose, 19.2 parts by weight of disintegrant 1 sodium croscarmellose, 4.8 parts by weight of lubricant magnesium stearate; 172.8 parts by weight of filler 3 microcrystalline cellulose, and 76.8 parts by weight of disintegrant 2 sodium croscarmellose.

[0033] Specifically, the filler 3 and disintegrant 2 are added externally.

[0034] Specifically, the tablets also include a coating.

[0035] The coating includes blue opal coating powder; the blue opal coating powder is composed of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and indigo aluminum lake.

[0036] Preferably, the tablet is a tablet obtained by wet granulation.

[0037] The "tablet containing thiophene pyrimidine derivative mesylate" proposed in this invention is the first time it has been used in this invention.

[0038] The present invention also provides a method for preparing tablets containing thiophene pyrimidine derivative mesylate, the method comprising the following steps:

[0039] The tablets described above are produced by wet granulation and tableting: Weighing of added materials → sieving and mixing → initial mixing of intermediate powder → wet granulation (hand-kneading) → wet granulation (passing through a 25-30 mesh sieve) → drying (45-50℃ forced air drying) → dry granulation (passing through a 25-30 mesh sieve) → obtaining dry granules → adding fillers, lubricants, and disintegrants to the dry granules → total mixing → intermediate mixed granules → tableting; preferably, the process is as follows: Weighing of added materials → sieving and mixing → initial mixing of intermediate powder → wet granulation (hand-kneading) → wet granulation (passing through a 24 mesh sieve) → drying (50℃ forced air drying) → dry granulation (passing through a 30 mesh sieve) → obtaining dry granules → adding fillers, lubricants, and disintegrants to the dry granules → total mixing → intermediate mixed granules → tableting.

[0040] The tablets described above are produced by dry granulation and tableting: Weighing of internal materials → Sieving and mixing → Preliminary mixing of intermediate powder → Dry granulation → Addition of lubricant and disintegrant to dry granules → Total mixing → Mixing of intermediate granules → Tableting.

[0041] In this invention, the preparation method further includes coating the obtained tablets.

[0042] The present invention also provides a pharmaceutical / pharmaceutical composition comprising tablets as described above.

[0043] Furthermore, the drug / drug composition can be used alone and / or in combination with one or more drugs that regulate protein kinases involved in multiple disease states, antitumor drugs that inhibit one or more biological targets, chemotherapy drugs, radiotherapy, immunotherapy drugs, etc.

[0044] The term "combined use" includes the co-administration of the drug / pharmaceutical composition of the present invention with other biologically active ingredients (e.g., but not limited to, a second different antitumor drug) and non-pharmacological therapies (e.g., but not limited to, surgery or radiation therapy). For example, the drug / pharmaceutical composition of the present invention can be used with other pharmaceutically active compounds, preferably compounds capable of enhancing the effect of the drug / pharmaceutical composition of the present invention. The drug / pharmaceutical composition of the present invention can be administered simultaneously (as a single formulation or separate formulation) or sequentially with other drug therapies. Generally, combination therapy involves the administration of two or more drugs in a single cycle or course of therapy.

[0045] Specifically, the pharmaceutical / pharmaceutical composition described in this invention can be administered co-administered with one or more other pharmaceuticals that regulate protein kinases involved in various disease states. Examples of these kinases may include, but are not limited to, serine / threonine-specific kinases, receptor tyrosine-specific kinases, and non-receptor tyrosine-specific kinases. Serine / threonine kinases include mitosis-activated protein kinase (MAPK), meiosis-specific kinase (Aurora), RAF, and Aurora kinase. Examples of receptor kinase families include epidermal growth factor receptor (EGFR) (e.g., HER2 / neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4, Xmrk, DER, Let23); fibroblast growth factor (FGF) receptors (e.g., FGF-R1, GFF-R2 / BEK / CEK3, FGF-R3 / CEK2, FGF-R4 / TKF, KGF-R); hepatocyte growth / diffusion factor receptor (HGFR) (e.g., MET, RON, SEA, SEX); and insulin receptors. (e.g., IGFI-R); Eph (e.g., CEK5, CEK8, EBK, ECK, EEK, EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Axl (e.g., Mer / Nyk, Rse); RET; and platelet-derived growth factor receptor (PDGFR) (e.g., PDGFα-R, PDGβ-R, CSF1-R / FMS, SCF-R / C-KIT, VEGF-R / FLT, NEK / FLK1, FLT3 / FLK2 / STK-1). Non-receptor tyrosine kinase families include, but are not limited to, BCR-ABL (e.g., p43abl, ARG); BTK (e.g., ITK / EMT, TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK, and SYK.

[0046] Specifically, the drug / drug composition described in this invention can be combined with antitumor drugs (e.g., small molecules, monoclonal antibodies, antisense RNA, and fusion proteins) that inhibit one or more biological targets, such as vorinostat (Zolinza), tykerb, Gleevec, Sutent, Sprycel, Nexavar, Sorafinib, CNF2024, RG108, BMS387032, Affinitak, Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322, Obatadax, ABT737, and AEE788. Such combinations can enhance efficacy compared to the effects achieved by any single drug and can prevent or delay the emergence of drug-resistant mutants.

[0047] Specifically, the drug / pharmaceutical composition described in this invention is administered in combination with a chemotherapy drug. The chemotherapy drug is administered at various stages of the disease to shrink tumors, destroy cancer cells that remain after surgery, and cause, maintain, and / or alleviate symptoms associated with cancer or its treatment. Examples of these drugs include, but are not limited to, alkylated drugs such as mustard gas derivatives (nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimine (thiotepa, hexamethylmelamine), alkyl sulfonates / esters (busulfan), hydrazine and triazine (hexamethylmelamine, procarbazine, temozolomide, and temozolomide), nitrosoureas (carmustine, lomustine, and streptozotocin), ifosfamides and metal salts (carboplatin, cisplatin, and oxaliplatin); plant alkaloids such as podophyllotoxin (etoposide and tenisopide), taxanes (paclitaxel and docetaxel), vinca alkaloids (vincristine, vinblastine, vinorelbine, and vinorelbine), and camptothecin analogs (irinotecan and topotecan); and antitumor antibiotics such as chromomycin (actinomycin D and procamycin). Anthracyclines (doxorubicin, daunorubicin, epirubicin, mitoxantrone, penoxuridine, and demethoxydaunorubicin), and other antibiotics such as mitomycin, actinomycin D, and bleomycin; antimetabolites such as folic acid antagonists (methotrexate, pemetrexed, raltitrexed, aminopterin), pyrimidine antagonists (5-fluorouracil, fluorouracil deoxyribonucleoside, cytarabine, capecitabine, and gemcitabine), and purine antagonists (6-mercaptopurine). Inhibitors of adenosine deaminase (cladribine, fludarabine, mercaptopurine, clofarabine, thioguanine, nerabine, and pentostatin); topoisomerase inhibitors such as topoisomerase I inhibitors (irinotecan, topotecan) and topoisomerase II inhibitors (acridine, etoposide, etoposide phosphate, teniposide); monoclonal antibodies (alemumab, gemtuzumab ozogamicin, rituximab, trastuzumab, tiimomab, cetuximab, panitumumab, tosimomab, bevacizumab); and other antitumor drugs such as ribonucleotide reductase inhibitors (hydroxyurea); corticosteroid inhibitors (mitotan); enzymes (asparaginase and pegaspargase); antimicrotubule drugs (estradiol mustard); and retinoids (bexarotin, isotretinoin, retinoic acid (ATRA)).

[0048] Specifically, the drug / drug composition described in this invention is administered together with a chemotherapy drug. The chemotherapy drug serves to protect the body or minimize the side effects of chemotherapy. Examples of such drugs include, but are not limited to, Amfostine, mesna, and dexrazoxane.

[0049] In one aspect of the invention, the drug / drug composition described herein is administered in conjunction with radiotherapy. The radioactive material is typically delivered inward (to implant radioactive material near the cancer site) or outward from a machine employing proton (X-ray or gamma-ray) or particle radiation. When the combination therapy also includes radiotherapy, the radiotherapy can be administered at any suitable time, as long as the combined effect of the therapeutic drug and the radiotherapy is achieved. For example, in suitable cases, the beneficial effect can still be achieved when radiotherapy is temporarily suspended for several days or even weeks while the therapeutic drug is being administered.

[0050] Specifically, the pharmaceutical / pharmaceutical composition described in this invention can be used in combination with immunotherapeutic drugs. One form of immunotherapy is to induce an active, systemic, tumor-specific immune response in the host by administering a vaccine composition at a site distant from the tumor. Various types of vaccines have been proposed, including isolated tumor antigen vaccines and vaccines against individual genes. Another approach is to use tumor cells from the subject to be treated, or derivatives of such cells (reviewed by Schirrmacher et al. (1995) J. Cancer Res. Clin. Oncol. 121:487). In U.S. Patent 5,484,596, Hanna Jr. et al. claimed protection for a method of treating resectable cancer to prevent recurrence or metastasis, comprising surgically removing the tumor, dispersing the cells with collagenase, irradiating the cells, and immunizing the patient with at least three consecutive doses of approximately 10⁷ cells.

[0051] In one embodiment, the pharmaceutical / pharmaceutical composition of the present invention can be used to induce or inhibit apoptosis, a physiological cell death process crucial for normal development and homeostasis. Alterations in the apoptosis pathway contribute to the pathogenesis of a variety of human diseases. The tablets of the present invention, as regulators of apoptosis, can be used to treat a variety of human diseases associated with apoptosis abnormalities, including cancers (particularly, but not limited to, follicular lymphoma, cancers associated with p53 mutations, hormone-related tumors of the breast, prostate, and ovaries, and precancerous lesions such as familial adenomatous polyposis), viral infections (including, but not limited to, herpesviruses, poxviruses, Epstein-Barr virus, Sindbis virus, and adenoviruses), autoimmune diseases (including, but not limited to, lupus erythematosus, systemic lupus erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes), blood disorders (chronic anemia and aplastic anemia), and cancer pain.

[0052] The drug / drug composition described in this invention may be included in a container, package, or dispenser along with instructions for administration.

[0053] The present invention also provides the use of the tablets containing thiophene pyrimidine derivative mesylate as described above, the pharmaceutical / pharmaceutical composition as described above, or the preparation method as described above in the preparation of a medicament for treating diseases caused by abnormal cell proliferation due to overexpression of EGFR.

[0054] In the tablets, preparation methods, pharmaceutical / pharmaceutical compositions, and applications of the present invention as described above, the structural formula of the thiophene pyrimidine derivative mesylate is shown in formula (I).

[0055] And / or, the thiophene pyrimidine derivative methanesulfonate is a crystalline compound having one or more characteristics selected from the group consisting of:

[0056] 1) The crystalline compound has a basic X-ray powder diffraction pattern as shown in Figure 3;

[0057] 2) The crystalline compound has a basic XRPD peak finding report as shown in Figure 4;

[0058] 3) The crystalline compound has a basic DSC spectrum as shown in Figure 5;

[0059] 4) The crystalline compound has a TGA spectrum as shown in Figure 5;

[0060] 5) The crystalline compound has the basic characteristics shown in Figure 6. 1 HNMR spectrum;

[0061] 6) The crystalline compound has a DSC curve as shown in Figure 7 after heating to 150°C;

[0062] 7) The crystalline compound has essentially the XRPD overlay images before and after heating shown in Figure 8; and / or,

[0063] The crystalline compound is an anhydrous crystal with a single melting point and characteristic XRPD diffraction peaks; its initial melting point is around 226°C; it exhibits good physical and chemical stability within 2 weeks under high temperature (60°C) and accelerated conditions (40°C / 75% RH); and / or,

[0064] The preparation method of the crystalline compound includes the following steps: placing a thiophene pyrimidine derivative methanesulfonate sample in a glass bottle, adding an appropriate amount of solvent, sonicating to promote dissolution, filtering through a 0.45-0.5 μm filter membrane into a new sample bottle, placing the sample bottle open in a fume hood, allowing the solvent to evaporate naturally at room temperature, and obtaining the sample after a large amount of solid has precipitated is the crystalline compound; wherein, the solvent includes one or more of dichloromethane, methanol, etc.

[0065] The beneficial effects of this invention include: through the research and development of patented thiophene pyrimidine derivatives, this invention has for the first time successfully screened and prepared tablets containing thiophene pyrimidine derivative mesylate. Attached Figure Description

[0066] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0067] Figure 1 is a polarized light microscope image (×100) of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0068] Figure 2 is an XRPD diagram of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0069] Figure 3 is an XRPD diagram (with numbers) of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0070] Figure 4 is the XRPD peak finding report of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0071] Figure 5 is the DSC & TGA diagram of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0072] Figure 6 shows the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of this invention. 1 H NMR spectrum;

[0073] Figure 7 is a DSC image of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention after heating to 150°C;

[0074] Figure 8 is an XRPD overlay of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention before and after heating. Detailed Implementation

[0075] The present invention will be further described in detail below with reference to specific embodiments. Except for the contents specifically mentioned below, the processes, conditions, and experimental methods for implementing the present invention are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations.

[0076] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0077] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0078] This invention discloses a tablet containing a thiophene pyrimidine derivative mesylate, its preparation method, and its application. The tablet comprises wet granulation and dry granulation. The wet granulation method comprises: 350-355 parts by weight of the thiophene pyrimidine derivative mesylate, 185-90 parts by weight of filler, 2165-170 parts by weight of filler, 115-20 parts by weight of disintegrant, and 15-20 parts by weight of binder; the wet granulation method comprises: 3150-155 parts by weight of filler, 240-45 parts by weight of disintegrant, and 4-5 parts by weight of lubricant. This invention also discloses the application of the tablet and its preparation method in the preparation of a medicament for treating diseases caused by abnormal cell proliferation due to EGFR overexpression.

[0079] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.

[0080] Example 1: Preparation of crystalline compounds of thiophene pyrimidine derivative methanesulfonate

[0081] In this invention, three portions of thiophene pyrimidine derivative methanesulfonate sample (yellow powder), approximately 80 mg / portion, were weighed and placed in a glass bottle. An appropriate amount of the solvent corresponding to that in Table 1 was added, and the sample was sonicated to dissolve it. The solution was then filtered through a 0.45 μm filter membrane into a new sample bottle. The sample bottle was placed open in a fume hood, and the solvent was allowed to evaporate naturally at room temperature (19.6℃~23.0℃). After a large amount of solid precipitated out, the sample was characterized by XRPD.

[0082] The crystalline compounds of the thiophene pyrimidine derivative methanesulfonate prepared in this invention were analyzed using the following methods:

[0083] 1. Polarizing microscopy observation (PLM)

[0084] Take a small amount of sample, place it on a graduated glass slide, add an appropriate amount of liquid paraffin to disperse it, cover it with a coverslip, and observe the particle shape, size and crystal properties under a 10x objective lens of a microscope. Use an orthogonal polarizer to display the birefringence properties and crystal habit of the sample, and take a picture with a digital camera.

[0085] 2. Powder X-ray diffraction analysis (XRPD)

[0086] The light source was Cu K, the X-ray intensity was 40 kV / 40 mA, the scanning mode was Theta-theta, the scanning angle range was 4° to 40°, the step size was 0.05°, and the scanning speed was 0.5 seconds / step.

[0087] 3. Differential Scanning Calorimetry (DSC)

[0088] Weigh an appropriate amount of sample and place it in a non-sealed aluminum dish. In a nitrogen flow environment (50 mL / min), equilibrate the sample at 25°C, and then heat it from 25°C to 300°C at a heating rate of 10°C / min.

[0089] 4. Thermogravimetric analysis (TGA)

[0090] Weigh an appropriate amount of sample and place it in a platinum sample pan. In an environment with nitrogen flow of sample (60 mL / min) and nitrogen flow of balance (40 mL / min), heat from room temperature to 300°C at a heating rate of 10°C / min.

[0091] 5. One-dimensional proton NMR spectrum (NMR) 1 H NMR)

[0092] Weigh approximately 5 mg of sample into an NMR tube, add 0.6 mL of deuterated dimethyl sulfoxide (DMSO d6) to dissolve the sample into a clear solution, and scan the sample solution using a Bruker Advance III 400 MHz NMR spectrometer according to the general method to acquire sample data.

[0093] The experimental results show that the sample obtained in the dichloromethane and methanol system is a crystalline compound of thiophene pyrimidine derivative methanesulfonate. The experimental results are summarized in Table 1. The PLM (polarizing light microscopy), DSC, TGA, XRPD and NMR characterization results of the crystalline compound are shown in Figures 1 to 6.

[0094] The aforementioned crystalline compound exhibits significant birefringence under polarized light microscopy, displaying granular crystallites with a particle size range of 0–30 μm. X-ray powder diffraction analysis reveals multiple distinct characteristic diffraction peaks, confirming its crystalline nature. DSC & TGA curves show an initial melting point of 226.05 °C. The DSC heat flow curve shows two endothermic peaks before 150 °C, corresponding to a 1.815% weight loss on the TGA curve. 1 Based on the H NMR results, it is speculated that the endothermic peak and weight loss are caused by the volatilization of a small amount of residual acetone solvent in the sample.

[0095] After heating the above crystalline compound to 150°C using TGA, the two endothermic peaks before 150°C disappeared, indicating that the residual acetone solvent had been removed (Figure 7). Furthermore, the crystal form of the compound remained unchanged after heating (Figure 8), indicating that acetone was only a small amount of solvent adsorbed on the surface and did not enter the crystal lattice. Based on the combined results of DSC, TGA, and heating experiments, the crystalline compound is an anhydrous and solvent-free crystalline form (anhydrate).

[0096] According to salt type screening studies, the crystalline compound of the thiophene pyrimidine derivative methanesulfonate is a single anhydrous crystal with characteristic XRPD diffraction peaks; the initial melting point is around 226℃; and it exhibits good physical and chemical stability within 2 weeks under high temperature (60℃) and accelerated conditions (40℃ / 75%RH).

[0097] Table 1 Summary of experimental results using the solution evaporation method

[0098] Example 2

[0099] This invention investigates tablets containing thiophene pyrimidine derivative mesylate (both wet and dry granulation methods), with examples as follows:

[0100] 1. Wet granulation process for batch 1

[0101] 1.1 Prescription Information

[0102] 1.2. Preparation process

[0103] 1.2.1 Initial Mixing

[0104] Weigh the added materials according to the prescription, mix the materials through a sieve, and obtain the intermediate initial powder.

[0105] 1.2.2 Wet Granulation

[0106] Use 21% water as a wetting agent to prepare soft material, wet granulation: pass through a 24-mesh sieve.

[0107] 1.2.3 Drying

[0108] After granulation, the wet granules are spread evenly on a tray and dried in a 50°C forced-air drying oven for a total of 1.5 hours. The moisture content of the material at the end of the drying process is 0.99%.

[0109] 1.2.4 Dry Granulation

[0110] Granulation screen mesh size: 30 mesh

[0111] Particle size distribution:

[0112] 1.2.5 Total Mixture

[0113] According to the formulation ratio, fillers, disintegrants, such as lubricants, are added to the granules, and the mixture is then mixed to obtain intermediate mixed granules.

[0114] 1.2.6 Tableting

[0115] Die: 19.18*9.66mm capsule-shaped die, specification 300mg, tablet weight 840mg.

[0116] Disintegration phenomenon: rapid expansion and cracking, with powder and particles rapidly dissolving and falling off.

[0117] 1.2.7 Coating

[0118] The above-mentioned raw films were coated, and the coating increased the weight by 3%.

[0119] Coated sheet properties:

[0120] Disintegration phenomenon: After the coating layer breaks, the coated tablets expand and crack rapidly, and the powder and particles dissolve and fall off quickly.

[0121] 2. Batch 2 Dry Granulation Process

[0122] 2.1. Prescription Information

[0123] 2.2. Preparation process

[0124] 2.2.1 Initial Mixing

[0125] Weigh the added materials according to the prescription, and after sieving and mixing the materials, obtain the intermediate initial powder.

[0126] Intermediate initial powder flowability test:

[0127] 2.2.2 Dry Granulation

[0128] The initial mixed powder is then subjected to dry granulation (air source pressure 0.05Mpa, pressure roller pressure 1962.5N, pressure roller speed 3.0rpm, feeding speed 120rpm) and granulation (0.8mm screen aperture, 400rpm).

[0129] Particle flowability test after one granulation:

[0130] Particle size distribution after one granulation:

[0131] Particle flowability test after secondary granulation:

[0132] Particle size distribution after secondary granulation:

[0133] In the granulation process, the proportion of fine powder obtained by the secondary granulation method is relatively small, and the flowability is acceptable.

[0134] 2.2.3 Total Mixing

[0135] According to the formulation ratio, fillers and disintegrants are added to the dry granules, and the mixture is then used to obtain intermediate mixed granules.

[0136] 2.2.4 Tableting

[0137] Die: 19.18*9.66mm capsule-shaped die, specification 300mg, tablet weight 960mg.

[0138] Disintegration phenomenon: Particles and powders dissolve and fall off relatively quickly, while tablets gradually dissolve and become smaller.

[0139] 2.2.5 Coating

[0140] The above-mentioned raw films were coated, and the coating increased the weight by 3%.

[0141] Coated sheet properties:

[0142] Disintegration phenomenon: After the coating layer breaks, the particles and powder dissolve and fall off relatively quickly, and the tablets gradually dissolve and become smaller.

[0143] 3. Stability Study

[0144] Accelerated stability studies were conducted on batches 1 and 2 at 40°C and 75% RH. Two sampling methods were employed: open and unpacked (HDPE bottle + 1g desiccant). The accelerated stability studies lasted for one month. Related substances tests were performed on the accelerated stability (40°C, 75% RH) samples from both the wet granulation process (batch 1) and dry granulation process (batch 2). The results showed that the single impurity was ≤0.2% and the total impurities were ≤2.0%, meeting the requirements.

[0145] Comparing the impurities of wet granulation (batch 1) and dry granulation (batch 2), the single impurity result of wet granulation is better than that of dry granulation, and the wet granulation process is preferred.

[0146] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0147] As used in this invention, the terms "comprising" and "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0148] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0149] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1 to 5” is disclosed, the described range should be interpreted as including ranges “1 to 4”, “1 to 3”, “1 to 2”, “1 to 2 and 4 to 5”, “1 to 3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range. Moreover, the technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0150] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of this invention are included in this invention and are protected by the appended claims.

Claims

1. A tablet containing a thiophene pyrimidine derivative mesylate, characterized in that, The tablets are wet-granulated, and the composition and content of the tablets include: 350-355 parts by weight of thiophene pyrimidine derivative methanesulfonate, 185-90 parts by weight of filler, 2165-170 parts by weight of filler, 115-20 parts by weight of disintegrant, and 15-20 parts by weight of binder; 3150-155 parts by weight of filler, 240-45 parts by weight of disintegrant, and 4-5 parts by weight of lubricant.

2. The tablet as described in claim 1, characterized in that, The filler 1 is selected from one or more of lactose monohydrate, mannitol, microcrystalline cellulose 101, and pregelatinized starch; and / or, the filler 2 is selected from one or more of lactose monohydrate 200, mannitol, microcrystalline cellulose 200, and pregelatinized starch; and / or, the disintegrant 1 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, and carboxymethyl starch sodium; and / or, the binder is selected from one or more of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose E5, and povidone K30; and / or, the filler 3 is selected from one of lactose monohydrate, mannitol, microcrystalline cellulose 101, and pregelatinized starch; and / or, the disintegrant 2 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, and carboxymethyl starch sodium; and / or, the lubricant is selected from one or two of magnesium stearate and sodium stearate fumarate.

3. The tablet as described in claim 1, characterized in that, The tablets comprise the following components and contents: 351.9 parts by weight of thiophene pyrimidine derivative methanesulfonate, 10189.1 parts by weight of microcrystalline cellulose, 200168 parts by weight of lactose monohydrate, 16.8 parts by weight of croscarmellose sodium, 16.8 parts by weight of hydroxypropyl cellulose; 151.2 parts by weight of microcrystalline cellulose, 42 parts by weight of croscarmellose sodium, and 4.2 parts by weight of magnesium stearate as a lubricant.

4. The tablet as described in claim 1, characterized in that, The filler 3, disintegrant 2, and lubricant are added externally; and / or, the tablets also include a coating.

5. The tablet as described in claim 4, characterized in that, The coating includes blue opal coating powder; wherein the blue opal coating powder is composed of: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and indigo aluminum lake.

6. A tablet containing a thiophene pyrimidine derivative mesylate, characterized in that, The tablets are dry-granulated, and the composition and content of the tablets include: 350-355 parts by weight of thiophene pyrimidine derivative methanesulfonate, 1160-165 parts by weight of filler, 2170-175 parts by weight of filler, 115-20 parts by weight of disintegrant, and 4-6 parts by weight of lubricant; 3170-175 parts by weight of filler and 275-80 parts by weight of disintegrant.

7. The tablet as described in claim 6, characterized in that, The filler 1 is selected from one or more of lactose monohydrate 316, mannitol, microcrystalline cellulose 200, and pregelatinized starch; and / or, the filler 2 is selected from one or more of lactose monohydrate 316, mannitol, microcrystalline cellulose 200, and pregelatinized starch; and / or, the disintegrant 1 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, and carboxymethyl starch sodium; and / or, the lubricant is selected from one or more of magnesium stearate and sodium stearate fumarate; and / or, the filler 3 is selected from one or more of lactose monohydrate 316, mannitol, microcrystalline cellulose 200, and pregelatinized starch; and / or, the disintegrant 2 is selected from one or more of croscarmellose sodium, croscarmellose XL-10, and carboxymethyl starch sodium.

8. The tablet as claimed in claim 6, characterized in that, The tablets comprise the following components and contents: 351.9 parts by weight of thiophene pyrimidine derivative methanesulfonate, 200 parts by weight of microcrystalline cellulose, 161.7 parts by weight of microcrystalline cellulose, 316 parts by weight of lactose monohydrate, 172.8 parts by weight of croscarmellose sodium, 4.8 parts by weight of magnesium stearate; 172.8 parts by weight of microcrystalline cellulose, and 76.8 parts by weight of croscarmellose sodium.

9. The tablet as claimed in claim 6, characterized in that, The filler 3 and disintegrant 2 are added externally; and / or, the tablets also include a coating.

10. The tablet as claimed in claim 9, characterized in that, The coating includes blue opal coating powder; wherein the blue opal coating powder is composed of: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and indigo aluminum lake.

11. A method for preparing a tablet as described in claim 1, characterized in that, The preparation method includes the following steps: wet granulation and tableting: weighing of internal materials → sieving and mixing → initial mixing of intermediate powder → wet granulation → wet granulation → drying → dry granulation → obtaining dry granules → adding fillers, lubricants and disintegrants to dry granules → total mixing → intermediate mixed granules → tableting.

12. A method for preparing a tablet as described in claim 6, characterized in that, The preparation method includes the following steps: dry granulation and tableting: weighing of internal materials → sieving and mixing → initial mixing of intermediate powder → dry granulation → adding lubricant and disintegrant to granulated dry granules → total mixing → mixing of intermediate granules → tableting.

13. A drug / drug composition, characterized in that, It includes tablets as described in any one of claims 1-10.

14. The pharmaceutical / pharmaceutical composition according to claim 13, characterized in that, The drug / drug composition may be used alone and / or in combination with one or more drugs that regulate protein kinases involved in multiple disease states, antitumor drugs that inhibit one or more biological targets, chemotherapy drugs, radiotherapy, or immunotherapy drugs.

15. The use of the tablet as described in any one of claims 1-10, or the preparation method as described in claim 11 or 12, or the drug / drug composition as described in claim 13 or 14 in the preparation of a medicament for treating a disease caused by abnormal cell proliferation due to overexpression of EGFR.

16. The tablet, preparation method, pharmaceutical / pharmaceutical composition, or application according to any one of claims 1-15, characterized in that, The structural formula of the thiophene pyrimidine derivative methanesulfonate is shown in formula (I). And / or, the thiophene pyrimidine derivative methanesulfonate is a crystalline compound having one or more characteristics selected from the group consisting of: 1) The crystalline compound has a basic X-ray powder diffraction pattern as shown in Figure 3; 2) The crystalline compound has a basic XRPD peak finding report as shown in Figure 4; 3) The crystalline compound has a basic DSC spectrum as shown in Figure 5; 4) The crystalline compound has a TGA spectrum as shown in Figure 5; 5) The crystalline compound has the basic characteristics shown in Figure 6. 1 H NMR spectrum; 6) The crystalline compound has a DSC curve as shown in Figure 7 after heating to 150°C; 7) The crystalline compound has essentially the XRPD overlay images before and after heating shown in Figure 8; and / or, The crystalline compound is an anhydrous crystal with a single melting point and characteristic XRPD diffraction peaks; the initial melting point is around 226°C; and it exhibits good physical and chemical stability within 2 weeks under high temperature (60°C) and accelerated conditions (40°C / 75% RH). And / or, The preparation method of the crystalline compound includes the following steps: placing a thiophene pyrimidine derivative methanesulfonate sample in a glass bottle, adding an appropriate amount of solvent, sonicating to promote dissolution, filtering through a 0.45-0.5 μm filter membrane into a new sample bottle, placing the sample bottle open in a fume hood, allowing the solvent to evaporate naturally at room temperature, and obtaining the sample after a large amount of solid has precipitated is the crystalline compound; wherein, the solvent includes one or more of dichloromethane and methanol.

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