New combination drug regimen for chemotherapy-refractory cancer

Abstract

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a therapeutically effective amount of paclitaxel and a low dose of gemcitabine, and use thereof in treating cancer in a subject, as well as a kit comprising the above combination.

Description

[0001] This application claims priority to Chinese patent application CN201811195239.3, filed on October 12, 2018. The entire contents of this application are incorporated herein by reference. Technical Field

[0002] The present invention relates to a pharmaceutical composition for treating chemotherapy-refractory cancer. Technical Background

[0003] Cancer remains a leading cause of death worldwide. Despite advances in treating certain types of cancer through surgery, radiation therapy, and chemotherapy, cancer is still incurable. Even when effective treatments are available for specific cancers, the side effects of such treatments can be severe and result in a reduced quality of life for the patient, and the cancer often becomes refractory to chemotherapy.

[0004] Most conventional chemotherapy drugs have significant toxicity and limited efficacy, especially for patients with advanced solid tumors. Conventional chemotherapy drugs can also damage normal human cells while killing cancer cells. This chemotherapeutic index (i.e., a measure of the therapeutic ability to distinguish cancer cells from normal cells) may be very low. Usually, the dose of chemotherapy drugs that effectively kill cancer cells will also kill normal cells, especially those normal cells (such as epithelial cells and bone marrow cells) that undergo frequent cell division. When normal cells are affected by the treatment, side effects usually include alopecia, hematopoietic suppression and nausea. Depending on the patient's overall health, these adverse events may hinder the further use of chemotherapy, or at least cause cancer patients to suffer extremely unpleasant side effects. Even if cancer patients who respond to chemotherapy with tumor regression often relapse soon after the initial response to chemotherapy. This recurrent cancer is usually highly resistant or refractory to chemotherapy.

[0005] Cancer stem cells (CSCs, also known as, for example, tumor initiating cells, cancer stem-like cells, stem-like cancer cells, highly tumorigenic cells, or hypermalignant cells) or highly stem cancer cells (cancer cells with high stemness) cause rapid tumor recurrence and resistance to further traditional chemotherapy. Increasing evidence shows that CSCs exist as a unique population in almost all tumor types, generating most of the differentiated cells that form the tumor mass and the differentiated cells that phenotypically characterize the disease. CSCs have been shown to be fundamentally involved in cancer occurrence, cancer metastasis, cancer recurrence, and cancer relapse (e.g., Figure 1 CSCs are inherently resistant to conventional chemotherapy, meaning that they are spared by conventional treatments that kill most normal tumor cells (e.g. Figure 2). Therefore, the existence of CSCs has multiple implications for cancer and its treatment. This includes, for example, identifying diseases, selecting drug targets, preventing cancer metastasis and recurrence, treating cancers that are refractory to chemotherapy and / or radiotherapy, treating cancers that are intrinsically resistant to chemotherapy or radiotherapy, and developing new anticancer strategies.

[0006] STAT3 is a powerful transcriptional regulator that targets a large number of genes involved in cell cycle, cell survival, tumorigenesis, tumor invasion and metastasis, including but not limited to Bcl-xl, c-Myc, cyclin D1, IDO1, PDL1, VEGF, MMP-2 and survivin (e.g. Figure 3 ). The collective expression of these STAT3-responsive genes maintains the stemness of cancer stem cells (CSCs) required for their survival and reproduction. Therefore, STAT3 has become a promising target for inhibiting the survival of cancer stem cells and controlling metastasis. Anti-STAT3 agents with anti-CSCs activity bring great hope to cancer patients (Boman, BM, et al. J. Clin. Oncol. 2008. 26 (17): p. 2795-99).

[0007] According to PCT patent WO2009 / 036059, the compound of formula (I)

[0008]

[0009] It is an inhibitor of CSCs growth and survival. The compound of formula (I) has a cell IC of ~0.25 μM. 50 Inhibit Stat3 pathway activity. The compound of formula (I) can be synthesized according to PCT patent WO2009 / 036059, for example, Example 13. In some embodiments, the compound of formula (I) is used in a method for treating cancer. According to PCT patent WO2014 / 169078, Example 6, the compound of formula (I) is selected to enter clinical trials for the treatment of patients with advanced cancer. According to PCT patent WO2009 / 036101, the two-drug combination of the compound of formula (I) and another second anticancer agent has a potential synergistic anticancer effect. Based on the development potential of new anticancer strategies for inhibiting the CSCs pathway in preventing cancer metastasis and recurrence, treating cancers that are refractory to chemotherapy and / or radiotherapy, and treating cancers that are inherently resistant to chemotherapy or radiotherapy, there is an urgent need to further develop new, alternative, and more effective new combination drug treatment regimens based on the compound of formula (I) for specific cancer patients.

[0010] Pancreatic cancer is a common type of cancer, characterized by rapid disease progression, poor prognosis, latent early stage disease, low surgical resection rate, easy postoperative recurrence, and low chemotherapy efficacy. Currently, surgery is the only possible cure, but more than 80% of patients with metastatic pancreatic cancer have already developed to the local advanced stage or metastasis at the time of diagnosis. For the few patients who can receive surgical treatment, most will eventually develop advanced pancreatic cancer, with a 5-year survival rate of less than 5% (Hidalgo, 2010). Currently, the first-line standard chemotherapy regimens for this type of unresectable metastatic pancreatic cancer mainly include: FOLFIRINOX (5-fluorouracil (5-FU), leucovorin (LV), irinotecan and oxaliplatin) combination chemotherapy, for which the median overall survival (mOS) is 11.1 months for untreated patients (Conroy, 2011); and gemcitabine combined with albumin-bound paclitaxel combination chemotherapy, in a recently completed phase II / III trial MPACT (Von Hoff, 2013), the mOS of this combination group was 8.7 months, and the 3-year survival rate of the combination group reached an unprecedented 4% (Goldstein, 2014). For patients whose disease progresses after first-line treatment, the available treatment options are very limited. For example, for patients who have not used gemcitabine in the first line, standard-dose gemcitabine can be used in the second line; for patients who have used gemcitabine in the first line, 5-FU / LV is usually used as the second-line treatment. The mOS of pancreatic cancer patients after failure of first-line treatment is about 4 to 5 months. Recently, a study of Onivyde combined with 5-FU / LV treatment showed that for patients with metastatic pancreatic cancer who progressed after gemcitabine-based first-line treatment, the mOS of this combined treatment regimen increased to 6.1 months (Chen, 2015). At present, researchers are still working hard and urgently need to develop new treatment options to improve the survival of patients with metastatic pancreatic cancer, especially those with metastatic pancreatic cancer after failure of first-line treatment.

[0011] Brief description of the invention

[0012] Disclosed herein is a novel pharmaceutical composition for use in treating chemotherapy-refractory cancers, the composition comprising a therapeutically effective amount of a compound of formula (I)

[0013]

[0014] or a pharmaceutically acceptable salt or solvate thereof, a low dose of gemcitabine or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of paclitaxel or a pharmaceutically acceptable salt or solvate thereof.

[0015] The present invention unexpectedly discovered that a treatment regimen of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, combined with a low dose of gemcitabine or a pharmaceutically acceptable salt or solvate thereof, and paclitaxel or a pharmaceutically acceptable salt or solvate thereof, produces anti-tumor activity and a durable response in patients with metastatic pancreatic cancer who have previously failed treatment.

[0016] In some embodiments, disclosed herein is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a low dose of gemcitabine or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of paclitaxel or a pharmaceutically acceptable salt or solvate thereof.

[0017] The compound of formula (I), low-dose gemcitabine, and paclitaxel can be administered to the patient simultaneously, concurrently, separately, and / or sequentially. Therefore, in certain embodiments, the compound of formula (I) and low-dose gemcitabine are administered to the patient simultaneously, concurrently, separately, and / or sequentially. In certain embodiments, the compound of formula (I) and paclitaxel are administered to the patient simultaneously, concurrently, separately, and / or sequentially.

[0018] The compound of formula (I) may be administered daily in a single or divided dose. The therapeutically effective amount of the compound of formula (I) may be administered daily in a dose of about 80-960 mg, about 80-480 mg. The compound of formula (I) may be administered twice daily in a dose of about 80 mg, about 160 mg, or about 240 mg. Paclitaxel may be administered weekly. Paclitaxel may be administered at 10-100 mg / m 2 Administer weekly. Wherein the therapeutically effective amount of paclitaxel is about 80 mg / m 2 , about 60mg / m 2 , about 40 mg / m 2 The low dose of gemcitabine can be administered weekly. The low dose of gemcitabine can be 100-800 mg / m 2 Weekly administration, wherein the low dose of gemcitabine may be less than 50% of the recommended effective dose. The low dose of gemcitabine is administered at about 600 mg / m 2 , about 550mg / m 2 , about 500mg / m 2 , about 450mg / m 2 , about 400mg / m 2 , about 300mg / m 2 , about 200 mg / m 2 or about 100 mg / m 2Administer by weekly infusion.

[0019] In some embodiments, the cancer is advanced, metastatic, unresectable, refractory, or recurrent pancreatic cancer. In some embodiments, the cancer is pancreatic cancer that is refractory to chemotherapy. In some embodiments, the cancer is pancreatic cancer that has progressed after at least one prior treatment. In some embodiments, the cancer is pancreatic cancer that has progressed after at least one prior chemotherapy. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma. In some embodiments, the pancreatic cancer is metastatic pancreatic cancer that has progressed after at least one prior treatment.

[0020] In some embodiments, disclosed herein is a method for resensitizing a subject to at least one therapeutic regimen, comprising administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I) selected from a compound having formula (I):

[0021]

[0022] or pharmaceutically acceptable salts and solvates thereof.

[0023] In some embodiments, disclosed herein are methods of resensitizing a subject to at least one therapeutic regimen, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0024] In some embodiments, disclosed herein are methods of resensitizing a subject to at least one prior treatment regimen, comprising administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I) selected from a compound having formula (I):

[0025]

[0026] or pharmaceutically acceptable salts and solvates thereof.

[0027] In some embodiments, disclosed herein is a pharmaceutical composition for use in a method of resensitizing a subject to at least one prior treatment regimen, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0028] In some embodiments, disclosed herein is a method for resensitizing a subject to at least one prior treatment regimen, comprising administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I) selected from a compound having formula (I):

[0029]

[0030] or pharmaceutically acceptable salts and solvates thereof.

[0031] In some embodiments, the at least one prior treatment regimen is selected from a chemotherapy regimen. In some embodiments, the at least one prior treatment regimen is selected from a gemcitabine regimen. In some embodiments, the at least one prior treatment regimen is selected from a gemcitabine-based monotherapy or combination chemotherapy regimen. In some embodiments, the at least one prior treatment regimen is selected from a paclitaxel chemotherapy regimen. In some embodiments, the at least one prior treatment regimen is selected from FOLFIRINOX, mFOLFIRINOX or Gem-Abraxane (gemcitabine-albumin paclitaxel) regimen. In some embodiments, the at least one prior treatment regimen is selected from commonly used cancer treatment regimens such as surgery, radiotherapy, targeted therapy, and immunotherapy.

[0032] In some embodiments, disclosed herein is a method of resensitizing a subject to a chemotherapeutic regimen, comprising administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I) selected from a compound having formula (I):

[0033]

[0034] or a pharmaceutically acceptable salt and solvate thereof, a low dose of gemcitabine, and a therapeutically effective amount of paclitaxel. In some embodiments, the subject is a pancreatic cancer patient who has previously failed treatment. In some embodiments, the subject is a metastatic pancreatic cancer patient who has previously failed treatment.

[0035] In some embodiments, disclosed herein are methods of resensitizing a subject to a chemotherapeutic regimen, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0036] In some embodiments, disclosed herein is a method for simultaneously inhibiting, reducing and / or attenuating the survival and / or proliferation of cancer stem cells and heterogeneous cancer cells selected from a pancreatic cancer subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a low dose of gemcitabine and a therapeutically effective amount of paclitaxel.

[0037] In some embodiments, a kit is disclosed, comprising at least one compound selected from a compound of formula (I), a prodrug, a derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates. In some embodiments, a kit is disclosed, comprising at least one gemcitabine selected from gemcitabine, a prodrug, a derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates. In some embodiments, a kit is disclosed, comprising at least one paclitaxel selected from paclitaxel, a prodrug, a derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates. In some embodiments, a kit is disclosed, comprising at least one compound selected from a compound of formula (I), a prodrug, a derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates, at least one gemcitabine selected from gemcitabine, a prodrug, a derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates, and at least one paclitaxel selected from paclitaxel, a prodrug, a derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates.

[0038] Aspects and embodiments disclosed herein are set forth in or will become apparent from the following detailed description of the invention.It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to be limiting of the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Heterogeneous cancer cells are shown to form from cancer stem cells.

[0041] Figure 2 Cancer stem cell specific therapy and conventional cancer therapy are shown.

[0042] Figure 3 The STAT3 pathway in cancer is shown.

[0043] Figure 4 According to certain embodiments disclosed herein, exemplary effects of 2-acetylnaphtho[2,3-b]furan-4,9-dione, gemcitabine (Gemzer), and combination therapy of 2-acetylnaphtho[2,3-b]furan-4,9-dione and gemcitabine on tumor volume in a xenograft tumor mouse model are shown.

[0044] Figure 5 The therapeutic effects of 2-acetylnaphtho[2,3-b]furan-4,9-dione, paclitaxel, and 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with paclitaxel on the protein levels of cancer stemness markers p-Stat3 and β-catenin in pancreatic cancer stem cells (Panc-1) in vitro are shown. DETAILED DESCRIPTION OF THE INVENTION

[0046] The following are definitions of terms used in this specification. The initial definitions provided for a group or term herein apply to the group or term throughout this specification, either alone or as part of other groups, unless otherwise indicated.

[0047] When the term "approximately" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of these numerical values. In general, the term "approximately" is used herein to modify the value with a variance of 20%, 10%, 5% or 1% above and below the set value. In some embodiments, the term "approximately" is used to modify the value with a variance of 10% above and below the set value. In some embodiments, the term "approximately" is used to modify the value with a variance of 5% above and below the set value. In some embodiments, the term "approximately" is used to modify the value with a variance of 1% above and below the set value. When the term "less than" is used in conjunction with a numerical range, it is intended to cover each optional value and sub-range that is less than the range, except for the range. For example, "less than 5 mg" is intended to include 1 mg, 2 mg, 3 mg, 4 mg. In some embodiments, such as less than 600 mg / m 2 Administration included 599 mg / m 2 Administration, 598 mg / m 2 Application, etc.

[0048] The phrase "and / or" used in the teachings and claims herein should be understood as "one or both" of the connected elements, i.e., in some cases, they are present in combination and in some other cases, they are present separately. Thus, as a non-limiting example, when used in conjunction with open language (such as "comprising"), a reference to "A and / or B" may refer to only A (optionally including other elements in addition to B) in one embodiment; only B (optionally including other elements in addition to A) in another embodiment; and both A and B (optionally including other elements) in yet another embodiment; and so on. When a range of values ​​is listed herein, it is intended to cover every value and sub-range within that range. For example, "1-5 mg" is intended to include 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 1-2 mg, 1-3 mg, 1-4 mg, 1-5 mg, 2-3 mg, 2-4 mg, 2-5 mg, 3-4 mg, 3-5 mg, and 4-5 mg.

[0049] The terms "administer," "administering," and "administration" are used herein in their broadest sense. These terms refer to any method of administering a compound or pharmaceutical composition described herein to a subject, and may include, for example, administering the compound to a subject systemically, topically, or in situ. Thus, the compounds disclosed herein produced in a subject from a composition (whether or not it includes the present compound) are encompassed by these terms. When these terms are used in conjunction with "systemic" or "systemically," they generally refer to systemic absorption or accumulation of a compound or composition in the blood, followed by distribution throughout the body.

[0050] The term "subject" generally refers to an organism to which a compound or pharmaceutical composition as described herein can be administered. The subject can be a mammal or a mammalian cell, including a human or a human cell. The term also refers to an organism, including a donor or a receptor of a cell or the cell. In various embodiments, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, mammals, and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, fish, nematodes, and insects, which will be receptors for compounds or pharmaceutical compositions as described herein. In some cases, the terms "subject" and "patient" are used interchangeably herein with respect to human subjects.

[0051] As used herein, the term "therapeutically effective amount" refers to its meaning as generally accepted in the art. The term generally refers to the amount of a compound or composition that will elicit a desired biological or medical response in a cell, tissue, system, animal or human. For example, if a given clinical treatment is considered effective when a measurable parameter associated with a disease or disorder is reduced by at least about 25%, then the therapeutically effective amount of a drug for treating the disease or disorder refers to the amount necessary to reduce the parameter by at least about 25%.

[0052] In the context of treating cancer, a "therapeutically effective amount" refers to an amount that is capable of causing one or more of the following effects: (1) inhibiting cancer or tumor growth to some extent, including slowing growth or completely stopping growth; (2) reducing the number of cancer or tumor cells; (3) reducing tumor size; (4) inhibiting (i.e., reducing, slowing or completely stopping) cancer or tumor cell infiltration into peripheral organs; (5) inhibiting (i.e., reducing, slowing or completely stopping) metastasis; (6) enhancing anti-tumor immune responses, which may but need not result in tumor regression or rejection; or (7) alleviating to some extent one or more measurable symptoms associated with cancer or tumors. In some embodiments, a "therapeutically effective amount" refers to an amount that is administered systemically, topically or in situ (e.g., the amount of a compound produced in situ in a subject). A therapeutically effective amount can vary depending on factors such as the individual's disease state, age, sex, and weight, and the ability of one or more anticancer agents to elicit a desired response in the individual. A "therapeutically effective amount" is also an amount in which any toxic or deleterious effects are outweighed by the therapeutically beneficial effects.

[0053] As used herein, terms such as "treating," "treatment," "to treat," "alleviating," or "to alleviate" refer to (1) curing, slowing, alleviating, and / or halting the progression of a diagnosed pathological condition or disorder, and (2) prophylactic or preventative measures that prevent or slow the progression of a target pathological condition or disorder ("prevention" or "to prevent"). Those in need of treatment therefore include those already suffering from the disorder; those susceptible to developing the disorder; and those in need of prevention of the disorder.

[0054] The terms "treating cancer", "cancer treatment" or their synonyms refer to reducing, decreasing, or inhibiting the replication of cancer cells; reducing, decreasing, or inhibiting the spread of cancer (formation of metastases); reducing tumor size; reducing the number of tumors (i.e., reducing tumor burden); reducing or decreasing the number of cancer cells in the body; preventing cancer recurrence after surgical removal or other anti-cancer therapy; and / or improving measurable treatment endpoints (i.e., outcomes).

[0055] As used herein, the term "standard treatment" is a term recognized in the art, and is understood to refer to a cancer treatment method widely used in the clinic, generally referring to chemotherapy for cancer treatment, which can be combined with surgery and / or radiotherapy. Its specific scheme can be found in websites such as those maintained by the National Cancer Institute (www.cancer.gov), the American Society for Clinical Oncology (www.asco.org), and the National Comprehensive Cancer Network (www.nccn.org). In some embodiments, the term "first-line treatment" or "first-line therapy" is a term recognized in the art, and is understood to refer to the first treatment of the disease, which is usually part of a standard treatment regimen, such as surgical treatment and subsequent chemotherapy and radiotherapy, used as the best treatment, also known as primary treatment or primary therapy. In some embodiments, the term "second-line treatment" or "second-line therapy" is a term recognized in the art, and is understood to refer to chemotherapy treatment given when the initial or primary treatment (first-line or primary therapy) is ineffective or stops working, and it can also be combined with surgery, radiotherapy and / or immunotherapy. As used herein, the term "prior treatment" may include all treatments for the disease received by the patient before receiving the treatment regimen of the present invention, including but not limited to first-line treatment, second-line treatment, third-line treatment, etc.

[0056] As used herein, the terms "synergistically," "synergistic," "synergistically," or "enhanced" refer to the interaction or combination of two or more components to produce a sum (or "additive effect") of effects greater than their individual effects.

[0057] The term "cancer" refers to the presence of cells with typical characteristics of oncogenic cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth rate and rapid proliferation rate, and specific morphological characteristics. Typically, cancer cells will be in the form of a tumor or mass, but such cells may exist alone within a subject, or may circulate in the blood as independent cells, such as leukemia or lymphoma cells.

[0058] The term "cancer" includes, for example, AIDS-related cancers, breast cancer, digestive / gastrointestinal cancers, endocrine and neuroendocrine cancers, eye cancers, genitourinary cancers, germ cell cancers, gynecological cancers, head and neck cancers, hematologic cancers, musculoskeletal cancers, nervous system cancers, respiratory / thoracic cancers, skin cancers, childhood cancers, and cancers of unknown primary site.

[0059] Exemplary AIDS-related cancers include, but are not limited to, AIDS-related lymphoma, primary central nervous system lymphoma, and Kaposi's sarcoma.

[0060] Exemplary cancers of the digestive tract / gastrointestinal tract include, but are not limited to, anal cancer, cancer of the anal region, appendix cancer, benign gastrointestinal carcinomas, bile duct cancer, carcinoid tumors, gastrointestinal cancer, colon cancer, esophageal cancer, gallbladder cancer, gastrointestinal stromal tumors (GIST), islet cell tumors, pancreatic neuroendocrine tumors, liver cancer, pancreatic cancer, rectal cancer, colorectal adenocarcinoma, small intestine cancer, gastroesophageal junction (GEJ) cancer, gastric adenocarcinoma, and gastric cancer.

[0061] Exemplary endocrine and neuroendocrine cancers include, but are not limited to, adrenocortical carcinoma, gastrointestinal carcinoid tumors, islet cell tumors, pancreatic neuroendocrine tumors, adrenocortical carcinoma, Merkel cell carcinoma, non-small cell lung neuroendocrine tumors, small cell lung neuroendocrine tumors, parathyroid carcinoma, pheochromocytoma, pituitary tumors, and thyroid cancer.

[0062] Exemplary genitourinary cancers include, but are not limited to, bladder cancer, kidney (renal cell) cancer, penile cancer, prostate cancer, renal pelvis and ureter cancer, transitional cell carcinoma, testicular cancer, urethral cancer, Wilms tumor, and other childhood kidney tumors.

[0063] Exemplary gynecological cancers include, but are not limited to, cervical cancer, endometrial cancer, uterine cancer, fallopian tube cancer, gestational trophoblastic tumor, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant potential tumor, primary peritoneal cancer, uterine sarcoma, vaginal cancer, and vulvar cancer.

[0064] Exemplary head and neck cancers include, but are not limited to, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, squamous neck cancer with occult metastatic primary, oral cancer, nasopharyngeal cancer, oral cancer, lip and oropharyngeal cancer, paranasal sinus cancer and nasal cavity cancer, parathyroid cancer, pharyngeal cancer, salivary gland cancer, laryngeal cancer, and thyroid cancer.

[0065] Exemplary hematologic cancers include, but are not limited to, leukemia, acute lymphocytic leukemia, adult, acute lymphocytic leukemia in children, acute myeloid leukemia in adults, acute myeloid leukemia in children, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, pregnancy Hodgkin lymphoma, mycosis fungoides, childhood non-Hodgkin lymphoma, adult non-Hodgkin lymphoma, pregnancy non-Hodgkin lymphoma, primary central nervous system lymphoma, Sezary syndrome, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, chronic myeloproliferative neoplasms, Langerhans cell histiocytosis, multiple myeloma / plasmacytoma, myelodysplastic syndrome, and myelodysplastic / myeloproliferative neoplasms.

[0066] Exemplary musculoskeletal cancers include, but are not limited to, bone cancer, Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma of bone, childhood rhabdomyosarcoma, chondrosarcoma, and soft tissue sarcoma.

[0067] Exemplary neurological cancers include, but are not limited to, adult brain tumors, pediatric brain tumors, astrocytomas, brain and spinal cord tumors, brain stem gliomas, glioblastoma multiforme, atypical teratoid / rhabdoid CNS tumors, embryonic CNS tumors, germ cell CNS tumors, astrocytomas, ependymomas, schwannomas, medulloblastomas, meningiomas craniopharyngiomas, neuroblastomas, pituitary tumors, pituitary adenomas, and primary central nervous system (CNS) lymphomas.

[0068] Exemplary respiratory / thoracic cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, thymoma, and thymic carcinoma.

[0069] Exemplary skin cancers include, but are not limited to, cutaneous T-cell lymphoma, Kaposi's sarcoma, melanoma, Merkel cell carcinoma, skin cancer, cutaneous T-cell lymphoma, mycosis fungoides, intraocular melanoma, and Sezary syndrome.

[0070] Cancer includes refractory forms of any of the above, or a combination of one or more of the above cancers. Some exemplary cancers are included in the general term and this term. For example, urological cancer, a general term, includes bladder cancer, prostate cancer, kidney cancer, testicular cancer, etc.; and hepatobiliary cancer, another general term, includes liver cancer (itself a general term including hepatocellular carcinoma or bile duct cancer), gallbladder cancer, biliary tract cancer or pancreatic cancer. Urinary system cancer and hepatobiliary cancer are both covered by the present invention and included in the term "cancer".

[0071] "Solid tumors" are also included in the term "cancer" of the present invention. "Solid tumors" as used herein refer to those conditions in which abnormal tumor masses (such as sarcomas, carcinomas and lymphomas) are formed, such as cancer. Examples of solid tumors include, but are not limited to, non-small cell lung cancer (NSCLC), neuroendocrine tumors, thyroid tumors, fibrous tumors, metastatic colorectal cancer (mCRC), etc. In some embodiments, solid tumor diseases are adenocarcinomas, squamous cell carcinomas, large cell carcinomas, etc.

[0072] In some embodiments, the cancer is selected from pancreatic cancer, gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, gastroesophageal adenocarcinoma, non-small cell lung cancer (NSCLC), breast cancer, triple negative breast cancer (TNBC; i.e., breast cancer that tests negative for estrogen receptor (ER-), progesterone receptor (PR-), and HER2 (receptor tyrosine protein kinase erbB-2, also known as CD340 (differentiation cluster 340), proto-oncogene Neu, ERBB2 (human); HER2-)), ovarian cancer, platinum-resistant ovarian cancer (PROC), melanoma, small cell lung cancer, and bile duct cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma.

[0073] Exemplary pancreatic neuroendocrine tumors (pancreatic NETs or PNETs) include, but are not limited to, gastrinomas (Zollinger-Ellison syndrome), glucagonomas, insulinomas, somatostatinomas, VIPomas (Verner-Morrison syndrome), watery diarrhea and hypokalemic achlorhydria (WDHA), nonfunctional islet cell tumors, and multiple endocrine neoplasia type 1 (MEN1; also known as Wermer syndrome).

[0074] Exemplary pancreatic exocrine tumors include, but are not limited to, adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), acinar cell carcinoma, intraductal papillary mucinous neoplasm (IPMN), mucinous cystadenocarcinoma, solid pseudopapillary neoplasm, and pancreatoblastoma.

[0075] In some embodiments, the cancer is unresectable, advanced, refractory, recurrent, or metastatic.

[0076] As used herein, the terms "progress," "progressed," and "progression" refer to at least one of the following: (1) a response to prior treatment (such as chemotherapy) manifested as progressive disease (PD); (2) the appearance of one or more new lesions after prior treatment (such as chemotherapy); (3) an increase in the total diameter of target lesions by at least 5% (such as 10%, 20%), with the minimum total diameter on study as reference (which includes the baseline total diameter if it is the minimum total diameter on study); and (4) clear progression of non-target lesions.

[0077] As used herein, the term "sensitizing" or its synonyms (e.g., "sensitize" or "sensitization") refers to making a subject that was tolerant, unresponsive, or slightly responsive to a previous treatment regimen (e.g., traditional chemotherapy, targeted therapy, or immunotherapy) sensitive, responsive, or more responsive to the previous treatment regimen. In certain embodiments, the term "sensitizing" or its synonyms include "re-sensitizing" or its synonyms, which refers to making a subject that was tolerant, unresponsive, or slightly responsive to a treatment regimen due to previous exposure to the treatment regimen (e.g., traditional chemotherapy, targeted therapy, or immunotherapy) sensitive, responsive, or more responsive to the treatment regimen.

[0078] As used herein, the term "at least one compound of formula (I)" refers to a compound selected from the group consisting of compounds having formula (I)

[0079]

[0080] Prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing. The term "compound of formula (I)" refers to a compound selected from the group consisting of compounds having formula (I)

[0081]

[0082] or pharmaceutically acceptable salts and solvates thereof.

[0083] In some embodiments, prodrugs and derivatives of compounds of formula (I) are Stat3 inhibitors. Non-limiting examples of prodrugs of compounds of formula (I) are phosphates and phosphodiesters of compounds No. 4011 and 4012 described in PCT patent WO2009 / 036099, and are also suitable compounds described in U.S. Patent No. 9,150,530. Non-limiting examples of derivatives of compounds of formula (I) include derivatives disclosed in PCT patent WO2009 / 036059. PCT patents WO2009 / 036099, WO2009 / 036059 and U.S. Patent No. 9,150,530 are all incorporated herein by reference for any purpose.

[0084] As shown below, a compound having formula (I)

[0085]

[0086] Also known as 2-acetylnaphtho[2,3-b]furan-4,9-dione, napabucasin, GB201 and including tautomers thereof.

[0087] Suitable methods for preparing 2-acetylnaphtho[2,3-b]furan-4,9-dione (including crystalline forms thereof and additional cancer stem cell inhibitors) are described in PCT applications WO2009 / 036099, WO2009 / 036101, WO2011 / 116398, WO2011 / 116399 and WO2014 / 169078, the entire contents of each of which may be incorporated herein by reference for any purpose.

[0088] As used herein, the term "at least one gemcitabine" refers to a compound selected from gemcitabine, a prodrug, a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. In some embodiments, the "gemcitabine" refers to a compound selected from gemcitabine, or a pharmaceutically acceptable salt and solvate thereof.

[0089] As used herein, the term "at least one paclitaxel" refers to a compound selected from paclitaxel, a prodrug, a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. The term "paclitaxel" refers to a compound selected from paclitaxel, or a pharmaceutically acceptable salt and solvate thereof. In some embodiments, the "paclitaxel" refers to a paclitaxel injection approved for production by the China Food and Drug Administration (now the State Drug Administration).

[0090] As used herein, the term "pharmaceutical composition" includes "compound of formula (I)", "paclitaxel" and "gemcitabine" which can be mixed together to form a single administration unit or can be independently used as administration units. These active ingredients can be used together, simultaneously, sequentially, continuously or separately.

[0091] The term "salt" as used herein includes acidic salts and / or basic salts formed with inorganic and / or organic acids and bases. The term "pharmaceutically acceptable salt" as used herein refers to salts that are suitable for contact with the tissues of a subject within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic reaction and / or the like, and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0092] Pharmaceutically acceptable salts can be made from inorganic or organic acids. Suitable inorganic acids, non-limiting examples, include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid. Suitable organic acids, non-limiting examples, include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid. Other non-limiting examples of suitable pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate. The organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. In some embodiments, the organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0093] Salts can be prepared in situ during the isolation and purification of the compounds disclosed herein, or separately by reacting the compounds with a suitable base or acid. Non-limiting examples of pharmaceutically acceptable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Suitable alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts and aluminum salts. Suitable pharmaceutically acceptable salts further include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, low alkyl sulfonates and aryl sulfonates, as appropriate. Non-limiting examples of suitable organic bases from which salts can be derived include primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine). In some embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts.

[0094] The term "solvate" refers to an aggregate comprising one or more molecules of the compounds disclosed herein and one or more solvent molecules or solvents. Solvates of the compounds disclosed herein include, for example, hydrates.

[0095] As used herein, the term "low-dose" refers to a therapeutically effective dose that is lower than the standard therapeutic dose, for example, the recommended standard dose of gemcitabine is 1000-1200 mg / m 2 In some embodiments, the low dose of gemcitabine is less than about 800 mg / m 2 , about 600mg / m 2 , about 550mg / m 2 , about 500mg / m 2 , about 450mg / m 2 , about 400mg / m 2 , about 350mg / m 2 , about 300mg / m 2 , about 250mg / m 2 , about 200mg / m 2 , about 150mg / m 2 or about 100 mg / m 2 Administration is weekly. In some embodiments, the low dose of gemcitabine is less than 50% or less of the recommended effective dose.

[0096] In some embodiments, gemcitabine and paclitaxel are administered on days 1, 8, and 15 of each 28-day cycle according to the regimen. In some embodiments, low doses of gemcitabine (e.g., about 600 mg / m 2 , about 550mg / m 2 , about 500mg / m 2 , about 450mg / m 2 , about 400mg / m 2 , about 350mg / m 2 , about 300mg / m 2 , about 250mg / m 2 , about 200mg / m 2 , about 150mg / m 2 or about 100 mg / m 2 In some embodiments, low doses of gemcitabine (e.g., about 600 mg / m 2 , about 550mg / m 2 , about 500mg / m 2 , about 450mg / m 2 , about 400mg / m 2 , about 350mg / m 2 , about 300mg / m 2, about 250mg / m 2 , about 200mg / m 2 , about 150mg / m 2 or about 100 mg / m 2 ) up to 7 weeks. In some embodiments, low doses of gemcitabine (e.g., about 600 mg / m ) are administered weekly for 3 of every 4 weeks. 2 , about 550mg / m 2 , about 500mg / m 2 , about 450mg / m 2 , about 400mg / m 2 , about 350mg / m 2 , about 300mg / m 2 , about 250mg / m 2 , about 200mg / m 2 , about 150mg / m 2 or about 100 mg / m 2 In some embodiments, low doses of gemcitabine 100-800 mg / m are administered weekly. 2 , preferably 100-600 mg / m 2 In some embodiments, a low dose of gemcitabine of about 800 mg / m is administered weekly. 2 , about 600mg / m 2 , about 300mg / m 2 , or about 100 mg / m 2 In some embodiments, a low dose of gemcitabine less than 600 mg / m is administered weekly. 2 In some embodiments, paclitaxel is administered at about 100 mg / m 2 , about 80mg / m 2 , about 70mg / m 2 , about 60mg / m 2 , about 50mg / m 2 , about 40 mg / m 2 , about 30mg / m 2 , about 20 mg / m 2 , or about 10 mg / m 2 In some embodiments, paclitaxel is administered at about 100 mg / m 2 , about 80mg / m 2 , about 70mg / m 2 , about 60mg / m 2 , about 50mg / m 2 , about 40 mg / m 2 , about 30mg / m 2 , about 20 mg / m 2 , or about 10 mg / m2 In some embodiments, paclitaxel is administered weekly at about 100 mg / m 3 weeks out of every 4 weeks. 2 , about 80mg / m 2 , about 70mg / m 2 , about 60mg / m 2 , about 50mg / m 2 , about 40 mg / m 2 , about 30mg / m 2 , about 20 mg / m 2 , or about 10 mg / m 2 In some embodiments, paclitaxel is administered weekly at about 100 mg / m 3 weeks out of every 4 weeks. 2 , about 80mg / m 2 , about 70mg / m 2 , about 60mg / m 2 , about 50mg / m 2 , about 40 mg / m 2 , about 30 mg / m 2 , about 20 mg / m 2 , or about 10 mg / m 2 In some embodiments, paclitaxel is administered weekly at 10-100 mg / m 2 , preferably 40-80 mg / m 2 In some embodiments, paclitaxel is administered at about 80 mg / m 2 , about 60mg / m 2 , or about 40 mg / m 2 In some embodiments, less than 80 mg / m2 of paclitaxel is administered weekly. 2 In some embodiments, paclitaxel is administered at 80 mg / m 2 Intravenous administration, starting at least 2 hours after taking the compound of formula (I) on the same day, the infusion duration is about 60 minutes. In some embodiments, gemcitabine is administered at 600 mg / m 2 The intravenous administration begins immediately after the paclitaxel infusion and lasts approximately 30-60 minutes.

[0097] In some embodiments, the compound of formula (I) is administered at a total daily dose ranging from about 80 mg to about 960 mg. In some embodiments, the compound of formula (I) is administered at a total daily dose ranging from about 80 mg to about 480 mg. In some embodiments, the compound of formula (I) is administered at a total daily dose ranging from about 160 mg to about 480 mg. In some embodiments, the total daily dose of the compound of formula (I) is administered once a day. In some embodiments, the compound of formula (I) is administered at a dose of about 480 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 400 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 320 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 240 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 160 mg per day. In some embodiments, the total amount of the compound of formula (I) is administered in divided doses more than once a day, for example twice a day (BID) or more often. In some embodiments, the compound of formula (I) is administered twice a day with a total daily dose ranging from about 80 mg to 480 mg. In some embodiments, the compound of formula (I) is administered twice a day with a total daily dose ranging from about 80 mg to 240 mg. In some embodiments, the compound of formula (I) is administered twice a day with a total daily dose of about 240 mg. In some embodiments, the compound of formula (I) is administered twice a day with a total daily dose of about 480 mg. In some embodiments, the compound of formula (I) is administered twice a day with a total daily dose of about 160 mg. In some embodiments, the compound of formula (I) is administered twice a day with a total daily dose of about 80 mg. In some embodiments, the compound of formula (I) is administered twice a day with a total daily dose of about 240 mg, 2 times a day, 8-12 hours apart. In some embodiments, the compound of formula (I) is administered at about 80 mg, 2 times a day, 8-12 hours apart.

[0098] The compounds disclosed herein may be in the form of a pharmaceutical composition (pharmaceutical preparation). In some embodiments, the pharmaceutical composition (pharmaceutical preparation) may include a compound of formula (I) and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition (pharmaceutical preparation) may include a compound of formula (I), paclitaxel, and low-dose gemcitabine. In some embodiments, the pharmaceutical composition (pharmaceutical preparation) may include a compound of formula (I) and paclitaxel. In some embodiments, the pharmaceutical composition (pharmaceutical preparation) may include a compound of formula (I) and low-dose gemcitabine.

[0099] As used herein, the term "carrier" refers to a pharmaceutically acceptable material, composition or vehicle, for example, a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which participates in or is capable of carrying or transporting the subject drug compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic, compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0100] The pharmaceutical compositions (pharmaceutical formulations) disclosed herein are suitable for oral administration and can be in the form of capsules, cachets, pills, tablets, lozenges (with flavoring agents, usually sucrose and acacia or tragacanth), powders, granules, solutions in aqueous or non-aqueous liquids, suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, water-in-oil emulsions, elixirs, syrups, lozenges (with an inert base such as gelatin, glycerin, sucrose and / or acacia) and / or mouthwashes, each containing a predetermined amount of at least one compound of formula (I).

[0101] The pharmaceutical compositions (pharmaceutical preparations) disclosed herein can be administered as pills, granules, or pastes.

[0102] Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) can be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; humectants, such as glycerol; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glycerol monostearate and polyethylene oxide-polypropylene oxide copolymers; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0103] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition, cyclodextrins (e.g., hydroxypropyl β-cyclodextrin) may be used for dissolving compounds.

[0104] Pharmaceutical compositions (pharmaceutical preparations) may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, perfuming agents and preservatives. In addition to the compounds of the present invention, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0105] The pharmaceutical composition (pharmaceutical preparation) disclosed herein can be administered to the rectum or vagina in the form of a suppository, which can be prepared by mixing one or more compounds disclosed herein with one or more suitable non-irritating excipients or carriers, wherein the excipient or carrier includes, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, which is solid at room temperature and liquid at body temperature, so it will melt in the rectum or vaginal cavity and release the active agent of the present disclosure. Pharmaceutical compositions suitable for vaginal administration may also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations containing suitable carriers known in the art.

[0106] The dosage form of pharmaceutical composition (pharmaceutical preparation) or pharmaceutical tablet disclosed herein for topical or transdermal administration may include powder, spray, ointment, paste, cream, lotion, gel, solution, patch and inhalant. Pharmaceutical composition or pharmaceutical tablet can be mixed with pharmaceutically acceptable carrier and any preservative, buffer or propellant that may be needed under aseptic conditions.

[0107] Ointments, pastes, creams and gels may contain, in addition to the pharmaceutical compositions (pharmaceutical preparations) or pharmaceutical tablets disclosed herein, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0108] In addition to pharmaceutical compositions (pharmaceutical preparations) or pharmaceutical tablets disclosed herein, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. In addition, sprays can contain conventional propellants (such as chlorofluorocarbons) and volatile unsubstituted hydrocarbons (such as butane and propane).

[0109] Ophthalmic preparations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this disclosure.

[0110] Compositions (pharmaceutical preparations) suitable for parenteral administration may comprise at least one pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension or emulsion or sterile powder (which may be reconstituted into a sterile injectable solution or dispersion before use), which may contain antioxidants, buffers, bacteriostatics, solutes that render the preparation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0111] In various embodiments, the compounds of formula (I) described herein are included in pharmaceutical compositions. The pharmaceutical compositions (pharmaceutical formulations) include a compound selected from a compound of formula (I) and a pharmaceutically acceptable salt thereof and a solvate thereof, and one or more surfactants. In some embodiments, the surfactant is sodium laurate sulfate (SLS), sodium dodecyl sulfate (SDS), or one or more polyoxyglyceryl esters. For example, the polyoxyglyceryl ester can be lauryl polyoxyglyceryl ester (sometimes referred to as Gelucire TM ) or linoleoyl polyoxyglyceryl ester (sometimes called Labrafil TM ). Examples of these compositions are shown in PCT Patent WO2014 / 169078, the entire contents of which are incorporated herein.

[0112] CSCs have at least four characteristics that are believed to cause malignant tumors: stemness, dysregulation of stemness signaling pathways, resistance to traditional cancer treatments, and a tendency to metastasize. As used herein, "stemness" generally refers to the ability of a stem cell population to self-renew and transform into cancer stem cells (Gupta PB et al., Nat. Med. 2009; 15 (9): 1010-1012). Although CSCs account for only a small percentage of the cancer cell population in a tumor (Clarke MF, Biol. Blood Marrow Transplant. 2009; 11 (2 suppl 2): ​​14-16), they can produce heterogeneous lineages of differentiated cancer cells that make up most tumors (Gupta et al. 2009). In addition, CSCs have the ability to move to different parts of the body, thereby regenerating tumors in these parts (Jordan CT et al. N. Engl. J. Med. 2006; 355 (12): 1253-1261).

[0113] The induction and maintenance of stem cell properties of CSCs is caused by the progressive dysregulation of stemness signaling pathways, including but not limited to those related to Janus kinase / signal transducer and activator of transcription (JAK / STAT), Hedgehog (Desert (DHH), Indian (IHH), and Sonic (SHH)) / PATCHED / (PTCH1) / SMOOTHENED (SMO), NOTCH / DELTA-LIKE (DLL1, DLL3, DLL4) / JAGGED (JAG1, JAG2) / CSL (CBF1 / Su(H) / Lag-1), WNT / APC / GSK3 / P-CATENIN / TCF4 and NANOG (Boman BM et al., J. Clin. Oncol. 2008; 26(17):2828-2838).

[0114] It is speculated that it is the dysregulation of stemness signaling pathways in these CSCs (Boman et al. 2008) that leads to the resistance of CSCs to chemotherapy and radiotherapy, ultimately leading to the recurrence and spread of cancer. Therefore, although chemotherapy and radiotherapy can kill most rapidly dividing cancer cells in a tumor, the dysregulation of stemness signaling pathways in CSCs can enable CSCs to avoid chemotherapy- and radiotherapy-induced cell death and explain how surviving CSCs acquire the ability to metastasize to sites in the body away from the primary tumor.

[0115] Signal transducer and activator of transcription 3 (also known as acute phase response factor, APRF, DNA binding protein APRF, ADMI03, HIES; herein referred to as STAT3) acts at the junction of multiple cytokine signal transduction pathways. For example, Figure 3 . (Catlett-Falcone, R., et al. Immunity, 1999. 10 (1): p. 105-15; Bromberg, JF, et al. Cell, 1999. 98 (3): p. 295-303; Kanda, N., et al. Oncogene, 2004. 23 (28): p. 4921-29; Schlette, EJ, et al. J Clin Oncol, 2004. 22 (9): p. 1682-88; Niu, G., et al. Oncogene, 2002. 21 (13): p. 2000-08; Xie, TX, et al. Oncogene, 2004. 23 (20): p. 3550-60) STAT3 not only regulates the control of cell cycle (CYCLIN D1, D2 and c-MYC), cell survival (BCL-XL, BCL-2, MCL-1) and angiogenesis (HIF1a, VEGF) gene expression (Furqan et al. Journal of Hematology & Oncology (2013) 6: 90), and is also a key negative regulator of tumor immune surveillance and immune cell recruitment. (Kortylewski, M., et al. Nat. Med., 2005. 11 (12): p. 1314-21; Burdelya, L., et al. J. Immunol., 2005. 174 (7): p. 3925-31; and Wang, T., et al. Nat. Med., 2004. 10 (1): p. 48-54)

[0116] In normal cells, STAT3 activation is transient and tightly regulated, for example, lasting from about 30 minutes to several hours. However, in a variety of human tumors, including all major cancers and some blood tumors, STAT3 was found to be abnormally active (Lin et al., Oncogene (2000) 19, 2496-2504; Bromberg J. Clin. Invest. (2002) 109: 1139-1142; Buettner et al., Clinical Cancer Research (2002) 8, 945-954; Frank Cancer Letters 251 (2007) 199-210; Yu et al. Nature Reviews Cancer (2004) 4, 97-105). Sustained activation of STAT3 occurs in more than half of breast cancer, lung cancer, colorectal cancer (CRC), ovarian cancer, hepatocellular carcinoma, multiple myeloma and pancreatic cancer, as well as more than 95% of head and neck cancers.

[0117] Blocking STAT3 signaling by antisense oligonucleotides, siRNA, dominant negative forms of STAT3, and / or targeted inhibition of STAT3-dependent tyrosine kinase activity leads to cancer cell growth arrest, apoptosis, and reduced metastasis frequency in vitro and / or in vivo, suggesting that the stemness of CSCs depends on the sustained activation of the STAT3 transcription factor. Pedranzini, L., et al. J Clin. Invest., 2004. 114(5): p. 619-22; Bromberg, JF, et al. Cell, 1999. 98(3): p. 295-303; Darnell, JENat. Med., 2005. 11(6): p. 595-96; and Zhang, L., et al. Cancer Res, 2007. 67(12): p. 5859-64. Therefore, STAT3 may play a key role in the survival and self-renewal capacity of CSCs in a wide spectrum of cancers.

[0118] As described above, disclosed herein are methods for treating at least one disease associated with aberrant STAT3 pathway activity in a subject. Aberrant STAT3 pathway activity can be identified by expression of phosphorylated STAT3 ("pSTAT3") or its surrogate upstream or downstream regulators.

[0119] The STAT3 pathway can be activated in response to cytokines, such as IL-6, or by one or more tyrosine kinases, such as EGFR, JAKs, ABL, KDR, c-MET, SRC, and HER2, see, e.g., Figure 3. Downstream effectors of STAT3 include, but are not limited to, BCL-XL, c-MYC, cyclin D1, VEGF, MMP-2, and survival proteins. Same as above. The STAT3 pathway has been found to be abnormally activated in many types of cancer. Sustained activation of the STAT3 pathway can occur in more than half of breast cancer, lung cancer, hepatocellular carcinoma, multiple myeloma, and more than 95% of head and neck cancer. Blocking the STAT3 pathway in vitro and / or in vivo causes cancer cell growth arrest, apoptosis, and reduced metastasis frequency. STAT3 activation has also been confirmed in many autoimmune and inflammatory diseases. In addition, since interleukin-6 (IL-6)-mediated inflammation has been disclosed as a common pathogenic source of atherosclerosis, peripheral vascular disease, coronary artery disease, hypertension, osteoporosis, type 2 diabetes, and dementia, and gp130-JAKS-STATs has been disclosed as the main pathway for IL-6 activation, inhibiting the STAT3 pathway may also treat or prevent these diseases. (Libby, P., et al. Circulation, 2002.105(9): p.1135-43; Stephens, JW, et al. Mol. Genet. Metab., 2004.82 (2): p. 180-86; Cesari, M., et al. al.Circulation,2003.108(19):p.2317-22; Orshal,JMand RA Khalil.

[0120] In some embodiments, the at least one disorder can be selected from cancers associated with abnormal STAT3 pathway activity, such as activated pSTAT3 detected in pancreatic cancer cells (Wei et al. Oncogene (2003) 22(3):319-329; Scholz et al. Gastroenterology (2003) 125:891-905; Toyonaga et al. Cancer Lett. (2003) 10;201(1):107-16; Qiu et al. Cancer Sci. (2007) 98(7):1099-106).

[0121] In some embodiments, the at least one disorder may be selected from autoimmune diseases associated with aberrant STAT3 pathway activity and inflammatory diseases associated with aberrant STAT3 pathway activity. In some embodiments, the disease associated with aberrant STAT3 pathway activity may be selected from inflammatory bowel disease, arthritis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, asthma, allergies, and systemic lupus erythematosus.

[0122] In some embodiments, the at least one disorder may be selected from CNS diseases associated with abnormal STAT3 pathway activity. In some embodiments, CNS diseases may be selected from autoimmune demyelinating disorders, Alzheimer's disease, stroke, ischemia-reperfusion injury, and multiple sclerosis. In some embodiments, the at least one disorder is selected from diseases caused by inflammation and associated with abnormal STAT3 pathway activity. In some embodiments, diseases caused by inflammation and associated abnormal STAT3 pathway activity may be selected from peripheral vascular disease, coronary artery disease, hypertension, osteoporosis, type 2 diabetes, and dementia.

[0123] As discussed above, CSCs are a subpopulation of cancer cells (found in solid tumors or blood cancers) that have characteristics commonly associated with stem cells. These cells grow faster after chemotherapy reduces non-stem common cancer cells, which may be a mechanism that causes cancer to frequently recur after chemotherapy. In contrast to most non-tumorigenic cancer cells, CSCs are tumorigenic (tumor-forming). In human acute myeloid leukemia, the proportion of these cells is less than one in ten thousand. Bonnet, D. and J. E. Dick. Nat. Med., 1997. 3 (7): p. 730-37.

[0124] In the early days of trials, the effectiveness of cancer treatments was often measured by the number and size of tumor masses they eliminated. Because CSCs form a very small proportion of the tumor cell population and have significantly different biological characteristics than their differentiated progeny, the measurement of tumor masses may not be used to select drugs that act specifically on CSCs. In fact, CSCs are resistant to radiation and are difficult to treat with chemotherapeutic drugs and targeted drugs. Normal human stem cells are naturally resistant to chemotherapy drugs - they have a variety of pumps that allow drugs to be effluxed (for example, multidrug resistance protein pumps), higher DNA repair capabilities, and slow cell renewal rates (chemotherapeutic drugs naturally target rapidly replicating cells). CSCs are mutated copies of normal stem cells, and they may also have similar functions that allow them to survive treatment. In other words, conventional chemotherapy kills differentiated (or differentiating) cells that form the bulk of the tumor but cannot produce new tumor cells. For example, Figure 2. The CSCs population that generates new tumor cells can remain unchanged and cause disease recurrence. Moreover, after treatment with chemotherapy drugs, only chemotherapy-resistant CSCs may remain, increasing the possibility that subsequent tumors will be resistant to chemotherapy. In addition, cancer stem cells have been shown to be resistant to radiation therapy (XRT). Hambardzumyan, et al. Cancer Cell, 2006. 10(6): p.454-56; and Baumann, M., et al. Nat. Rev. Cancer, 2008. 8(7): p.545-54.

[0125] Because surviving CSCs can regenerate tumors and cause recurrence, anticancer therapies targeting CSCs hold great promise for the treatment of malignant tumors. Jones RJ et al., J Natl Cancer Inst. 2004; 96(8): 583-585. CSCs-targeted therapeutic approaches can be used to treat patients with aggressive, unresectable tumors and patients with refractory or recurrent tumors, as well as to prevent tumor metastasis and recurrence. Therefore, the development of special therapies targeting CSCs pathways is expected to prolong the survival of cancer patients and improve their quality of life, especially for those patients with cancer metastasis.

[0126] Recent studies have revealed that cancer stem cells (CSCs) can regenerate tumors (e.g. Figure 1 ). It was revealed that these cancer stem cells are functionally related to the continued malignant growth, metastasis, recurrence and resistance to cancer drugs of the tumor. Cancer stem cells and their differentiated progeny show significantly different biological characteristics. They persist as a unique, but rare population in the tumor. Conventional cancer drug screening relies on measuring the amount of tumor mass, so it is impossible to identify drugs that specifically act on stem cells. In fact, it has been revealed that cancer stem cells are resistant to standard chemotherapy and are enriched after standard chemotherapy treatment, see, for example, Figure 2. This leads to refractory cancer and cancer recurrence. CSCs have also been shown to be resistant to radiotherapy. Baumann, M., et al. Nat. Rev. Cancer, 2008. 8 (7): p. 545-54. Reported cancer types from which cancer stem cells have been isolated include pancreatic cancer, breast cancer, head cancer, neck cancer, lung cancer, ovarian cancer, colorectal cancer, prostate cancer, melanoma, multiple myeloma, Kaposi's sarcoma, Ewing's sarcoma, liver cancer, medulloblastoma, brain tumors and leukemia. STAT3 has been identified as a factor for cancer stem cell survival and self-renewal. Therefore, STAT3 inhibitors can kill cancer stem cells and / or inhibit the self-renewal of cancer stem cells. According to some embodiments, cancer stem cells refer to a micro-population of cancer stem cells with self-renewal ability and tumorigenicity. In previous studies, it has been shown that the compound of formula (I) can effectively inhibit the STAT3 pathway, thereby inhibiting the growth and survival of CSCs. In clinical trials, the compound of formula (I) can be used to treat patients with advanced cancer. Based on the previous experiments, the present invention unexpectedly discovered for the first time that the novel drug combination of the compound of formula (I), low-dose gemcitabine and paclitaxel can also effectively treat patients with advanced cancer, especially patients with metastatic pancreatic cancer after previous treatment failure. Prior to this, it has never been reported that a combined chemotherapy regimen containing low-dose gemcitabine and paclitaxel can be effectively used for the treatment of patients with advanced pancreatic cancer. Therefore, the present invention provides a new option for improving the survival of patients with advanced metastatic pancreatic cancer, especially after the failure of first-line treatment.

[0127] Disclosed herein is a method of inhibiting, reducing and / or weakening cancer stem cell survival and / or self-renewal, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. Also disclosed herein is a method of inhibiting, reducing and / or weakening cancer stem cell survival and / or self-renewal, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective amount of paclitaxel. Also disclosed herein is a method of inhibiting, reducing and / or weakening cancer stem cell survival and / or self-renewal, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine and a therapeutically effective amount of paclitaxel. In some embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0128] Disclosed herein is a method for treating at least one subject cancer refractory to conventional chemotherapy and / or targeted therapy, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. Disclosed herein is a method for treating at least one subject cancer refractory to conventional chemotherapy and / or targeted therapy, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective amount or a low dose of paclitaxel administered weekly. Disclosed herein is a method for treating at least one subject cancer refractory to conventional chemotherapy and / or targeted therapy, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine and a therapeutically effective amount or a low dose of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0129] Disclosed herein is a method for treating or preventing a subject's cancer recurrence or metastasis, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. Also disclosed herein is a method for treating or preventing a subject's cancer recurrence or metastasis, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective amount or a low dose of paclitaxel administered weekly. Also disclosed herein is a method for treating or preventing a subject's cancer recurrence or metastasis, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine and a therapeutically effective amount or a low dose of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition. In various embodiments, the subject is a pancreatic cancer patient after previous treatment failure. In various embodiments, the subject is a metastatic pancreatic cancer patient after previous treatment failure.

[0130] Disclosed herein is a method for treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. Disclosed herein is a method for treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective amount or a low dose of paclitaxel administered weekly. Disclosed herein is a method for treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine and a therapeutically effective amount or a low dose of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0131] Disclosed herein is a method for treating cancer in a subject, comprising a therapeutically effective amount of a compound of formula (I), a low dose of gemcitabine, and a therapeutically effective amount or a low dose of paclitaxel administered weekly. The compound of formula (I) is administered daily at a dose of 80-960 mg. The paclitaxel may be administered at a dose of 10-100 mg / m 2 Administer weekly. The gemcitabine may be 100-800 mg / m 2In some preferred embodiments, the compound of formula (I) is administered at a total daily dose ranging from about 80 mg to about 480 mg. In some preferred embodiments, the paclitaxel is administered at 40-80 mg / m 2 In some preferred embodiments, the gemcitabine is administered at 100-600 mg / m 2 Administration is weekly. In some embodiments, the subject is a pancreatic cancer patient after failure of previous treatment. In various embodiments, the subject is a metastatic pancreatic cancer patient after failure of previous treatment.

[0132] In some embodiments, the cancer may be advanced, metastatic, unresectable, refractory, or recurrent. In some embodiments, the cancer may be pancreatic cancer. In some embodiments, the cancer may be pancreatic cancer that has progressed after a previous treatment. In some embodiments, the pancreatic cancer may be a pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer may be a pancreatic ductal adenocarcinoma. In some embodiments, the cancer may be metastatic pancreatic cancer. In some embodiments, the cancer may be metastatic pancreatic cancer that has progressed after a previous treatment. In some embodiments, the cancer may be associated with activated pSTAT3 overexpression. In some embodiments, the cancer may be associated with nuclear β-catenin localization. Example

[0133] The following examples are provided to further illustrate the various features of the present invention. These examples also illustrate useful methods of practicing the present invention. These examples do not limit the claimed invention.

[0134] Disclosed herein are methods of administering low doses of gemcitabine, weekly doses of paclitaxel, and a compound of formula (I) to a subject in need thereof.

[0135] Example 1

[0136] The compound of formula (I), 2-acetyl naphtho[2,3-b]furan-4,9-dione, gemcitabine, and the combination of 2-acetyl naphtho[2,3-b]furan-4,9-dione and gemcitabine were studied. Specifically, vehicle control, 2-acetyl naphtho[2,3-b]furan-4,9-dione (100 mg / kg, PO, bid), gemcitabine (Gemzar, 80 mg / kg, IV, q3d), or the combination of 2-acetyl naphtho[2,3-b]furan-4,9-dione and gemcitabine were administered to immunosuppressed mice with human pancreatic cancer (Panc-1). Tumor size was assessed regularly during treatment. Each point represents the mean ± SEM of five tumors. As Figure 4As shown, although 2-acetylnaphtho[2,3-b]furan-4,9-dione or gemcitabine showed some effect in inhibiting tumor growth, the combination significantly reduced tumor growth in the mouse model.

[0137] Example 2

[0138] The effect of the compound of formula (I), 2-acetylnaphtho[2,3-b]furan-4,9-dione, on cancer stem cell markers was examined in a cancer xenograft model with and without paclitaxel.

[0139] Human cancer cells were implanted subcutaneously into the right abdomen of 5-7 week-old athymic nude mice. 3 Animals were treated with 2-acetylnaphtho[2,3-b]furan-4,9-dione (eg, 50 mg / kg (BID) by oral gavage (n=3 / group)), paclitaxel, or 2-acetylnaphtho[2,3-b]furan-4,9-dione plus paclitaxel. Tumors were harvested 24 hours after the first dose.

[0140] The collected tissues were fixed in 3.7% neutral buffered formaldehyde at 4°C overnight. Embedded in paraffin. Cut into approximately 5 microns and fixed on positively charged slides. After baking and deparaffinization, slides with tumor or control tissues were incubated in 10 mM sodium citrate (pH 6.0) for 10 minutes. After antigen retrieval, slides were labeled with primary antibodies P-STAT3 (rabbit source, CellSignaling, 1:100), β-catenin (mouse source, Santa Cruz, 1:400) at 4°C overnight, and then with Alexa Fluor fluorescent dye-conjugated secondary antibodies (1:500, Invitrogen). After sealing,

[0141] Slides with Prolong mounting medium containing DAPI (Invitrogen) were examined under a Zeiss fluorescence microscope with a 20x objective and analyzed using Zen software.

[0142] like Figure 5 As shown, paclitaxel alone resulted in enhanced staining of stem cell markers, 2-acetylnaphtho[2,3-b]furan-4,9-dione alone significantly reduced the expression of both stem cell markers p-STAT3 and β-catenin, and when 2-acetylnaphtho[2,3-b]furan-4,9-dione was combined with paclitaxel, the expression of stem cell markers was reduced even further.

[0143] Example 3

[0144] In a phase II / III extension, open-label, international, multicenter trial, the effect of the compound of formula (I), 2-acetylnaphtho[2,3-b]furan-4,9-dione, in combination with paclitaxel and low-dose gemcitabine in patients with advanced pancreatic cancer who had failed previous treatment was investigated.

[0145] In this clinical study, the antitumor activity and safety of 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with weekly paclitaxel and low-dose gemcitabine were observed in patients with advanced pancreatic cancer who had previously failed treatment. Patients had previously received at least one line of systemic therapy and failed, with radiographic disease progression. Previous treatment included gemcitabine-based single-agent or combination chemotherapy, and / or FOLFIRINOX / mFOLFIRINOX chemotherapy.

[0146] Patients were treated with 2-acetylnaphtho[2,3-b]furan-4,9-dione, 240 mg orally twice a day (total daily dose of 480 mg), combined with paclitaxel and low-dose gemcitabine in a 4-week (28-day) treatment cycle. Paclitaxel 80 mg / m was given starting on day 1 of the first treatment cycle. 2 IV, followed by gemcitabine 600 mg / m 2 IV, administered on days 1, 8, and 15 of every 28-day treatment cycle. If drug toxicity occurs, the dose can be adjusted (reduced or discontinued).

[0147] Tumor response and progression were evaluated according to RECIST 1.1 criteria. To evaluate the antitumor activity of 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with paclitaxel and low-dose gemcitabine.

[0148] Among the patients with advanced pancreatic cancer who have been enrolled, one patient had undergone third-line chemotherapy (first-line gemcitabine + S-1; second-line gemcitabine; third-line avelumab) and had disease progression before enrollment. After enrollment and treatment, the target lesions shrank by 9.1% in the first assessment (8 weeks after randomization into the trial), and the tumor response was SD (disease stability). The target lesions shrank by 41% in the second assessment (20 weeks after randomization into the trial), and the tumor response reached PR (partial response), and non-target lesions were significantly reduced. One patient had undergone first-line chemotherapy (capecitabine + S-1) and had disease progression before enrollment. After enrollment and treatment, the target lesions shrank by 25.6% in the first assessment (8 weeks after randomization into the trial), and the tumor response was SD, and non-target lesions were significantly reduced. Two patients are currently still receiving treatment.

[0149] The adverse events related to 2-acetylnaphtho[2,3-b]furan-4,9-dione observed in all patients receiving treatment were mainly gastrointestinal adverse events (such as diarrhea, constipation, nausea, vomiting, etc.). This combination drug regimen did not increase the toxic side effects of patients and had good safety.

[0150] This trial showed that 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with paclitaxel and low-dose gemcitabine had good synergy. In patients with metastatic pancreatic cancer who had failed previous treatment, 2-acetylnaphtho[2,3-b]furan-4,9-dione (240 mg BID) was combined with 80 mg / m weekly 2 IV paclitaxel and gemcitabine 600 mg / m 2 IV administration was safe, tolerated, and had good antitumor activity.

[0151] It is obvious from the detailed description that many features and advantages disclosed herein are obvious, and therefore the appended claims are intended to cover all of these features and advantages that fall within the true spirit and scope of the disclosure herein. In addition, since many modifications and changes will be easily conceived by those skilled in the art, it is not desirable to limit the disclosure herein to the precise configuration and operation shown and described accordingly, and all suitable modifications and equivalents may be resorted to as falling within the scope of the invention.

[0152] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The methods recited herein can be performed in any order that is logically possible, other than the specific order disclosed.

[0153] Introduced by reference

[0154] The present disclosure makes reference to and cites other documents such as patents, patent applications, patent disclosures, journals, books, papers, and website contents, all of which are hereby incorporated by reference in their entirety for all purposes. If any material or part thereof incorporated by reference herein conflicts with other public materials defined, declared, or clearly stated herein, only the content that does not conflict between the referenced material and the present disclosure is incorporated. In the event of a conflict, the conflict should be resolved in favor of the present disclosure as a preferred disclosure.

Claims

1. Use of a pharmaceutical composition in the preparation of a drug for treating pancreatic cancer, the composition comprising a compound of formula (I): （I）， or a pharmaceutically acceptable salt thereof, A low dose of gemcitabine or a pharmaceutically acceptable salt thereof, and A low dose of paclitaxel or a pharmaceutically acceptable salt thereof, in, The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 80-960 mg per day, and a low dose of gemcitabine or a pharmaceutically acceptable salt thereof is administered at a dose of 100-600 mg / m 2 Low-dose paclitaxel or a pharmaceutically acceptable salt thereof is administered by weekly infusion at 40-80 mg / m 2 Administered by weekly infusion, The pancreatic cancer is refractory to conventional chemotherapy and / or targeted therapy, the patient is a pancreatic cancer patient who has failed at least one previous treatment or a metastatic pancreatic cancer patient who has progressed after at least one previous treatment; wherein the at least one previous treatment includes at least one first-line treatment.

2. A compound comprising formula (I): （I）， or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pancreatic cancer in a patient in combination with a low dose of gemcitabine or a pharmaceutically acceptable salt thereof and a low dose of paclitaxel or a pharmaceutically acceptable salt thereof, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is orally administered at a dose of 80-960 mg per day, and a low dose of gemcitabine or its pharmaceutically acceptable salt is orally administered at a dose of 100-800 mg / m 2 Low doses of paclitaxel or a pharmaceutically acceptable salt thereof are administered by weekly infusion at 40-100 mg / m 2 Administered by weekly infusion, The pancreatic cancer is refractory to conventional chemotherapy and / or targeted therapy, the patient is a pancreatic cancer patient who has failed at least one previous treatment or a metastatic pancreatic cancer patient who has progressed after at least one previous treatment; wherein the at least one previous treatment includes at least one first-line treatment.

3. A compound comprising formula (I): （I）， or a pharmaceutically acceptable salt thereof in the preparation of a method for use with a low dose of gemcitabine or a pharmaceutically acceptable salt thereof and Use of low doses of paclitaxel or a pharmaceutically acceptable salt thereof in combination with a drug for making pancreatic cancer patients who have failed at least one previous treatment responsive to a chemotherapy regimen, in, The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 80-960 mg per day, and a low dose of gemcitabine or a pharmaceutically acceptable salt thereof is administered at a dose of 100-600 mg / m 2 Low-dose paclitaxel or a pharmaceutically acceptable salt thereof is administered by weekly infusion at 40-80 mg / m 2 Administered by weekly infusion; wherein the at least one prior therapy comprises at least one line of therapy.

4. The use according to any one of claims 1 to 3, wherein the pancreatic cancer is an advanced, metastatic, unresectable, refractory, or recurrent chemotherapy-resistant cancer.

5. The use according to any one of claims 1 to 3, wherein the at least one prior treatment comprises a first-line treatment, a second-line treatment, or a third-line treatment.

6. The use according to any one of claims 1 to 3, wherein the at least one prior treatment is selected from a chemotherapy regimen selected from gemcitabine-based single-agent or combination chemotherapy, FOLFIRINOX, or mFOLFIRINOX chemotherapy regimens.

7. The use according to claim 6, wherein the gemcitabine-based combination chemotherapy comprises the Gem-Abraxane chemotherapy regimen.

8. The use according to claim 6, wherein the FOLFIRINOX is a combination chemotherapy regimen whose active ingredients are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan and oxaliplatin.

9. The use according to any one of claims 1 to 3, wherein the compound of formula (I), low-dose gemcitabine, and low-dose paclitaxel can be administered to the patient simultaneously, separately, and / or sequentially.

10. The use according to any one of claims 1 to 3, wherein the gemcitabine is administered as a weekly infusion for 3 weeks out of every 4 weeks.

11. The use according to any one of claims 1 to 3, wherein the gemcitabine is administered on days 1, 8 and 15 of each 28-day cycle.

12. The use according to any one of claims 1 to 3, wherein the paclitaxel is administered as a weekly infusion for 3 weeks out of every 4 weeks.

13. The use according to any one of claims 1 to 3, wherein the paclitaxel is administered on days 1, 8 and 15 of each 28-day cycle.

14. The use according to claim 9, wherein the compound of formula (I) is administered in divided doses.

15. The use according to claim 9, wherein the compound of formula (I) is administered at a dose of about 240 mg twice daily.

16. The use according to claim 9, wherein gemcitabine is administered at about 600 mg / m 2 , about 550mg / m 2 , about 500mg / m 2 , about 450mg / m 2 , about 400mg / m 2 , about 300mg / m 2 , about 200 mg / m 2 or about 100 mg / m 2 The infusion was administered weekly for 3 out of every 4 weeks.

17. The use according to claim 9, wherein paclitaxel is administered at about 80 mg / m 2 , about 70 mg / m 2 , about 60 mg / m 2 , about 50 mg / m 2 , or about 40 mg / m 2 Administer by weekly infusion.

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