A pharmaceutical composition for use in treatment of chemotherapy refractory pancreatic 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 dosage of gemcitabine and use thereof in the treatment of a subject with cancer, and a kit comprising the composition.

Description

New combination therapy regimens for treating chemotherapy-resistant cancers

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

[0002] This invention relates to a pharmaceutical composition for the treatment of chemotherapy-resistant cancers. Technical Background

[0003] Currently, cancer remains a leading cause of death worldwide. Despite advances in treating certain types of cancer through surgery, radiation therapy, and chemotherapy, cancer remains incurable. Even when effective treatments are available for specific cancers, the side effects can be severe, leading to a decline in patients' quality of life, and cancers often develop into chemotherapy-resistant forms.

[0004] Most conventional chemotherapy drugs have significant toxicity and limited efficacy, especially for patients with advanced solid tumors. While killing cancer cells, conventional chemotherapy drugs also damage normal human cells. This chemotherapeutic index (i.e., a measure of a treatment's ability to distinguish between cancer cells and normal cells) can be very low. Often, the doses of chemotherapy drugs that are effective at killing cancer cells also kill normal cells, especially those that undergo frequent cell division (such as epithelial cells and bone marrow cells). When normal cells are affected by this treatment, side effects commonly include hair loss, suppression of hematopoiesis, and nausea. Depending on the patient's overall health, these adverse events may prevent further chemotherapy or at least subject the cancer patient to extremely unpleasant side effects. Even in cancer patients who respond to chemotherapy to tumor regression, the cancer often relapses soon after the initial response. This relapsed 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-like cancer cells (highly stem-like cancer cells) contribute to rapid tumor recurrence and resistance to further conventional chemotherapy. Growing evidence suggests that CSCs exist as a distinct population in almost all tumor types, generating the majority of differentiated cells that form tumor masses and phenotypically characterize disease. CSCs have been shown to be fundamentally associated with cancer development, metastasis, recurrence, and relapse (Figure 1). CSCs are inherently resistant to conventional chemotherapy, meaning they are left behind by conventional treatments that kill most common tumor cells (Figure 2). Therefore, the presence of CSCs has multiple implications for cancer and its treatment. These include, for example, disease identification, drug target selection, prevention of cancer metastasis and recurrence, treatment of cancers refractory to chemotherapy and / or radiotherapy, treatment of cancers inherently resistant to chemotherapy or radiotherapy, and development of novel anti-cancer strategies.

[0006] STAT3 is a potent 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 (Figure 3). The collective expression of these STAT3-responsive genes maintains the stemness of cancer stem cells (CSCs) necessary for their survival and proliferation. Therefore, STAT3 has become a promising target for inhibiting cancer stem cell survival and controlling metastasis. Anti-STAT3 agents with anti-CSC activity offer great hope for cancer patients (Boman, BM, et al. J. Clin. Oncol. 2008. 26(17): p. 2795-99).

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

[0008]

[0009] It is an inhibitor of CSC growth and survival. Compound (I) has a cellular IC50 concentration of ~0.25 μM. 50Inhibition of Stat3 pathway activity. Compound (I) can be synthesized according to PCT patent WO2009 / 036059, for example, Example 13. In some embodiments, compound (I) is used in methods of treating cancer. According to PCT patent WO2014 / 169078, Example 6, compound (I) was selected for clinical trials for the treatment of patients with advanced cancer. According to PCT patent WO2009 / 036101, a two-drug combination regimen of compound (I) with another second anticancer agent has potential synergistic anticancer effects. Based on the development potential of novel anticancer strategies for inhibiting CSCs pathways in preventing cancer metastasis and recurrence, treating cancers refractory to chemotherapy and / or radiotherapy, and treating cancers inherently resistant to chemotherapy or radiotherapy, there is an urgent need to further develop new, alternative, and more effective new combination therapy regimens based on compound (I) for specific cancer patients.

[0010] Pancreatic cancer is a common type of cancer, characterized by rapid disease progression, poor prognosis, insidious early-stage disease, low surgical resection rate, high recurrence rate after surgery, and low response rate to chemotherapy. Currently, surgery is the only possible cure; however, more than 80% of patients with metastatic pancreatic cancer are diagnosed at a locally advanced stage or with metastases. Even among the few patients who can undergo surgery, 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) in combination chemotherapy, with a median overall survival (mOS) of 11.1 months for treatment-naïve patients (Conroy, 2011); and gemcitabine in combination chemotherapy with albumin-bound paclitaxel, which, in a recently completed phase II / III trial MPACT (Von Hoff, 2013), had an mOS of 8.7 months in the combination therapy group, and the 3-year survival rate in the combination therapy group reached an unprecedented 4% (Goldstein, 2014). For patients whose disease progresses after first-line treatment, current treatment options are very limited. For example, patients who have not received gemcitabine as first-line therapy can be treated with standard-dose gemcitabine as second-line therapy; for patients who have received gemcitabine as first-line therapy, 5-FU / LV is usually chosen as second-line treatment. The median overall survival (mOS) for pancreatic cancer patients who have failed first-line therapy is approximately 4–5 months. Recently, a study of Onivyde combined with 5-FU / LV therapy showed that for patients with metastatic pancreatic cancer who have progressed after gemcitabine-based first-line therapy, this combination therapy improved the mOS to 6.1 months (Chen, 2015). Currently, researchers are still working hard to develop new treatment options to improve the survival of patients with metastatic pancreatic cancer, especially those who have failed first-line therapy.

[0011] Invention Summary

[0012] This article discloses the use of a novel pharmaceutical composition in the treatment of chemotherapy-resistant cancers, the composition comprising a therapeutically effective amount of a compound of formula (I).

[0013]

[0014] Or a pharmaceutically acceptable salt or solvation thereof, low doses of gemcitabine or a pharmaceutically acceptable salt or solvation thereof, and therapeutically effective amounts of paclitaxel or a pharmaceutically acceptable salt or solvation thereof.

[0015] The present invention has unexpectedly discovered that a treatment regimen of compound (I) or a pharmaceutically acceptable salt or solvation thereof, in combination with a low dose of gemcitabine or a pharmaceutically acceptable salt or solvation thereof, or with paclitaxel or a pharmaceutically acceptable salt or solvation thereof, produces antitumor activity and a durable response in patients with metastatic pancreatic cancer who have failed prior treatment.

[0016] In some embodiments, this document discloses a method of treating cancer comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof, a low dose of gemcitabine or a pharmaceutically acceptable salt or solvation thereof, or a therapeutically effective amount of paclitaxel or a pharmaceutically acceptable salt or solvation thereof.

[0017] The compound of formula (I), a low dose of gemcitabine, and paclitaxel may be administered to the patient simultaneously, concurrently, separately, and / or sequentially. Therefore, in some embodiments, the compound of formula (I) and a low dose of gemcitabine are administered to the patient simultaneously, concurrently, separately, and / or sequentially. In some 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 single or multiple doses. The therapeutically effective amount of the compound of formula (I) may be administered daily at a dose of approximately 80-960 mg, or approximately 80-480 mg. The compound of formula (I) may be administered twice daily at a dose of approximately 80 mg, approximately 160 mg, or approximately 240 mg. Paclitaxel may be administered weekly. Paclitaxel may be administered at a dose of 10-100 mg / m². 2 Administer weekly. The therapeutically effective dose of paclitaxel is approximately 80 mg / m². 2 Approximately 60 mg / m 2 Approximately 40 mg / m 2 Administered weekly via infusion. The low-dose gemcitabine can be administered weekly. The low-dose gemcitabine can be 100-800 mg / m². 2 Administered weekly, with low doses of gemcitabine less than 50% of the recommended effective dose. Low-dose gemcitabine is typically administered at approximately 600 mg / m². 2 Approximately 550 mg / m 2 Approximately 500 mg / m 2 Approximately 450 mg / m 2 Approximately 400 mg / m 2 Approximately 300 mg / m 2 Approximately 200 mg / m 2 or approximately 100 mg / m 2Administered via weekly infusion.

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

[0020] In some embodiments, this document discloses the use of a pharmaceutical composition in a method of resensitizing a subject to at least one treatment regimen, comprising administering to the subject in need: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I):

[0021]

[0022] Or its pharmaceutically acceptable salts and solvates.

[0023] In some implementations, this document discloses a method for resensitizing a subject to at least one treatment regimen, comprising administering a therapeutically effective amount of a compound of formula (I) to the subject in need.

[0024] In some embodiments, this document discloses a method for resensitizing a subject to at least one prior treatment regimen, comprising administering to the subject in need: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I):

[0025]

[0026] Or its pharmaceutically acceptable salts and solvates.

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

[0028] In some embodiments, this document discloses the use of a pharmaceutical composition in a method of resensitizing a subject to at least one prior treatment regimen, comprising administering to the subject in need: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I):

[0029]

[0030] Or its pharmaceutically acceptable salts and solvates.

[0031] In some embodiments, the at least one prior treatment regimen is selected from chemotherapy regimens. In some embodiments, the at least one prior treatment regimen is selected from gemcitabine regimens. In some embodiments, the at least one prior treatment regimen is selected from gemcitabine-based single-agent or combination chemotherapy regimens. In some embodiments, the at least one prior treatment regimen is selected from paclitaxel chemotherapy regimens. In some embodiments, the at least one prior treatment regimen is selected from FOLFIRINOX, mFOLFIRINOX, or Gem-Abraxane (gemcitabine-albumin-paclitaxel) regimens. 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 implementations, this document discloses a method for restoring sensitivity to a chemotherapy regimen in a subject, comprising administering to the subject in need: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I):

[0033]

[0034] Or pharmaceutically acceptable salts and solvates thereof, low doses of gemcitabine, and therapeutically effective amounts of paclitaxel. In some embodiments, the subject is a patient with pancreatic cancer who has failed prior treatment. In some embodiments, the subject is a patient with metastatic pancreatic cancer who has failed prior treatment.

[0035] In some implementations, this document discloses a method for resensitizing a subject to a chemotherapy regimen, which involves administering a therapeutically effective amount of a compound of formula (I) to the subject in need.

[0036] In some embodiments, the use of a pharmaceutical composition in a method of simultaneously inhibiting, reducing and / or attenuating the survival and / or proliferation of cancer stem cells and heterogeneous cancer cells selected from pancreatic cancer subjects is disclosed, the method comprising administering to a subject in need 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 compounds of formula (I), prodrugs, derivatives, any of the pharmaceutically acceptable salts of the foregoing, and any of the foregoing solvates. In some embodiments, a kit is disclosed comprising at least one gemcitabine selected from gemcitabine, prodrugs, derivatives, any of the pharmaceutically acceptable salts of the foregoing, and any of the foregoing solvates. In some embodiments, a kit is disclosed comprising at least one paclitaxel selected from paclitaxel, prodrugs, derivatives, any of the pharmaceutically acceptable salts of the foregoing, and any of the foregoing solvates; at least one gemcitabine selected from gemcitabine, prodrugs, derivatives, any of the pharmaceutically acceptable salts of the foregoing, and any of the foregoing solvates; and at least one paclitaxel selected from paclitaxel, prodrugs, derivatives, any of the pharmaceutically acceptable salts of the foregoing, and any of the foregoing solvates.

[0038] The aspects and embodiments disclosed herein are set forth in the following detailed description of the invention, or will become apparent therefrom. It should be understood that the foregoing overview and the following detailed description are exemplary and explanatory only, and are not intended to limit the claims.

[0039] Brief description of the attached diagram

[0040] Figure 1 shows the formation of heterogeneous cancer cells from cancer stem cells.

[0041] Figure 2 shows cancer stem cell-specific therapy and conventional cancer therapy.

[0042] Figure 3 shows the STAT3 pathway in cancer.

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

[0044] Figure 5 shows the therapeutic effects of 2-acetylnaphtho[2,3-b]furan-4,9-dione, paclitaxel, and 2-acetylnaphtho[2,3-b]furan-4,9-dione in combination with paclitaxel on the protein levels of the cancer stem cell markers p-Stat3 and β-catenin in vitro in pancreatic cancer stem cells (Panc-1).

[0045] Invention Details

[0046] The following are definitions of terms used in this specification. The initial definitions provided for groups or terms herein apply, individually or as part of other groups, to groups or terms throughout this specification, 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 those values. Generally, the term "approximately" is used herein to modify a value by a variance of 20%, 10%, 5%, or 1% above and below a set value. In some embodiments, the term "approximately" is used to modify a value by a variance of 10% above and below a set value. In some embodiments, the term "approximately" is used to modify a value by a variance of 5% above and below a set value. In some embodiments, the term "approximately" is used to modify a value by a variance of 1% above and below a set value. When the term "less than" is used in conjunction with a numerical range, it is intended to encompass every optional value and subrange smaller than the range, excluding the range itself. For example, "less than 5 mg" is intended to include 1 mg, 2 mg, 3 mg, and 4 mg. In some embodiments, such as less than 600 mg / m³... 2 Administration includes 599 mg / m² 2 Administered at 598 mg / m² 2 Application, etc.

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

[0049] The terms “administer” (“administering”, “administration”) are used herein in their broadest sense. These terms refer to any method of administering the compound or pharmaceutical composition described herein to a subject, and may include, for example, administering the compound to the subject systemically, locally, or in situ. Thus, compounds disclosed herein that are generated in the body of a subject from a composition (whether or not it contains this compound) are included in these terms. When these terms are used in conjunction with “systemic” or “generally”, they generally refer to the systemic absorption or accumulation of the compound or composition in the bloodstream, followed by distribution throughout the body.

[0050] The term "subject" generally refers to an organism to which the compound or pharmaceutical composition described herein may be administered. A subject may be a mammal or mammalian cell, including a human or human cell. The term also refers to an organism, including cells or donors or recipients of such cells. In various embodiments, the term "subject" refers to any animal (e.g., a 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 a recipient of the compound or pharmaceutical composition described herein. In some cases, the terms "subject" and "patient" are used interchangeably herein for the purpose of referring to human subjects.

[0051] As used herein, the term "therapeuticly effective amount" means as is commonly accepted in the art. This term generally refers to the amount of a compound or composition that will elicit a necessary biological or medical response in cells, tissues, systems, animals, or humans. 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 a therapeutically effective amount of a medicine used to treat that disease or disorder is the amount necessary to reduce that parameter by at least about 25%.

[0052] In the context of cancer treatment, a “therapeutic effective amount” is an amount capable of producing one or more of the following effects: (1) inhibiting cancer or tumor growth to a certain extent, including slowing 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) the infiltration of cancer or tumor cells into peripheral organs; (5) inhibiting (i.e. reducing, slowing or completely stopping) metastasis; (6) enhancing the antitumor immune response, which may, but is not required, lead to tumor regression or rejection; or (7) alleviating to a certain extent one or more measurable symptoms associated with cancer or tumor. In some implementations, a “therapeutic effective amount” refers to an amount administered systemically, locally or in situ (e.g., the amount of a compound produced in situ in a subject). A therapeutic effective amount can vary depending on factors such as an individual’s disease state, age, sex and weight, and the ability of one or more anticancer agents to elicit the desired response in an individual. A “therapeutic effective amount” is also the amount by which any toxic or adverse effects are exceeded by the beneficial therapeutic effect.

[0053] As used herein, terms such as “treating,” “treatment,” “to treat,” “alleviating,” or “to alleviate” refer to (1) curing, slowing, alleviating symptoms, and / or stopping the progression of a pathological condition or disorder, and (2) prophylactic or preventative measures to prevent or slow the progression of a target pathological condition or disorder (“prevention” or “to alleviate”). Therefore, those who require treatment include those who already have the disorder; those who are prone to developing the disorder; and those who need to prevent the disorder.

[0054] The terms “treatment of cancer”, “treatment of cancer”, 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 anticancer therapies; and / or improving measurable treatment endpoints (i.e. outcomes).

[0055] As used herein, the term "standard treatment" is an accepted term in the art and is understood to refer to a widely used cancer treatment method in clinical practice, typically referring to chemotherapy for cancer, which may be combined with surgery and / or radiation therapy. Specific protocols are available on websites maintained by organizations such as 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 implementations, the term "first-line treatment" or "first-line therapy" is an accepted term in the art and is understood to refer to the initial treatment of the disease, which is typically part of a standard treatment regimen, such as surgery followed by chemotherapy and radiation therapy, used as the best treatment, also known as primary treatment or primary therapy. In some implementations, the term "second-line treatment" or "second-line therapy" is an accepted term 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 has ceased to be effective, which may also be combined with surgery, radiation therapy, and / or immunotherapy. As used herein, the term "previous treatment" may include all treatments for the disease that the patient received prior to 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 “synergy,” “synergy,” “synergistically,” or “enhancement” refer to the effect (or “additive effect”) produced by the interaction or combination of two or more components that is greater than the sum of their individual effects.

[0057] The term "cancer" refers to cells that exhibit typical characteristics of cancerous cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rates, and specific morphological features. Typically, cancer cells will take the form of a tumor or mass, but such cells can exist alone within a subject or circulate as independent cells in the bloodstream, 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 / chest 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, anal region cancer, appendix cancer, benign gastrointestinal cancer, bile duct cancer, carcinoid tumor, gastrointestinal cancer, colon cancer, esophageal cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), islet cell tumor, pancreatic neuroendocrine tumor, liver cancer, pancreatic cancer, rectal cancer, colorectal adenocarcinoma, small bowel cancer, gastroesophageal junction (GEJ) cancer, gastric adenocarcinoma, and gastric cancer.

[0061] Exemplary endocrine and neuroendocrine carcinomas 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 pulmonary neuroendocrine tumors, small cell pulmonary neuroendocrine tumors, parathyroid carcinoma, pheochromocytoma, pituitary adenoma, and thyroid cancer.

[0062] Exemplary urogenital 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, nephroblastoma, and other pediatric 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, low-grade malignant potential ovarian 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, occult metastatic squamous neck cancer, oral cancer, nasopharyngeal cancer, oral cavity cancer, lip and oropharyngeal cancer, sinus cancer and nasal cavity cancer, parathyroid cancer, pharyngeal cancer, salivary gland cancer, laryngeal cancer, and thyroid cancer.

[0065] Exemplary hematologic malignancies include, but are not limited to, leukemia, acute lymphoblastic leukemia, adult and pediatric acute lymphoblastic leukemia, adult acute myeloid leukemia, pediatric acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, pediatric Hodgkin lymphoma, gestational Hodgkin lymphoma, mycosis fungoides, pediatric non-Hodgkin lymphoma, adult non-Hodgkin lymphoma, gestational non-Hodgkin lymphoma, primary central nervous system lymphoma, Sezary syndrome, cutaneous T-cell lymphoma, Waldenstrom macroglobulinemia, chronic myeloproliferative neoplasm, Langerhans cell histiocytosis, multiple myeloma / plasma cell tumor, myelodysplastic syndrome, and myelodysplastic / myeloproliferative neoplasm.

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

[0067] Exemplary neurocancers include, but are not limited to, adult brain tumors, childhood brain tumors, astrocytomas, brain and spinal cord tumors, brainstem gliomas, glioblastomas multiforme, atypical teratoid / rhabditis central nervous system tumors, embryonic central nervous system tumors, germ cell central nervous system tumors, astrocytomas, ependymomas, schwannomas, medulloblastomas, meningiomas, craniopharyngiomas, neuroblastomas, pituitary adenomas, 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 any of the foregoing refractory types, or one or more combinations of the foregoing cancers. Some example cancers are included in both the general term and this terminology. For example, urinary system cancers, a general term, include bladder cancer, prostate cancer, kidney cancer, testicular cancer, etc.; and hepatobiliary cancers, another general term, include liver cancer (which is itself a general term including hepatocellular carcinoma or bile duct cancer), gallbladder cancer, bile duct cancer, or pancreatic cancer. Both urinary system cancers and hepatobiliary cancers are covered by this invention and included in the term "cancer".

[0071] The term "solid tumor" is also included in the term "cancer" in this invention. As used herein, "solid tumor" refers to those conditions that form abnormal tumor masses (e.g., sarcomas, carcinomas, and lymphomas), such as cancer. Examples of solid tumors include, but are not limited to, non-small cell lung cancer (NSCLC), neuroendocrine tumors, thyroid adenomas, fibrous tumors, metastatic colorectal cancer (mCRC), etc. In some embodiments, the solid tumor disease is adenocarcinoma, squamous cell carcinoma, large cell carcinoma, etc.

[0072] In some implementations, 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 is negative for the following tests: estrogen receptor (ER-), progesterone receptor (PR-), and HER2 (receptor tyrosine protein kinase erbB-2, also known as CD340 (differentiation group 340), proto-oncogene Neu, ERBB2 (human); HER2-)), ovarian cancer, platinum-resistant ovarian cancer (PROC), melanoma, small cell lung cancer, and cholangiocarcinoma. In some implementations, the cancer is pancreatic cancer. In some implementations, the cancer is pancreatic ductal adenocarcinoma.

[0073] Exemplary pancreatic neuroendocrine tumors (pancreatic NETs or PNETs) include, but are not limited to, gastrinoma (Zollinger-Ellison syndrome), glucagonoma, insulinoma, somatostatinoma, VIPomas (Verner-Morrison syndrome), watery diarrhea and hypokalemic acidosis (WDHA), nonfunctional islet cell tumors, and type 1 multiple endocrine tumors (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 tumor (IPMN), mucinous cystadenocarcinoma, solid pseudopapillary tumor, and pancreatoblastoma.

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

[0076] As used herein, the term “progress” (“progressed” and “progression”) means at least one of the following: (1) a response to prior treatment (such as chemotherapy) that is disease progression (PD); (2) the appearance of one or more new lesions following prior treatment (such as chemotherapy); (3) an increase in the total diameter of target lesions by at least 5% (e.g., 10%, 20%), with reference to the minimum total in the study (which includes the baseline total if it is the minimum total in the 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 a subject who was tolerant, unresponsive, or only slightly responsive to a prior treatment regimen (e.g., conventional chemotherapy, targeted therapy, or immunotherapy) becoming sensitive, responsive, or more responsive to that prior treatment regimen. In some embodiments, the term “sensitizing” or its synonyms include “resensitization” or its synonyms, referring to a subject who was tolerant, unresponsive, or only slightly responsive to a treatment regimen due to prior exposure to that regimen (e.g., conventional chemotherapy, targeted therapy, or immunotherapy) becoming sensitive, responsive, or more responsive to that treatment regimen.

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

[0079]

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

[0081]

[0082] Or its pharmaceutically acceptable salts and solvates.

[0083] In some embodiments, the prodrug and derivative having formula (I) are Stat3 inhibitors. Non-limiting examples of prodrugs having formula (I) are phosphate esters and phosphate diesters of compounds 4011 and 4012 described in PCT patent WO2009 / 036099, and also suitable compounds described in U.S. Patent No. 9,150,530. Non-limiting examples of derivatives having formula (I) include those 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, compounds having formula (I)

[0085]

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

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

[0088] As used herein, the term "at least one gemcitabine" means a compound selected from gemcitabine, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any of the foregoing solvates. In some embodiments, "gemcitabine" means a compound selected from gemcitabine, or pharmaceutically acceptable salts and solvates thereof.

[0089] As used herein, the term "at least one paclitaxel" means a compound selected from paclitaxel, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any of the foregoing solvates. The term "paclitaxel" means a compound selected from paclitaxel, or its pharmaceutically acceptable salts and solvates. In some embodiments, "paclitaxel" refers to paclitaxel injection approved for production by the China Food and Drug Administration (now the National Medical Products Administration).

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

[0091] As used herein, the term "salt" includes acidic and / or basic salts that form with inorganic and / or organic acids and bases. The term "pharmaceutically acceptable salt" as used herein refers to salts that, within reasonable medical judgment, are suitable for contact with the tissues of a subject without undue toxicity, irritation, allergic reactions, and / or similar conditions, 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 prepared from inorganic or organic acids. Suitable inorganic acids, without limitation, include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Suitable organic acids, without limitation, include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Other suitable pharmaceutically acceptable salts, without limitation, include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid, camphor sulfonate, citrate, cyclopentane propionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glycerol phosphate, glucuronate, hemisulfate, and heptanoate. Salts, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valerates. In some embodiments, the organic acids from which the 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 individually by reacting the compounds with suitable bases or acids. Non-limiting examples of pharmaceutically acceptable base-derived salts include alkali metal salts, alkaline earth metal salts, ammonium salts, and N2 salts. + (C 1-4 Alkyl)4 salts. Suitable alkali metal or alkaline earth metal salts, in non-limiting examples, include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Further non-limiting examples of suitable pharmaceutically acceptable salts include, where appropriate, the use of non-toxic ammonium, quaternary ammonium, and amine cations formed from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Suitable organic bases for derivatizing salts, in non-limiting examples, 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 may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

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

[0095] As used herein, the term "low-dose" refers to a therapeutically effective dose below the standard therapeutic dose, such as the recommended standard dose of gemcitabine, which is 1000-1200 mg / m². 2 In some implementations, the low dose of gemcitabine is less than about 800 mg / m². 2 Approximately 600 mg / m 2 Approximately 550 mg / m 2 Approximately 500 mg / m 2 Approximately 450 mg / m 2 Approximately 400 mg / m 2 Approximately 350 mg / m 2 Approximately 300 mg / m 2 Approximately 250 mg / m 2 Approximately 200 mg / m 2 Approximately 150 mg / m 2 or approximately 100 mg / m 2 Administer weekly. In some implementations, the low dose of gemcitabine is less than 50% or less of the recommended effective dose.

[0096] In some implementations, gemcitabine and paclitaxel are administered on days 1, 8, and 15 of every 28-day cycle, according to a regimen. In some implementations, a low dose of gemcitabine (e.g., approximately 600 mg / m²) is administered weekly. 2 Approximately 550 mg / m 2 Approximately 500 mg / m 2 Approximately 450 mg / m 2 Approximately 400 mg / m 2 Approximately 350 mg / m 2 Approximately 300 mg / m 2 Approximately 250 mg / m 2 Approximately 200 mg / m 2 Approximately 150 mg / m 2 or approximately 100 mg / m 2 In some implementations, a low dose of gemcitabine (e.g., about 600 mg / m²) is administered weekly. 2 Approximately 550 mg / m 2 Approximately 500 mg / m 2 Approximately 450 mg / m 2 Approximately 400 mg / m 2 Approximately 350 mg / m 2 Approximately 300 mg / m 2Approximately 250 mg / m 2 Approximately 200 mg / m 2 Approximately 150 mg / m 2 or approximately 100 mg / m 2 Up to 7 weeks. In some implementations, a low dose of gemcitabine (e.g., about 600 mg / m²) is administered weekly for 3 weeks out of every 4 weeks. 2 Approximately 550 mg / m 2 Approximately 500 mg / m 2 Approximately 450 mg / m 2 Approximately 400 mg / m 2 Approximately 350 mg / m 2 Approximately 300 mg / m 2 Approximately 250 mg / m 2 Approximately 200 mg / m 2 Approximately 150 mg / m 2 or approximately 100 mg / m 2 In some implementation methods, a low dose of gemcitabine (100-800 mg / m²) is administered weekly. 2 Preferred concentration: 100-600 mg / m³ 2 In some implementations, a low dose of gemcitabine, approximately 800 mg / m², is administered weekly. 2 Approximately 600 mg / m 2 Approximately 300 mg / m 2 or approximately 100 mg / m 2 In some implementations, a low dose of gemcitabine, less than 600 mg / m², is administered weekly. 2 In some implementation methods, approximately 100 mg / m² of paclitaxel is administered weekly. 2 Approximately 80 mg / m 2 Approximately 70 mg / m 2 Approximately 60 mg / m 2 Approximately 50 mg / m 2 Approximately 40 mg / m 2 Approximately 30 mg / m 2 Approximately 20 mg / m 2 or about 10mg / m 2 In some implementation methods, approximately 100 mg / m² of paclitaxel is administered weekly. 2 Approximately 80 mg / m 2 Approximately 70 mg / m 2 Approximately 60 mg / m 2 Approximately 50 mg / m 2 Approximately 40 mg / m 2 Approximately 30 mg / m 2 Approximately 20 mg / m 2 or about 10mg / m2 Up to 7 weeks. In some implementations, paclitaxel is administered weekly at approximately 100 mg / m² for 3 out of every 4 weeks. 2 Approximately 80 mg / m 2 Approximately 70 mg / m 2 Approximately 60 mg / m 2 Approximately 50 mg / m 2 Approximately 40 mg / m 2 Approximately 30 mg / m 2 Approximately 20 mg / m 2 or about 10mg / m 2 In some implementation schemes, paclitaxel is administered weekly at approximately 100 mg / m² for three out of every four weeks. 2 Approximately 80 mg / m 2 Approximately 70 mg / m 2 Approximately 60 mg / m 2 Approximately 50 mg / m 2 Approximately 40 mg / m 2 Approximately 30 mg / m 2 Approximately 20 mg / m 2 or about 10mg / m 2 In some implementation methods, paclitaxel is administered at a dose of 10-100 mg / m² per week. 2 Preferred concentration: 40-80 mg / m³ 2 In some implementation methods, approximately 80 mg / m² of paclitaxel is administered weekly. 2 Approximately 60 mg / m 2 or approximately 40 mg / m 2 In some implementation methods, the weekly dose of paclitaxel is less than 80 mg / m². 2 In some implementations, paclitaxel is administered at a dose of 80 mg / m² according to the protocol. 2 Intravenous administration is initiated at least 2 hours after the administration of compound (I) on the same day, with the infusion lasting approximately 60 minutes. In some embodiments, gemcitabine is administered at a dose of 600 mg / m² according to the regimen. 2 Intravenous administration should begin immediately after paclitaxel infusion and last for 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 daily. In some embodiments, the compound of formula (I) is administered at a dose of about 480 mg daily. In some embodiments, the compound of formula (I) is administered at a dose of about 400 mg daily. In some embodiments, the compound of formula (I) is administered at a dose of about 320 mg daily. In some embodiments, the compound of formula (I) is administered at a dose of about 240 mg daily. In some embodiments, the compound of formula (I) is administered at a dose of about 160 mg daily. In some embodiments, the total amount of the compound of formula (I) is administered in separate doses more than once daily, such as twice daily (BID) or more frequently. In some embodiments, compound (I) is administered twice daily at a total daily dose ranging from about 80 mg to 480 mg. In some embodiments, compound (I) is administered twice daily at a total daily dose ranging from about 80 mg to 240 mg. In some embodiments, compound (I) is administered twice daily at a total daily dose of about 240 mg. In some embodiments, compound (I) is administered twice daily at a total daily dose of about 480 mg. In some embodiments, compound (I) is administered twice daily at a total daily dose of about 160 mg. In some embodiments, compound (I) is administered twice daily at a total daily dose of about 80 mg. In some embodiments, compound (I) is administered twice daily at a total daily dose of about 240 mg, with an interval of 8-12 hours. In some embodiments, compound (I) is administered twice daily at a total daily dose of about 80 mg, with an interval of 8-12 hours.

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

[0099] As used herein, the term "carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material that participates in or is capable of carrying or transporting a main pharmaceutical compound from one organ or body part to another. Each carrier must be "acceptable" in the sense that it is compatible with other components in the formulation and harmless 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; astragalus gum 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 buffer; and other non-toxic and compatible substances used in pharmaceutical preparations. Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymer), as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0100] The pharmaceutical compositions (pharmaceutical preparations) disclosed herein are suitable for oral administration and may be in the form of capsules, pouches, pills, tablets, lozenges (using flavoring agents, typically sucrose and gum arabic 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 (using inert bases such as gelatin, glycerin, sucrose and / or gum arabic) and / or mouthwashes, each form comprising a predetermined amount of at least one compound of formula (I).

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

[0102] Solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) intended for oral administration may 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 silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; humectants, such as glycerin; disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, sodium carbonate, and sodium starch glycolate; solution blockers, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glyceryl monostearate, and polyethylene oxide-polypropylene oxide copolymers; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions can be filled in capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycol, etc., as fillers for soft and hard gelatin.

[0103] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, 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-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, and mixtures thereof. Additionally, cyclodextrins (e.g., hydroxypropyl β-cyclodextrin) may be used to dissolve the compound.

[0104] The pharmaceutical composition (pharmaceutical formulation) may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aromatizers and preservatives. In addition to the compounds of the present invention, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0105] The pharmaceutical compositions (pharmaceutical formulations) disclosed herein can be administered rectally or vaginally in the form of suppositories. They can be prepared by mixing one or more of the compounds disclosed herein with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature and liquid at body temperature, thus melting in the rectal or vaginal cavity and releasing the active pharmaceutical agent disclosed herein. Pharmaceutical compositions suitable for vaginal administration may also include vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays containing suitable carriers known in the art.

[0106] The pharmaceutical compositions (pharmaceutical formulations) or tablets disclosed herein for topical or transdermal administration may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The pharmaceutical compositions or tablets may be mixed under aseptic conditions with pharmaceutically acceptable carriers and any necessary preservatives, buffers, or propellants.

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

[0108] In addition to the pharmaceutical compositions (pharmaceutical formulations) or tablets disclosed herein, powders and sprays may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Furthermore, sprays may contain conventional propellants (such as chlorofluorocarbons) and volatile unsubstituted hydrocarbons (such as butane and propane).

[0109] Eye drops, ointments, powders, solutions, etc. are also included within the scope of this disclosure.

[0110] Compositions (pharmaceutical formulations) suitable for parenteral administration may contain at least one pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersant, suspension or emulsion or sterile powder (which may be reconstituted into a sterile injectable solution or dispersion just before use), and may contain antioxidants, buffers, antimicrobial agents, solutes that make the formulation isotonic with the blood of the designated recipient, or suspending agents or thickeners.

[0111] In various embodiments, the compounds of formula (I) described herein are included in a pharmaceutical composition. The pharmaceutical composition (pharmaceutical formulation) comprises a compound selected from those of formula (I) and its pharmaceutically acceptable salt and solvate, and one or more surfactants. In some embodiments, the surfactant is sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS), or one or more polyoxyglycerol esters. For example, the polyoxyglycerol ester may be lauryl polyoxyglycerol ester (sometimes called Gelucire). TM ) or linoleyl polyoxyglycerol ester (sometimes called Labrafil) TM Examples of these compositions are shown in PCT patent WO2014 / 169078, the entire contents of which are incorporated herein by reference.

[0112] CSCs have at least four characteristics believed to contribute to malignancy: stemness, dysregulation of stemness signaling pathways, resistance to conventional cancer treatments, and metastatic tendency. As used in this article, “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 constitute only a small percentage of the cancer cell population in tumors (Clarke MF, Biol. Blood Marrow Transplant. 2009; 11(2 suppl 2):14-16), they can generate a heterogeneous lineage of differentiated cancer cells that make up the majority of tumors (Gupta et al. 2009). In addition, CSCs have the ability to migrate to different parts of the body, thereby regenerating tumors in these sites (Jordan CT et al. N. Engl. J. Med. 2006; 355(12):1253-1261).

[0113] The induction and maintenance of stem cell characteristics in CSCs are caused by progressive dysregulation of stem signaling pathways, including but not limited to those associated with Janus kinase / signal transduction and transcription activator (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 hypothesized that the dysregulation of stem cell signaling pathways in these cancer stem cells (CSCs) (Boman et al. 2008) leads to their resistance to chemotherapy and radiotherapy, ultimately resulting in cancer recurrence and metastasis. Therefore, while chemotherapy and radiotherapy can kill most rapidly dividing cancer cells in a tumor, dysregulation of stem cell signaling pathways in CSCs can prevent chemotherapy and radiotherapy-induced cell death, and explain how surviving CSCs acquire the ability to metastasize to sites far 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; referred to as STAT3 in this paper) acts at the junctions of signal transduction pathways of multiple cytokines. 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 and controls the cell cycle (CYCLIN) Gene expression of D1, D2, and c-MYC, cell survival (BCL-XL, BCL-2, MCL-1), and angiogenesis (HIF1a, VEGF) (Furqan et al. Journal of Hematology & Oncology (2013) 6:90) 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, lasting from approximately 30 minutes to several hours. However, STAT3 has been found to be abnormally active in a variety of human tumors, including all major cancers and some hematologic malignancies (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 STAT3 activation 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 in more than 95% of head and neck cancers.

[0117] By inhibiting STAT3 signaling through antisense oligonucleotides, siRNA, dominant-inactive forms of STAT3, and / or targeted inhibition of STAT3-dependent tyrosine kinase activity, growth arrest, apoptosis, and reduced metastasis frequency in cancer cells can be achieved in vitro and / or in vivo, suggesting that the stemness of cancer cells (CSCs) depends on the sustained activation of the STAT3 transcription factor. (References: 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 crucial role in the survival and self-renewal capacity of CSCs in a broad spectrum of cancers.

[0118] As described above, this article discloses a method for treating at least one disease associated with abnormal STAT3 pathway activity in subjects. Abnormal STAT3 pathway activity can be identified by the expression of phosphorylated STAT3 (“pSTAT3”) or its substitutes' upstream or downstream regulators.

[0119] The STAT3 pathway responds to activation of cytokines, such as IL-6, or by activation by one or more tyrosine kinases, such as EGFR, JAKs, ABL, KDR, c-MET, SRC, and HER2 (see, for example, Figure 3). Downstream effectors of STAT3 include, but are not limited to, BCL-XL, c-MYC, cyclin D1, VEGF, MMP-2, and survival proteins. Ibid. The STAT3 pathway is found to be aberrantly activated in many cancers. Persistent activation of the STAT3 pathway occurs in more than half of breast cancer, lung cancer, hepatocellular carcinoma, multiple myeloma, and more than 95% of head and neck cancers. In vitro and / or in vivo blocking of the STAT3 pathway leads to growth arrest, apoptosis, and a reduced metastasis rate in cancer cells. STAT3 activation has also been observed in many autoimmune and inflammatory diseases. Furthermore, since interleukin-6 (IL-6)-mediated inflammation has been publicly disclosed as a common pathogenic factor for atherosclerosis, peripheral vascular disease, coronary artery disease, hypertension, osteoporosis, type 2 diabetes, and dementia, and gp130-JAKS-STATs has been publicly disclosed as a major 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.Circulation,2003.108(19):p.2317-22; Orshal,JMand RA Khalil.

[0120] In some embodiments, the at least one disorder may be selected from cancers associated with abnormal STAT3 pathway activity, such as pancreatic cancer cells where activated pSTAT3 has been detected (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 and inflammatory diseases associated with abnormal STAT3 pathway activity. In some embodiments, diseases associated with abnormal 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 inflammation-induced diseases 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 subset of cancer cells (found in solid tumors or blood cancers) that possess characteristics typically associated with stem cells. These cells grow faster after chemotherapy reduces non-stem cancer cells, which may be a mechanism leading to frequent cancer recurrence after chemotherapy. Unlike most cancer cells that are non-tumorigenic, CSCs are tumorigenic (forming tumors). In human acute myeloid leukemia, these cells account for less than one in ten thousand. Bonnet, D. and JEDick. Nat. Med., 1997. 3(7): p. 730-37.

[0124] In the early stages of trials, the efficacy of cancer treatments is often measured by the number and size of tumor masses they eliminate. Because CSCs form a very small proportion of the tumor cell population and have significantly different biological characteristics compared to their differentiated progeny, the determination of tumor masses may not be useful for selecting drugs that specifically target CSCs. In fact, CSCs are radiation-resistant and difficult to treat with chemotherapy drugs and targeted therapies. Normal human stem cells are naturally resistant to chemotherapy drugs—they possess multiple pumps that expel drugs (e.g., multidrug resistance protein pumps), higher DNA repair capabilities, and a slow cell turnover rate (chemotherapeutic drugs naturally target rapidly replicating cells). CSCs are mutated copies of normal stem cells, and they may also possess similar functions that allow them to survive treatment. In other words, conventional chemotherapy kills differentiated (or in-differentiation) cells that form the bulk of the tumor but cannot generate new tumor cells. See Figure 2, for example. The population of CSCs that generate new tumor cells can remain unchanged, thus causing disease relapse. Moreover, chemotherapy may leave only chemotherapy-resistant cancer stem cells (CSCs), increasing the likelihood of subsequent tumor resistance to chemotherapy. Additionally, cancer stem cells have been shown to be resistant to radiotherapy (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 cancer stem cells (CSCs) can regenerate tumors and cause recurrence, anticancer therapies targeting CSCs hold great promise for treating malignant tumors. (Jones RJ et al., J Natl Cancer Inst. 2004; 96(8):583-585). CSC-targeted therapy can treat patients with aggressive, unresectable tumors and those with refractory or recurrent tumors, as well as prevent tumor metastasis and recurrence. Therefore, the development of specific therapies targeting CSCs holds promise for prolonging the survival of cancer patients and improving their quality of life, especially for those with metastatic cancer.

[0126] Recent studies have revealed that cancer stem cells (CSCs) can regenerate tumors (Figure 1). These cancer stem cells have been shown to be functionally associated with the continued malignant growth, metastasis, recurrence, and resistance to cancer drugs. Cancer stem cells and their differentiated progeny exhibit significantly different biological characteristics. They persist in tumors as a unique, but rare, population. Conventional cancer drug screening relies on measuring the amount of tumor mass, making it impossible to identify drugs that specifically target stem cells. In fact, cancer stem cells have been shown to be resistant to standard chemotherapy and enriched after standard chemotherapy treatment (see, for example, Figure 2). This leads to refractory cancers 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.) Cancer types from which cancer stem cells have been reportedly 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 sarcoma, liver cancer, medulloblastoma, brain tumors, and leukemia. STAT3 has been identified as a factor for the survival and self-renewal of cancer stem cells. Therefore, STAT3 inhibitors can kill cancer stem cells and / or inhibit their self-renewal. According to some implementation schemes, cancer stem cells refer to a micropopulation of cancer stem cells with self-renewal capacity and tumorigenicity. In previous studies, compound (I) has been shown to effectively inhibit the STAT3 pathway, thereby inhibiting the growth and survival of CSCs, and in clinical trials, compound (I) has been used to treat patients with advanced cancer. Based on previous experiments, this invention unexpectedly discovers for the first time that a novel drug combination of compound (I), low-dose gemcitabine, and paclitaxel can also effectively treat patients with advanced cancer, especially those with metastatic pancreatic cancer who have failed previous treatments. Prior to this, there had been no reports of effective combination chemotherapy regimens containing low-dose gemcitabine and paclitaxel for the treatment of patients with advanced pancreatic cancer. Therefore, this invention provides a new option for improving the survival of patients with advanced, especially metastatic, pancreatic cancer who have failed first-line therapy.

[0127] This document discloses methods for inhibiting, reducing, and / or attenuating 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. This document also discloses methods for inhibiting, reducing, and / or attenuating 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. This document further discloses methods for inhibiting, reducing, and / or attenuating 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] This document discloses a method for treating at least one type of cancer in a subject that is 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. This document also discloses a method for treating at least one type of cancer in a subject that is 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 of a low dose of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0129] This document discloses a method for treating or preventing cancer recurrence or metastasis in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. This document also discloses a method for treating or preventing cancer recurrence or metastasis 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 weekly paclitaxel. This document further discloses a method for treating or preventing cancer recurrence or metastasis 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 weekly paclitaxel. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition. In various embodiments, the subject is a pancreatic cancer patient who has failed prior treatment. In various embodiments, the subject is a metastatic pancreatic cancer patient who has failed prior treatment.

[0130] This document discloses 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. This document also discloses 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 of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0131] This article discloses the use of a pharmaceutical composition in a method of treating cancer in a subject, the composition comprising a therapeutically effective amount of a compound of formula (I), a low dose of gemcitabine, and a therapeutically effective or 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 / m². 2 Administer weekly. Gemcitabine can be administered at doses of 100-800 mg / m². 2Administered weekly. In 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 a dose of 40-80 mg / m². 2 Administer weekly. In some preferred regimens, gemcitabine is administered at 100-600 mg / m². 2 Administered weekly. In some embodiments, the subject is a pancreatic cancer patient who has failed previous treatment. In other embodiments, the subject is a metastatic pancreatic cancer patient who has failed 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 prior treatment. In some embodiments, the pancreatic cancer may be pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer may be pancreatic ductal adenocarcinoma. In some embodiments, the cancer may be metastatic pancreatic cancer. In some embodiments, the cancer is metastatic pancreatic cancer that has progressed after prior treatment. In some embodiments, the cancer may be associated with overexpression of activated pSTAT3. In some embodiments, the cancer may be associated with nuclear β-catenin localization. Example

[0133] The following embodiments are provided to further illustrate different features of the invention. These embodiments also illustrate useful methods for carrying out the invention. These embodiments do not limit the claimed invention.

[0134] This article discloses methods for administering low doses of gemcitabine, weekly paclitaxel, and compound (I) to subjects in need of this treatment.

[0135] Example 1

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

[0137] Example 2

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

[0139] Human cancer cells were subcutaneously implanted into the right abdomen of 5-7 week old athymic nude mice. When the tumor size reached 200 mm... 3 Animals were treated with 2-acetylnaphtho[2,3-b]furan-4,9-dione (e.g., by oral gavage at 50 mg / kg (BID) (n = 3 / group)), paclitaxel, or 2-acetylnaphtho[2,3-b]furan-4,9-dione in combination with paclitaxel. Tumors were collected 24 hours after the first administration.

[0140] The collected tissues were fixed overnight at 4°C in 3.7% neutral buffered formaldehyde. They were then paraffin-embedded. The tissues were cut into approximately 5 μm pieces and fixed onto positively charged slides. After baking and deparaffining, slides containing tumor or control tissues were incubated for 10 min in 10 mM sodium citrate (pH 6.0). After antigen retrieval, slides were labeled overnight at 4°C with primary antibody P-STAT3 (rabbit, Cell Signaling, 1:100) and β-catenin (mouse, Santa Cruz, 1:400), followed by secondary antibody (1:500, Invitrogen) conjugated with Alexa Fluor. After mounting, the slides were...

[0141] Detection of DAPI (Invitrogen)-containing slides with Prolong mounting medium under a Zeiss fluorescence microscope 20x objective and analysis using Zen software.

[0142] As shown in Figure 5, paclitaxel monotherapy leads to enhanced staining of stem cell markers. 2-acetylnaphtho[2,3-b]furan-4,9-dione monotherapy significantly reduces the expression of stem cell markers p-STAT3 and β-catenin. When 2-acetylnaphtho[2,3-b]furan-4,9-dione is combined with paclitaxel, the expression of stem cell markers decreases even further.

[0143] Example 3

[0144] In an extended Phase II / III international multicenter trial, the effects of compound (I), 2-acetylnaphtho[2,3-b]furan-4,9-dione, in combination with paclitaxel and low-dose gemcitabine, were investigated in patients with advanced pancreatic cancer who had failed prior therapy.

[0145] This clinical study investigated the antitumor activity and safety of 2-acetylnaphtho[2,3-b]furan-4,9-dione in combination with weekly paclitaxel and low-dose gemcitabine in patients with advanced pancreatic cancer who had failed prior therapy. Patients had failed at least one first-line systemic therapy and experienced radiographic disease progression. Prior treatment included gemcitabine-based monotherapy or combination chemotherapy, and / or FOLFIRINOX / mFOLFIRINOX chemotherapy.

[0146] Enrolled patients received 2-acetylnaphtho[2,3-b]furan-4,9-dione orally twice daily (total daily dose 480 mg) in combination with paclitaxel and low-dose gemcitabine, in 4-week (28-day) treatment cycles. Paclitaxel 80 mg / m² was started on day 1 of the first treatment cycle. 2 IV, followed by gemcitabine 600 mg / m² 2 IV. Administered on days 1, 8, and 15 of every 28-day treatment cycle. Dosage adjustments (reduction or discontinuation) may be made should a drug toxicity reaction occur.

[0147] Tumor remission and progression were evaluated according to RECIST 1.1 criteria. The antitumor activity of 2-acetylnaphtho[2,3-b]furan-4,9-dione in combination with paclitaxel and low-dose gemcitabine was assessed.

[0148] Among the enrolled patients with advanced pancreatic cancer, one patient had previously received three lines of chemotherapy (first-line gemcitabine + tegafur; second-line gemcitabine; third-line avelumab) and experienced disease progression. After enrollment and treatment, the first assessment (8 weeks after randomization) showed a 9.1% reduction in target lesions and stable disease (SD). The second assessment (20 weeks after randomization) showed a 41% reduction in target lesions and partial response (PR), with significant reduction in non-target lesions. Another patient had previously received first-line chemotherapy (capecitabine + tegafur) and experienced disease progression. After enrollment and treatment, the first assessment (8 weeks after randomization) showed a 25.6% reduction in target lesions and stable disease (SD), with significant reduction in non-target lesions. Both patients are currently still receiving treatment.

[0149] The adverse events associated with 2-acetylnaphtho[2,3-b]furan-4,9-dione observed in all treated patients were mainly gastrointestinal adverse events (such as diarrhea, constipation, nausea, vomiting, etc.). The combination therapy did not increase the toxic side effects in patients and had a good safety profile.

[0150] This trial demonstrated a good synergistic effect between 2-acetylnaphtho[2,3-b]furan-4,9-dione, paclitaxel, and low-dose gemcitabine in patients with metastatic pancreatic cancer who had failed prior treatment. The combination of 2-acetylnaphtho[2,3-b]furan-4,9-dione (240 mg BID) with 80 mg / m² weekly was also effective. 2 IV paclitaxel and gemcitabine 600 mg / m² 2 IV is safe, well-tolerated, and has good antitumor activity.

[0151] Many features and advantages disclosed herein will be apparent from the detailed description, and therefore the appended claims are intended to cover all such features and advantages that fall within the true spirit and scope of the disclosure herein. Furthermore, since many modifications and variations will readily occur to those skilled in the art, it is not intended to limit the disclosure to the precise configuration and operation shown and described accordingly; all suitable modifications and equivalents may be invoked and fall 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 pertains. The methods referenced herein may be implemented in any logically possible order other than the specific order disclosed.

[0153] Introduced by reference

[0154] This disclosure references and cites other documents such as patents, patent applications, patent publications, journals, books, papers, and website content, all of which are incorporated herein by reference in their entirety for all purposes. If any material or part thereof cited herein conflicts with other publicly available materials defined, stated, or expressly stated herein, only the portion of the cited material that does not conflict with this disclosure shall be incorporated. In the event of a conflict, the preferred disclosure shall prevail.

Claims

1. Use of a pharmaceutical composition in the treatment of chemotherapy-resistant pancreatic cancer, said composition comprising a therapeutically effective amount of a compound of formula (I): Or its pharmaceutically acceptable salts or solvates, Low doses of gemcitabine or its pharmaceutically acceptable salts or solvates, and A therapeutically effective weekly dose of paclitaxel or its pharmaceutically acceptable salts or solvates. in, A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 80-960 mg; a low dose of gemcitabine or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 100-800 mg / m². 2 Administered weekly by infusion, a therapeutically effective amount of paclitaxel or its pharmaceutically acceptable salts or solvates at approximately 10-100 mg / m². 2 Administered via weekly infusion.

2. The use according to claim 1, wherein the pancreatic cancer is resistant to conventional chemotherapy.

3. Use of a pharmaceutical composition in a method for resensitizing a subject with pancreatic cancer who has failed prior treatment to a chemotherapy regimen, said composition comprising a therapeutically effective amount of a compound of formula (I): Or its pharmaceutically acceptable salts or solvates, Low doses of gemcitabine or its pharmaceutically acceptable salts or solvates, and A therapeutically effective amount of paclitaxel or its pharmaceutically acceptable salts or solvates. in, A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 80-960 mg; a low dose of gemcitabine or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 100-800 mg / m². 2 Administered weekly by infusion, a therapeutically effective amount of paclitaxel or its pharmaceutically acceptable salts or solvates at approximately 10-100 mg / m². 2 Administered via weekly infusion.

4. Use of a pharmaceutical composition in a method of simultaneously inhibiting, reducing, and / or attenuating the survival and / or proliferation of cancer stem cells and heterogeneous cancer cells selected from pancreatic cancer subjects, said composition comprising: Therapeutic effective amount of compound (I) Or its pharmaceutically acceptable salts or solvates, Low doses of gemcitabine or its pharmaceutically acceptable salts or solvates, and A therapeutically effective amount of paclitaxel or its pharmaceutically acceptable salts or solvates. in, A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 80-960 mg; a low dose of gemcitabine or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 100-800 mg / m². 2 Administered weekly by infusion, a therapeutically effective amount of paclitaxel or its pharmaceutically acceptable salts or solvates at approximately 10-100 mg / m². 2 Administered via weekly infusion.

5. Use of a pharmaceutical composition in a method of treating or preventing cancer recurrence or metastasis in a subject, said composition comprising: Therapeutic effective amounts of compound (I): Or its pharmaceutically acceptable salts or solvates, Low doses of gemcitabine or its pharmaceutically acceptable salts or solvates, and A therapeutically effective amount of paclitaxel or its pharmaceutically acceptable salts or solvates. in, A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 80-960 mg; a low dose of gemcitabine or a pharmaceutically acceptable salt or solvation thereof is administered daily at a dose of approximately 100-800 mg / m². 2 Administered weekly by infusion, a therapeutically effective amount of paclitaxel or its pharmaceutically acceptable salts or solvates at approximately 10-100 mg / m². 2 Administered via weekly infusion.

6. The use according to any one of claims 1-5, wherein the cancer is an advanced, metastatic, unresectable, refractory, or recurrent chemotherapy-resistant cancer.

7. The use according to any one of claims 1-5, wherein the cancer is pancreatic cancer.

8. The use according to any one of claims 1-5, wherein the subject is a pancreatic cancer patient who has failed prior chemotherapy.

9. The use according to any one of claims 1-5, wherein the subject is a patient with metastatic pancreatic cancer that has progressed after prior treatment.

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

11. The use according to any one of claims 1-9, wherein the compound of formula (I) is administered daily at a dose of about 80-480 mg.

12. The use according to any one of claims 1-9, wherein the compound of formula (I) is administered in divided doses.

13. The use according to any one of claims 1-9, wherein the compound of formula (I) is administered twice daily at a dose of about 240 mg.

14. The use according to any one of claims 1-9, wherein gemcitabine is administered at approximately 600 mg / m². 2 Approximately 550 mg / m 2 Approximately 500 mg / m 2 Approximately 450 mg / m 2 Approximately 400 mg / m 2 Approximately 300 mg / m 2 Approximately 200 mg / m 2 or approximately 100 mg / m 2 Administered via weekly infusion.

15. The use according to any one of claims 1-9, wherein paclitaxel is administered at about 80 mg / m³. 2 Approximately 70 mg / m 2 Approximately 60 mg / m 2 Approximately 50 mg / m 2 Approximately 40 mg / m 2 Approximately 30 mg / m 2 Approximately 20 mg / m 2 or about 10mg / m 2 Administered via weekly infusion.

16. A kit comprising at least one compound of formula (I): At least one gemcitabine, and At least one paclitaxel.