Quinoline derivatives used in combination therapy for soft tissue sarcoma

Abstract

The present invention relates to a quinoline derivative used in combination therapy for soft tissue sarcoma, and more specifically, to the use of a quinoline derivative for treating soft tissue sarcoma in combination with a second-line therapeutic drug, wherein the second-line therapeutic drug may be a chemotherapy drug, a small molecule targeted anti-tumor drug, or an immunotherapy drug. The chemical name of the quinoline derivative compound I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine[1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine].

Description

Technology Field

[0001] <Cross-reference with related applications>

[0002] This application claims priority and interest to Chinese Patent Application No. 201910390149.8 filed with the Chinese Intellectual Property Office on May 10, 2019, the full text of which is incorporated herein by reference.

[0003] The present invention belongs to the field of pharmaceutical technology and relates to a quinoline derivative used in combination therapy for soft tissue sarcoma. More specifically, the present invention relates to the use of a quinoline derivative for treating soft tissue sarcoma in combination with a second-line therapeutic drug, wherein the second-line therapeutic drug may be a chemotherapy drug, a small molecule targeted anti-tumor drug, or an immunotherapy drug. Background Technology

[0004] Soft tissue sarcoma (STS) is a malignant tumor composed of intermingled mesenchymal and ectodermal neural tissues. It includes non-epithelial tissues—namely fibrous tissue, fat, muscle, and mesothelial tissue—excluding lymphohematopoietic tissue, as well as the blood vessels, lymphatic vessels, and peripheral nerves distributed within them. Generally, it is located in the hands, feet, trunk, and retroperitoneum, accounting for 1% of adult malignancies and 15% of pediatric tumors. It is primarily characterized by its wide distribution and diverse morphology.

[0005] The WHO classifies soft tissue sarcomas into more than 50 subtypes. Common subtypes include liposarcoma, leiomyosarcoma, angiosarcoma, synovial sarcoma, fibrosarcoma, pleomorphic undifferentiated sarcoma, and malignant schwann tumors. Due to the high malignancy of soft tissue sarcomas, the average survival time for patients is short.

[0006] WO2008112407 is a quinoline derivative tyrosine kinase inhibitor 1-[[[4-(4-fluoro-2-methyl-1) in Example 24 H-indole-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine[1-[[[4-(4-fluoro-2-methyl-1 H -indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine] and a method for preparing the same are disclosed, and said inhibitor has the structural formula of chemical formula I.

[0007] [Chemical Formula I]

[0008] Prior art literature

[0009] PCT Published Patent WO2008112407

[0010] In one aspect, the present application provides a pharmaceutical combination for use in treating soft tissue sarcoma comprising (i) a compound of formula I or a pharmaceutically acceptable salt thereof; and (ii) at least one secondary therapeutic drug.

[0011] [Chemical Formula I]

[0012]

[0013] In another aspect, the present application further provides a use of a pharmaceutical combination for manufacturing a drug for treating soft tissue sarcoma.

[0014] In another aspect, the present application further provides a method for treating soft tissue sarcoma comprising administering a therapeutically effective amount of a pharmaceutical combination described herein to an individual. The pharmaceutical combination comprises (i) a compound of Formula I or a pharmaceutically acceptable salt thereof, and (ii) at least one secondary therapeutic drug.

[0015] In one aspect, the present application provides a pharmaceutical combination for use in treating soft tissue sarcoma comprising (i) a compound of formula I or a pharmaceutically acceptable salt thereof, and (ii) at least one secondary therapeutic drug.

[0016] In some embodiments of the present application, the pharmaceutical combination comprises (i) a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, and (ii) at least one secondary therapeutic drug.

[0017] In some embodiments, the pharmaceutical combination comprises (i) a compound of Formula I or a pharmaceutically acceptable salt thereof, and (ii) at least one chemotherapy drug; optionally, the pharmaceutical combination is used in combination with radiation therapy. In some specific embodiments, a pharmaceutical combination for use in treating soft tissue sarcoma is provided, comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof, and (ii) epirubicin.

[0018] In some specific embodiments, the pharmaceutical combination comprises (i) a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in doses of 6 mg, 8 mg, 10 mg and / or 12 mg, and (ii) 50-150 mg / m² 2 It includes a pharmaceutical composition containing a dose of epirubicin.

[0019] In some specific embodiments, the pharmaceutical combination comprises (i) a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in doses of 6 mg, 8 mg, 10 mg and / or 12 mg, and (ii) 50, 54, 60, 72, 80, 90, 100, 110, 120, 135 and / or 150 mg / m² 2 It includes a pharmaceutical composition containing a dose of epirubicin.

[0020] In some embodiments, (i) a pharmaceutical composition comprising a 12 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof, and (ii) 90 mg / m² 2A pharmaceutical combination for use in treating soft tissue sarcoma is provided, comprising a pharmaceutical composition containing a dose of epirubicin.

[0021] In another aspect, the present application provides a use of a pharmaceutical combination for the preparation of a drug for use in treating soft tissue sarcoma, said pharmaceutical combination comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof, and (ii) at least one secondary therapeutic drug, optionally, said pharmaceutical combination is used in combination with radiation therapy.

[0022] In another aspect, the present application provides a method for treating soft tissue sarcoma comprising administering to a patient a therapeutically effective amount of (i) a compound of formula I or a pharmaceutically acceptable salt thereof, and (ii) at least one secondary therapeutic drug.

[0023] The present application provides a method for treating an individual having soft tissue sarcoma. In certain embodiments, for example, the individual having said soft tissue sarcoma is a patient diagnosed with undifferentiated pleomorphic sarcoma or alveolar soft tissue sarcoma. For example, in certain embodiments, said soft tissue sarcoma is a recurrent soft tissue sarcoma. In certain embodiments, said soft tissue sarcoma is a metastatic soft tissue sarcoma. In certain embodiments, said soft tissue sarcoma is an intractable soft tissue sarcoma. In certain embodiments, said soft tissue sarcoma is an unresectable soft tissue sarcoma. In some specific embodiments, the soft tissue sarcoma described herein is an undifferentiated pleomorphic sarcoma. In some specific embodiments, the soft tissue sarcoma described herein is an unresectable and / or metastatic undifferentiated pleomorphic sarcoma. In some other specific embodiments, said soft tissue sarcoma is an alveolar soft tissue sarcoma. In some specific embodiments, the soft tissue sarcomas described herein include those specified in the 2013 World Health Organization (WHO) classification, such as angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberance, malignant peripheral neurodermal tumor, clear cell sarcoma, malignant mesenchymal sarcoma, epithelioid sarcoma, undifferentiated sarcoma, and gastrointestinal stromal tumor, but are not limited thereto.

[0024] In some embodiments of the present application, the subject has previously undergone surgery, chemotherapy, and / or radiation therapy. In some specific embodiments, the subject has experienced a recurrence of the disease after being cured following surgery, chemotherapy, and / or radiation therapy. In some specific embodiments, the subject has been cured or failed some treatment following surgery, chemotherapy, and / or radiation therapy.

[0025] In some embodiments of the present application, the subject has not previously received systemic chemotherapy. In some embodiments, the subject has previously received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy. In some specific embodiments, the subject has not received systemic chemotherapy but has received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy. In some specific embodiments, the subject has relapsed after being cured following surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy. In some specific embodiments, the subject has been cured or failed partial treatment following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy. In some specific embodiments, the subject has metastasized cancer after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy.

[0026] In some embodiments of the present application, the soft tissue sarcoma includes a soft tissue sarcoma that has not previously received anthracycline chemotherapy. In some embodiments, for example, the anthracycline may be one or more of epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitosantron, aclarubicin, valubicin, zorubicin, physantron, etc., and may be one, two, or three or more.

[0027] In some embodiments of the present application, in the use or treatment method, the secondary treatment drug may be administered once a week (q1w), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w). In certain embodiments, epirubicin is administered once every three weeks.

[0028] The compound of Formula I or a pharmaceutically acceptable salt thereof may be administered once daily at a dose of 6 mg, 8 mg, 10 mg, or 12 mg according to a regimen of 1 week discontinuation after 2 weeks of continuous treatment and / or a regimen of 2 weeks discontinuation after 2 weeks of continuous treatment.

[0029] In some embodiments, the secondary therapeutic drug and the compound of Formula I or a pharmaceutically acceptable salt thereof are each subjected to the same or different treatment cycles. In some specific embodiments, the secondary therapeutic drug and the compound of Formula I or a pharmaceutically acceptable salt thereof are subjected to the same treatment cycle, e.g., a 1-week, 2-week, 3-week, or 4-week treatment cycle.

[0030] In some specific embodiments, the secondary treatment drug and the compound of formula I or a pharmaceutically acceptable salt thereof are applied in a 3-week treatment cycle.

[0031] In some embodiments of the treatment method described herein, epirubicin is 50 mg to 150 mg / m² 2 As doses, for example, 50, 54, 60, 72, 80, 90, 100, 110, 120, 135 and / or 150 mg / m² 2 It can be administered to patients in a given dose.

[0032] soft tissue sarcoma

[0033] The soft tissue sarcomas described herein include undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma), angiosarcoma, desmoid tumor, fibrosarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberance, neurocutaneous tumor, malignant peripheral neurocutaneous tumor, alveolar soft tissue sarcoma, clear cell sarcoma, malignant mesenchymal sarcoma, epithelioid sarcoma, alveolar soft tissue sarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, mixed liposarcoma, adult fibrosarcoma, low-grade fibromyxoid sarcoma, hyalinizing spindle cell tumor, sclerosing epithelioid fibrosarcoma, pericellular (perivascular) tumor, glomus tumor (and variants), glomus angioma, weak glomus tumor, perimyoma, myofibroma, angioleiomyoma, embryonic It may include, but is not limited to, rhabdomyosarcoma (including vegetative and retrograde), alveolar rhabdomyosarcoma (including solid and retrograde), pleomorphic rhabdomyosarcoma, spindle cell / sclerosing rhabdomyosarcoma, epithelioid hemangioma, soft tissue hemangioma, epithelioid malignant peripheral neurodermal tumor, malignant Triton tumor, malignant granular cell tumor, synovial sarcoma NOS, synovial sarcoma (spindle cell), synovial sarcoma (abnormal), soft tissue clear cell sarcoma, connective tissue-forming small cell tumor, extrarenal rhabdomyosarcoma, neoplasm with perivascular epithelioid differentiation (PEComa), endometrial sarcoma, undifferentiated / unclassified sarcoma, undifferentiated spindle cell sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid cell sarcoma, connective tissue-forming small cell tumor, low-grade fibromyxoid sarcoma and borderline fibrous tissue tumor.

[0034] In some specific embodiments, the soft tissue sarcoma is an undifferentiated pleomorphic sarcoma, alveolar soft tissue sarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberance, malignant peripheral neurodermal tumor, clear cell sarcoma, malignant mesenchymal histoma, epithelioid sarcoma, undifferentiated sarcoma, and gastrointestinal stromal tumor.

[0035] In some specific embodiments, the soft tissue sarcoma is an undifferentiated polymorphic sarcoma.

[0036] In some specific embodiments, the soft tissue sarcoma is a salicy soft tissue sarcoma.

[0037] In the present application, the clinical stage of soft tissue sarcoma may include, but is not limited to, local progression and / or progression (e.g., stages IIIB / IV) and / or metastatic soft tissue sarcoma; said metastatic soft tissue sarcoma may include, but is not limited to, single metastasis, disseminated metastasis and diffuse metastasis of the lesion; said metastatic lesions may include, but are not limited to, lesions of lymph nodes, pleura, bone, brain, pericardium, adrenal gland, and liver. In some embodiments, said soft tissue sarcoma is a soft tissue sarcoma with brain metastasis. In some embodiments, said pharmaceutical combination is used to treat soft tissue sarcoma, said soft tissue sarcoma may be a primary soft tissue sarcoma or a secondary soft tissue sarcoma. In some embodiments, said soft tissue sarcoma is a case where it has progressed or relapsed after receiving at least one chemotherapy. In some embodiments, said soft tissue sarcoma is a case where it is not resistant to chemotherapy. In a preferred embodiment, the soft tissue sarcoma is a case where systemic treatment has been previously received. In some embodiments, the soft tissue sarcoma is an undifferentiated pleomorphic sarcoma. In some other specific embodiments, the soft tissue sarcoma is a salicylic soft tissue sarcoma.

[0038] Second-line treatment drugs

[0039] In some embodiments of the present application, the secondary therapeutic drug may include, but is not limited to, chemotherapy drugs, small molecule targeted anti-tumor drugs, and immunotherapy drugs.

[0040] In some embodiments, the second therapeutic drug may be a chemotherapy drug comprising one or more of platinum-based drugs, fluoropyrimidine derivatives, anthracycline drugs, antibiotics, podophyllum drugs and an antimetabolite drugs, but is not limited thereto. Examples include platinum-based drugs (e.g., oxaliplatin, cisplatin, carboplatin, myriplatin, nedaplatin, and dicycloplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, difuradine, doxifluridine, tegafur, camofur, and trifluridine), taxane drugs (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), camptothecin drugs (e.g., camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, and topotecan), vinca alkaloid drugs (vinorelbine, vinblastine, vincristine, vindecin, and vinflunine), and anthracycline drugs (epirubicin, adriamycin, daunorubicin, pirarubicin, It may be listed including, but is not limited to, one or more of amrubicin, idarubicin, mitosantrone, aclarubicin, valubicin, zorubicin, and physantron), pemetrexid, camustine, melphalan, etoposide, tenifoside, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal adriamycin, actinomycin D (dactinomycin), bleomycin, pinyangmycin, temozolomide, dacarbazine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, tegafur-gimeracil-oteracil potassium, and ensekida.

[0041] In some embodiments, the chemotherapy drug is one or more selected from the group consisting of adriamycin, epirubicin, daunorubicin, aclaxinomycin, actinomycin D, amrubicin, mitomycin, pinyangmycin, pirarubicin, peplomycin, vincristine, cyclophosphamide, ifosfamide, bleomycin, camustine, etoposide, methotrexate, and cisplatin.

[0042] If desired, the above-mentioned secondary treatment drug is used in combination with an adjuvant for chemotherapy, which may include, but is not limited to, calcium folinate (CF), leucovorin, mesnar, bisphosphonates, amifostine, and hematopoietic stem cell colony-stimulating factors (CSFs). In some embodiments, the adjuvant for chemotherapy is CF, mesnar, or leucovorin.

[0043] In some embodiments, the second-line therapeutic drug may be a small molecule targeted anti-tumor drug including, but not limited to, protein kinase inhibitors, and the protein kinase inhibitors may be, but not limited to, tyrosine kinase inhibitors, serine and / or threonine kinase inhibitors and poly-ADP ribose polymerase (PARP) inhibitors, and the targets of the inhibitors are fascin-1 protein, HDAC (histone deacetylase), proteasome, CD38, SLAMF7 (CS1 / CD319 / CRACC), RANKL, epidermal growth factor receptor (EGFR), anaplastic lymphoma (ALK), ET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, discoidin death receptor 2 (DDR2) gene, fibroblast growth factor receptor 1 (FGFR1), neurotrophin tyrosine kinase type 1 receptor (NTRK1) gene and The KRAS gene may be, but is not limited to, the target of the above small molecule targeted anti-tumor drug is COX-2 (cyclooxygenase-2), APE1 (apurinic apirimidinic endonuclease), VEGFR (vascular endothelial growth factor receptor), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin, PEDF (pigmented epithelial-derived factor), AS, ES, OPG (osteopropergenin), Src, IFN, ALCAM (activated leukocyte cell adhesion molecule), HSP, JIP1, GSK-3 (glycogen synthesis kinase 3), CyclinD1 (cell cycle regulatory protein), CDK4 (cyclin-dependent kinase), TIMP1 (tissue inhibitor of metalloproteinase), THBS3, PTHR1 (parathyroid hormone-associated protein receptor), TEM7 (tumor endothelial marker 7), COPS3, and cathepsin K are additionally included. Examples of the above small molecule targeted anti-tumor drugs are imatinib, sennitinib, nilotinib, bosutinib, saracatinib, pazopanib, travectedin, regorafenib, cediranib,Bortezomib, Panobinostat, Carfilzomib, Ixazomib, Apatinib, Erlotinib, Apatinib, Crizotinib, Seritinib, Vemurafenib, Dabrafenib, Cabozantinib, Gefitinib, Dacomitinib, Osimertinib, Alectinib, Brigatinib, Loratinib, Trametinib, Larotrectinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Sorafenib, Olmutinib, Sabolitinib, Fluquintinib, Entrectinib, Dasatinib, Ensartinib, Lenvatinib, Itacitinib, Pirotinib, Binimetinib, Erdafitinib, Axitinib, Neratinib, Cobimetinib, Acalabrutinib, Famitinib, Masitib, Ibrutinib, Rosiletinib, Nintedanib, Lenalidomide, Everolimus, LOXO-292, Bororanib, Bemcentinib, Capmatinib, Entrectinib, TAK-931, ALT-803, Palbociclib, Famitinib L-Malate, LTT-462, BLU-667, Ninzetinib, Tipifanib, Poziotinib, DS-1205c, Capivasertip, SH-1028, Dimethyldiguanide, Celiciclive, OSE-2101, APL-101, Berzosertip, Idelalisib, Lerosiclib, Seralasertip, PLB-1003, Tomivosertip, AST-2818, SKLB-1028, D-0316, LY-3023414, Alitinib, MRTX-849, AP-32788, AZD-4205, Lipirafenib, Vactosertib, Mibebresib, Nafabukacin, Sitravatinib, TAS-114, Molibresib, CC-223, Rivoceranib, CK-101, LXH-254, Simotinib, GSK-3368715, TAS-0728, Masitinib, Tepotinib, HS-10296, AZD-4547, Merestinib, Olaptesed Pegol, Gallunisertib, ASN-003, Gedatorisib, Depactinib, Lazertinib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD-3759, Antroquinonol, SAF-189s, AT-101, TTI-101, Naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, Efitinib succinate, Tecevatinib,It may include, but is not limited to, one or more of SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, tarazoparib tosylate, DV-281, siremadelin, telagelenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tusidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mosetinostat and quisinostat, LCL-161 and KML-001. In some embodiments, the small molecule targeted anti-tumor drug is one or more of sorafenib, everolimus, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, loratinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, olmutinib, savolitinib, fluquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pirotinib, binimetinib, erdafitinib, axitinib, neratinib, cobimetinib, acalabrutinib, famitinib, macitinib, ibrutinib, and nintedanib.

[0044] In some embodiments, the second therapeutic drug may be an immunotherapeutic drug comprising one or more of interferons (interferon α, interferon α-1b and interferon α-2b), interleukins, sirolimus, everolimus, lidaporolimus and temsirolimus, but is not limited thereto.

[0045] In a specific embodiment, the secondary therapeutic drug is one or more of epirubicin, ifosfamide, irinotecan, and adriamycin.

[0046] In a specific embodiment, the secondary therapeutic drug is epirubicin.

[0047] In a specific embodiment, the secondary therapeutic drug is one or more of adriamycin and cyclophosphamide, for example, two. In a specific embodiment, the secondary therapeutic drug is AC therapy (adriamycin + cyclophosphamide).

[0048] In certain embodiments, the secondary treatment drug is one or more of cyclophosphamide, vincristine, mesnar, and adriamycin, for example, one, two, three, or four. In certain embodiments, the secondary treatment drug is the VCD regimen (cyclophosphamide + vincristine + mesnar + adriamycin).

[0049] In certain embodiments, the secondary treatment drug is one or both of ifosfamide and mesna. In certain embodiments, the secondary treatment drug is IE therapy (ifosfamide + mesna).

[0050] In certain embodiments, the secondary therapeutic drug is one, two, or three of cyclophosphamide, adriamycin, and etoposide. In certain embodiments, the secondary therapeutic drug is a CAE regimen (cyclophosphamide + adriamycin + etoposide).

[0051] In certain embodiments, the secondary treatment drug is one or both of adriamycin and dacarbazine. In certain embodiments, the secondary treatment drug is an AD regimen (adriamycin + dacarbazine).

[0052] In certain embodiments, the secondary treatment drug is one, two, or three of adriamycin, epirubicin, and ifosfamide. In certain embodiments, the secondary treatment drug is an AIM regimen (adriamycin + ifosfamide).

[0053] In certain embodiments, the secondary treatment drug is one, two, or three of adriamycin, ifosfamide, and dacarbazine. In certain embodiments, the secondary treatment drug is the MAID regimen (adriamycin + ifosfamide + dacarbazine).

[0054] In a specific embodiment, the secondary treatment drug is one or both of gemcitabine and docetaxel.

[0055] Compounds of Formula I or pharmaceutically derived compounds thereof Allowable salt

[0056] The chemical name of the compound in chemical formula I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine[1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine] and has the following structural chemical formula.

[0057] [Chemical Formula I]

[0058]

[0059] In this application, in any case, anlotinib refers to a compound of formula I.

[0060] The compound of the above chemical formula I is in its free base form or in vivo ( in vivo It may be administered in the form of a salt, hydrate, or prodrug that can be converted into a free base form. For example, within the scope of this application, a pharmaceutically acceptable salt of the compound of Formula I may be produced from various organic and inorganic acids according to methods generally known in the art.

[0061] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in the form of hydrochloride. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in the form of monohydrochloride. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in the form of dihydrochloride. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in the form of crystalline hydrochloride. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in the form of crystalline dihydrochloride.

[0062] The compound of Formula I or a pharmaceutically acceptable salt thereof and a secondary therapeutic drug may be administered via multiple administration routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, sublingual, intramuscular, rectal, buccal mucosa, nasal, inhalation, vaginal, ocular, topical, subcutaneous, intrafatular, intra-articular, and intrameningeal administration, but are not limited thereto. In certain embodiments, the drug is administered orally.

[0063] The dosage of the compound of Formula I or its pharmaceutically acceptable salt and the secondary treatment drug may be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, and the age and health of the individual. In some embodiments, the daily dose of the compound of Formula I or its pharmaceutically acceptable salt is 3 mg to 30 mg. In some embodiments, the daily dose of the compound of Formula I or its pharmaceutically acceptable salt is 5 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or its pharmaceutically acceptable salt is 8 mg to 16 mg. In some embodiments, the daily dose of the compound of Formula I or its pharmaceutically acceptable salt is 10 mg to 14 mg. In certain embodiments, the daily dose of the compound of Formula I or its pharmaceutically acceptable salt is 8 mg. In certain embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In certain embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. For example, in the case of tablets or capsules in this application, "containing 12 mg of the compound of Formula I on a unit dose basis" means that each tablet or capsule finally produced contains 12 mg of the compound of Formula I.

[0064] The compound of Formula I or a pharmaceutically acceptable salt thereof and a secondary therapeutic drug may be administered once or several times daily. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally in solid form once daily.

[0065] In the above treatment method, the route of administration may be determined based on the activity and toxicity of the drug, the individual's tolerance, etc. Preferably, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered according to an intermittent regimen. The intermittent regimen includes a treatment period and an interruption period. During the treatment period, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered once or several times daily. For example, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered daily during the treatment period, and then, after discontinuing treatment during an intermediate period, the treatment period and the interruption period are repeated. The ratio of the treatment period (days) to the interruption period is 2:0.5 to 2:5, preferably 2:0.5 to 2:3, more preferably 2:0.5 to 2:2, and even more preferably 2:0.5 to 2:1.

[0066] In some embodiments, the treatment is administered for 2 consecutive weeks and then discontinued for 2 weeks. In some embodiments, the treatment is administered once daily for 14 consecutive days and then discontinued for 14 days, and then administered once daily for 14 consecutive days and then discontinued for 14 days. The intermittent therapy may be repeated several times in a continuous 2 / 2-week treatment / discontinuation cycle.

[0067] In some embodiments, the treatment is administered for 2 consecutive weeks and then discontinued for 1 week. In some embodiments, the treatment is administered once daily for 14 consecutive days and then discontinued for 7 days, and then administered once daily for 14 consecutive days and then discontinued for 7 days. The intermittent therapy may be repeated several times in a continuous 2 / 1 week treatment / discontinuation cycle.

[0068] In some embodiments, the treatment is administered for 5 consecutive days and then discontinued for 2 days. In some embodiments, the treatment is administered once daily for 5 consecutive days and then discontinued for 2 days, and then administered once daily for 5 consecutive days and then discontinued for 2 days. The intermittent therapy may be repeated several times in a 5 / 2-day treatment / discontinuation cycle.

[0069] In a specific embodiment, the drug is administered once daily for two consecutive weeks at a dose of 12 mg, and then discontinued for one week.

[0070] Pharmaceutical combination

[0071] Each component of the pharmaceutical combination described herein may be used in an optional combination of one or more pharmaceutically acceptable carriers, said component may include the pharmaceutically acceptable carrier and / or excipient, respectively, or all or part of said component together. The components in the pharmaceutical combination described herein may be formulated separately, or all or part of said components may be formulated together. Preferably, the components of said pharmaceutical combination may be formulated separately into a suitable pharmaceutical composition, or each may be formulated individually. In some embodiments, the pharmaceutical combination described herein may be formulated into a pharmaceutical composition suitable for a single dose or multiple doses. In some specific embodiments, the pharmaceutical combination comprising the compound of Formula I or a pharmaceutically acceptable salt thereof may be selected from the group consisting of solid pharmaceutical compositions including tablets or capsules, but is not limited thereto.

[0072] The components of the pharmaceutical combinations described herein may be administered separately, or some or all of the components may be administered together. The components of the pharmaceutical combinations described herein may be administered sufficiently asynchronously, or some or all of the components may be administered sufficiently simultaneously.

[0073] The components of the pharmaceutical combinations described herein may be administered independently or via a suitable route for oral or parenteral administration (via intravenous, intramuscular, local, or subcutaneous routes), or all or part of said components may be administered together, but are not limited thereto. In some embodiments, the components of the pharmaceutical combinations described herein may be administered independently or via injection, e.g., intravenous injection or intraperitoneal injection, or all or part of said components may be administered together.

[0074] The components in the pharmaceutical combinations described herein may be independently suitable dosage forms, or all or part of the components may be formulated together in suitable dosage forms including, but not limited to, tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, and microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, and intraperitoneal), granules, emulsions, suspensions, solutions, dispersants, and sustained-release formulations for oral or parenteral administration.

[0075] In some embodiments of the present application, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

[0076] In some embodiments of the present application, the pharmaceutical combination is a non-fixed combination. In some embodiments, the secondary therapeutic drug and the compound of Formula I or a pharmaceutically acceptable salt thereof within the non-fixed combination are each in the form of a pharmaceutical composition.

[0077] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is used in combination with surgical resection and / or radiation therapy.

[0078] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with one or more secondary therapeutic drugs. In certain embodiments, one or more secondary therapeutic drugs are administered to an individual before the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, or before the combination of the compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, one or more secondary therapeutic drugs are administered again to an individual after the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, or after the combination of the compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to an individual before the administration of one or more secondary therapeutic drugs or before the combination of one or more secondary therapeutic drugs. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered again to an individual after the administration of one or more secondary therapeutic drugs or after the combination of one or more secondary therapeutic drugs. In certain embodiments, one or more secondary treatment drugs are not effective for cancer treatment. In some embodiments, the secondary treatment drugs may be any anticancer drugs described herein or known in the art.

[0079] In some embodiments, after administering the compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more secondary therapeutic drugs to an individual, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the individual in succession. In some embodiments, after administering the compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more secondary therapeutic drugs to an individual, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally to the individual in succession for 2 to 8 cycles. In some embodiments, after administering the compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more secondary therapeutic drugs to an individual, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally to the individual in succession for 6 to 24 weeks. In some embodiments, after administering the compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more secondary therapeutic drugs to an individual, the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to the individual for six consecutive cycles. In some embodiments, after administering the compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more secondary therapeutic drugs to an individual, the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to the individual for 18 consecutive weeks.

[0080] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof and the secondary therapeutic drug are formulated into a formulation suitable for oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, sublingual, intramuscular, rectal, buccal, nasal, inhalation, vaginal, ocular, topical, subcutaneous, intrafatular, intra-articular, and intrameningeal administration, preferably a formulation suitable for oral administration including tablets, capsules, powders, granules, drop pills, pastes, and pulvis, more preferably a tablet or a capsule. The tablet may be a regular tablet, a dispersible tablet, an effervescent tablet, a sustained-release tablet, a controlled-release tablet, or an enteric-coated tablet, and the capsule may be a regular capsule, a sustained-release capsule, a controlled-release capsule, or an enteric-coated capsule. The oral formulation may be prepared by conventional methods using a pharmaceutically acceptable carrier well known in the art. The above-mentioned pharmaceutically acceptable carrier comprises fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. The filler comprises starch, lactose, mannitol, microcrystalline cellulose, etc. The absorbent comprises calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc. The wetting agent comprises water, ethanol, etc. The binder comprises hydroxypropyl methylcellulose, polyvidon, microcrystalline cellulose, etc. The disintegrant comprises sodium croscarmellose, crospovidon, surfactants, low-substitution hydroxypropylcellulose, etc. The lubricant comprises magnesium stearate, talc powder, polyethylene glycol, sodium dodecyl sulfate, silica gel fine powder, etc. The above-mentioned pharmaceutically acceptable excipient further comprises coloring agents, sweeteners, etc.

[0081] In some embodiments of the present application, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

[0082] In some embodiments of the present application, the pharmaceutical combination is a non-fixed combination. In some embodiments, the secondary therapeutic drug and the compound of Formula I or a pharmaceutically acceptable salt thereof within the non-fixed combination are each in the form of a pharmaceutical composition.

[0083] Additionally, in some embodiments, a kit of pharmaceutical combinations for use in treating soft tissue sarcoma is provided, comprising (a) a primary pharmaceutical composition containing a chemotherapy drug as an active ingredient; and (b) a secondary pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient. Additionally, in some embodiments, a kit of pharmaceutical combinations for use in treating soft tissue sarcoma is provided, comprising (a) a primary pharmaceutical composition containing a small molecule targeted anti-tumor drug as an active ingredient; and (b) a secondary pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient. Additionally, in some embodiments, a kit of pharmaceutical combinations for use in treating soft tissue sarcoma is provided, comprising (a) a primary pharmaceutical composition containing an immunotherapy drug as an active ingredient; and (b) a secondary pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, in some embodiments, a kit of pharmaceutical combinations for use in treating soft tissue sarcoma is provided, comprising (a) a primary pharmaceutical composition containing epirubicin as an active ingredient; and (b) a secondary pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0084] Wherever the following terms used in this specification and claims have the following meanings for the purposes of the present invention, unless otherwise specified.

[0085] In this application, in any case, anlotinib refers to a compound of formula I.

[0086] The term “treatment failure” as used in this specification refers to hypersensitivity to toxicity and side effects, disease progression during treatment, or recurrence after treatment.

[0087] The term "subject" as used in this specification refers to mammals such as rodents, cats, dogs, and primates. Preferably, according to this application, the subject is a human.

[0088] “Administer,” “administration,” and “to administer” refer to the physical introduction of a composition containing a therapeutic agent into an individual using any various methods and delivery systems known to those skilled in the art. Routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, administered, for example, by injection or infusion. The term “parenteral administration” as used herein generally refers to a method of administration by injection, other than enteral and local administration, including intravenous, intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intracutaneous, intraperitoneal, intra-articular, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions and in vivo ( in vivo ) may include, but is not limited to, electroporation. In certain embodiments, the drug is administered via a non-injection route. In certain embodiments, the drug is administered orally. Other non-injection routes include local, epidermal, or mucosal administration routes, e.g., intranasal, intravaginal, rectal, sublingual, or local administration. Additionally, administration may be performed, e.g., once, multiple times, and / or over one or more extended periods.

[0089] "Entity" includes human or non-human animals. The term "non-human animal" may include, but is not limited to, non-human primates, vertebrates such as sheep and dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the entity is human. The terms "entity" and "subject" may be used interchangeably in certain parts of this specification.

[0090] The "therapeutic effective dose" or "therapeutic effective amount" of a drug or therapeutic agent is any dose of the drug that, when used alone or in combination with other therapeutic agents, protects an individual from the onset of disease or promotes disease regression, which is demonstrated by a reduction in the severity of disease symptoms or an increase in the frequency and duration of asymptomatic disease phases. The ability of a therapeutic agent to promote disease regression can be evaluated using various methods known to skilled physicians, such as in human subjects during clinical trials, in animal model systems predicting efficacy in humans, or in vitro ( in vitro It can be evaluated by determining the activity of the drug in the analysis.

[0091] For example, an "anticancer drug" promotes cancer regression in an individual or prevents further tumor growth. In certain embodiments, a therapeutically effective dose of the drug promotes cancer regression until the cancer is eliminated. "Promoting cancer regression" means administering an effective dose of the drug, either alone or in combination with an anti-tumor agent, that reduces tumor growth or size, tumor necrosis, reduces the severity of at least one disease symptom, or increases the frequency and duration of asymptomatic disease phases. Additionally, regarding treatment, the terms "effective" and "effectiveness" include pharmaceutical efficacy and physiological safety. Pharmaceutical efficacy refers to the ability of the drug to promote cancer regression in an individual. Physiological safety refers to the level of toxicity or other physiological adverse effects (side effects) at the cellular, organ, and / or organism level resulting from the administration of the drug.

[0092] As one example for treating a tumor, a therapeutically effective dose of an anticancer drug may inhibit cell growth or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% compared to an untreated subject, or, in certain embodiments, a subject treated with standard therapy. In other embodiments of the present application, tumor regression may be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Notwithstanding these final measurements of therapeutic efficacy, the evaluation of the drug must also take into account "immune-related" response patterns.

[0093] "Immune-related" response patterns refer to clinical response patterns often observed in cancer subjects treated with immunotherapies that exhibit anti-tumor effects by inducing cancer-specific immune responses or altering innate immune processes. These response patterns are defined by beneficial therapeutic effects resulting from an initial increase in tumor load or the development of new lesions; they are classified according to disease progression and are equated with drug failure in the evaluation of traditional chemotherapy. Accordingly, the appropriate evaluation of immunotherapies may require long-term monitoring of the efficacy of these agents against the target disease.

[0094] "Recurrent" cancer is the regeneration of cancer in the original site or a distant site after responding to initial treatment (e.g., surgery). "Local recurrent" cancer is the occurrence of cancer in the same location as the previously treated cancer after treatment.

[0095] "Irresectable" cancer is one that cannot be removed by surgery.

[0096] "Metastatic" cancer refers to cancer spreading from one part of the body (e.g., the lungs) to another part of the body.

[0097] The use of alternatives (e.g., "or") should be understood to refer to any one, two, or any combination of alternatives. As used herein, the indefinite articles "a" or "an" should be understood to mean "one or more" of the described or enumerated components.

[0098] The term “pharmaceutical acceptable” applies to the compounds, substances, compositions, and / or dosage forms described herein, within the scope of sufficient medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and within a reasonable benefit / risk ratio.

[0099] The term “pharmaceuticalally acceptable salt” includes salts formed by basic radicals and free acids and salts formed by acidic radicals and free bases, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, mesylate, benzenesulfonate and p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, mesylate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonia salt and amino acid salt, etc. In the present application, when a pharmaceutically acceptable salt is formed, the free acid and basic radicals have a molar ratio of about 1:0.5 to 1:8, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8. In the present application, when a pharmaceutically acceptable salt is formed, the free base and acid radicals have a molar ratio of about 1:0.5 to 1:8, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0100] The term "fixed combination" refers to the simultaneous administration of an active ingredient (e.g., a chemotherapy drug or a compound of Formula I or a pharmaceutically acceptable salt thereof) to an individual in the form of a single substance, pharmaceutical composition, or formulation, in a fixed total dose or a fixed dose ratio.

[0101] The term "non-fixed combination" refers to the administration of two or more of the aforementioned active ingredients as independent substances (e.g., pharmaceutical compositions and formulations) to an individual simultaneously, in parallel, or sequentially and transiently indefinitely, such that the active ingredients administered to the individual reach a therapeutically effective amount. For example, a non-fixed combination that can be listed is a cocktail therapy, for example, in which three or more active ingredients are administered. In a non-fixed combination, each active ingredient may be packaged, sold, or administered as a completely independent pharmaceutical composition. "Non-fixed combination" additionally includes the use of a combination of "fixed combinations" or independent substances of any one or more active ingredients.

[0102] As set forth in this specification, “combined use” or “use in combination” means that two or more active substances may be administered to an individual as a mixture, as a single formulation, simultaneously, or sequentially in any order as a single formulation.

[0103] The term “pharmaceutical composition” refers to a mixture of one or more active ingredients (e.g., a chemotherapy drug or a compound of Formula I or a pharmaceutically acceptable salt thereof) or a pharmaceutical combination disclosed herein, and pharmaceutically acceptable excipients. The pharmaceutical composition is intended to facilitate the administration of said compound or said pharmaceutical combination to an individual.

[0104] The term "18-week objective response rate (ORR)" refers to the percentage of individuals in whom a complete response (CR) or partial response (PR) is used as the best response, obtained by measuring the ORR in patients with progressive soft tissue sarcoma according to RECIST 1.1.

[0105] The term "progression-free survival (PFS)" refers to the time from the initial administration to objective progression or tumor death.

[0106] The term "overall survival (OS)" refers to the time from the initial administration to death from any cause. For individuals who failed to be followed up, the final follow-up time is generally considered the time of death calculated in days.

[0107] The term "safety" refers to the observation of adverse effects for combination drug therapy (according to CTCAE V4.0), where "CTCAE" refers to the general terminology standards for adverse effects.

[0108] The term "disease control rate (DCR)" refers to the disease control rate, which includes the percentage of cases in which complete remission, partial remission, and disease stability were achieved and sustained for 4 weeks or more in the efficacy evaluation subjects.

[0109] The term "complete response (CR)" means that all target lesions disappear and the diameter of all pathological lymph nodes (including target and non-target nodes) is reduced to less than 10 mm.

[0110] The term "partial response (PR)" means that the total diameter of the target lesion decreases by more than 30% from the baseline level.

[0111] The term "progressive disease (PD)" means that throughout this study, the sum of the measured diameters of all target lesions increases by more than 20% relative to the minimum value (or relative to the baseline if the baseline measurement is the minimum value).

[0112] The term "stable disease (SD)" refers to a state where the target lesion is not sufficiently reduced to the PR level, nor is it sufficiently increased to the PD level, but rather lies somewhere in between.

[0113] The term "PDX model" refers to a patient-derived tumor xenograft (PDX) model established by directly transplanting a patient's tumor-derived tissue into immunodeficient animals.

[0114] The terms “comprising,” “comprising,” and “comprising” or equivalents as used in this specification are open descriptions unless otherwise stated, and mean that unspecified elements, components, and steps may be additionally listed and included.

[0115] All patents, patent applications, and other identified publications are expressly incorporated herein by reference for the purposes of explanation and disclosure. These publications are provided because they were disclosed prior to the filing date of this application. Any description of the dates of these documents or the contents of these documents is based on information available to the applicant and does not imply the accuracy of the dates of these documents or the contents of these documents. Furthermore, in any country or region, any reference to these publications is not to be construed as forming part of the generally accepted knowledge in the relevant art. Specific details for implementing the invention

[0116] The present application is described in detail below with reference to specific embodiments. However, such embodiments are merely illustrative and are not intended to limit the scope of the application. Likewise, the present application is not limited to any specific preferred embodiment described herein. A person skilled in the art should recognize that equivalent substitutes or related modifications to the technical features of the present application are still within the scope of the present application. Unless otherwise stated, the reagents used in the following embodiments are commercially available products, and the solutions may be prepared by the ordinary art.

[0117] Examples 1. Human breeding PDX Regarding the model Epirubicin ( Epirubicin ) When combining of Anlotinib Therapeutic effects and toxicity

[0118] A human sarcoma SA-22-0003PDX nude mouse model was established.

[0119] Tumors were isolated from resected tissues of clinical malignant fibrous histiocytoma lesions and passaged to the fourth generation using BALB / c nude mice. Fourth-generation sarcoma tissue blocks (20-30 mm 3 A PDX model was established by subcutaneously inoculating BALB / c nude mice. On day 24, approximately 173 mm of subcutaneous tumor tissue from the PDX model was collected. 3 Animals were raised to [size] and divided into four groups according to therapy (6 nude mice per group): a blank control group, anlotinib group (3 mg / kg / d), an epirubicin group (2.5 mg / kg), and anlotinib and epirubicin combination group (3.0 mg / kg / d + 2.5 mg / kg). Route of administration: anlotinib was administered intragastrically daily; epirubicin was administered via tail vein once a week. Administration was performed for 5 weeks.

[0120] The systemic status of the above animals was observed; the growth of the transplanted tumors was measured, and tumor growth curves were plotted. Nude mice were sacrificed 5 weeks after administration, and biopsies were performed on the entire tumor. Blood was collected to measure the levels of hemoglobin (HGB), albumin (ALB), alanine transaminase (ALT), aspartate transaminase (AST), creatine kinase isoenzyme (CK-MB), cardiac troponin T (cTNT), and B-type N-terminal natriuretic peptide (NT-proBNP); Levels of Ki-67, EGFR, PDGFR-α, and PDGFR-β were measured, and microvessel density (MVD) in tumors was measured using the immunohistochemistry SP method. Cardiac muscle and tumors were observed using HE optical microscopy, and microstructures were observed using electron microscopy.

[0121] Results: In terms of tumor inhibitory effects, the average tumor weights for the four groups of nude mice were 2.62 ± 0.64 g, 0.71 ± 0.36 g, 1.20 ± 0.42 g, and 0.46 ± 0.20 g, respectively, among which the anlotinib and epirubicin combination group showed superior tumor inhibitory effects (p < 0.05). In the anlotinib and epirubicin combination group, Ki-67 and EGFR expression rates and MVD were significantly reduced (p < 0.05). In terms of safety, the nude mice in all three experimental groups were generally in good condition, and no significant differences were observed compared to the control group; regarding nutritional status (ALB, HBG), no significant differences were observed among the nude mice in all groups (p > 0.05), and body weight loss did not exceed 10%. In terms of toxicity, compared to the control group, nude mice in the three experimental groups exhibited specific liver damage (increased ALT and AST levels), but no significant differences were observed among the three groups (p < 0.05). Regarding cardiac function indicators, no significant differences were observed between groups in NT-proBNP and cTNT levels (p < 0.05); although CK-MB levels improved in all experimental groups compared to the control group, combination administration did not significantly improve CK-MB levels (p > 0.05). In the nude mice of the three experimental groups, no significant damage to the microstructure of cardiac muscle was observed under electron microscopy, and no significant differences were observed compared to the control group. HE staining of cardiomyocytes in the nude mice of the three experimental groups revealed no significant lesions in any part of the heart.

[0122] Conclusion: In the human sarcoma SA-22-0003PDX nude mouse model, the combination of anlotinib and epirubicin demonstrated a superior anti-tumor effect compared to the use of a single drug, and exhibited excellent safety without causing more severe malnutrition, greater liver damage, or cardiotoxicity.

[0123] Examples 2. Anlotinib and Epirubicin In combination, clinical trial for the first-line treatment of advanced soft tissue sarcoma

[0124] Patients aged 18–75 years diagnosed histopathologically with locally advanced or metastatic soft tissue sarcoma who were ineligible for surgery were selected, and epirubicin was administered intravenously in combination with oral anlotinib. Efficacy, safety, and the effect of the combination therapy were observed.

[0125] Research concluded

[0126] Primary study completion: Objective response rate (ORR) at Week 18; Secondary study completion: Progression-free survival (PFS), safety, disease control rate (DCR), and overall survival (OS)

[0127] Dosage

[0128] Anlotinib hydrochloride capsules (anlotinib dihydrochloride as the active ingredient) were administered orally before breakfast at a dose of 12 mg / day (1 capsule once daily) in a 3-week (21-day) cycle, and after administration for 2 consecutive weeks, discontinued for 1 week. If an adverse reaction occurred, the dose was adjusted to 10 mg or 8 mg.

[0129] Epirubicin is 90 mg / m² on the first day of each cycle. 2It was administered via continuous intravenous infusion (CIV) for 48 hours at a dose (concurrently used with dexrazoic acid for cardioprotection) on a 21-day cycle. In the event of an adverse reaction, the dose was adjusted to 80% or 60%.

[0130] After 6 cycles of combination therapy, if the condition was stable, oral administration of anlotinib (8-12 mg) alone was continued until PD or hypersensitivity occurred.

[0131] The dosage was adjusted during treatment based on adverse events. In accordance with CTCAE V4.0, no dosage adjustment was made for Grade 1 or 2 adverse events, and the original regimen was resumed upon recovery to Grade 1; for Grade 3 or 4 adverse events, administration was resumed after recovery to Grade 1. The investigator determined that the adverse event was caused by epirubicin or anlotinib; if the adverse event was associated with epirubicin, the dosage was reduced to 80%; if the adverse event was associated with anlotinib, the dosage was reduced to 10 mg qd; and if the adverse event was associated with both drugs, the dosages of both drugs were reduced. If Grade 3 or 4 adverse events recurred, the dosage of epirubicin could be reduced again to 60% and the dosage of anlotinib to 8 mg qd at the investigator's discretion.

[0132] This study allowed the use of drugs simply used to alleviate the side effects of supportive care and chemotherapy (e.g., antiemetics, first aid drugs, AE treatment drugs). Adjunctive antiemetics, gastroprotective drugs, and hepatoprotective drugs were used in a general manner.

[0133] Patient Case

[0134] A 48-year-old woman underwent laparoscopic total hysterectomy and bilateral salpingectomy in 2017, underwent laparoscopic bilateral oophorectomy + ovarian tumor resection + partial retinectomy + pelvic adhesiolysis under general anesthesia in November 2017, and initiated 6 cycles of GT chemotherapy in December 2017: gemcitabine 1400 mg d1, d8 + docetaxel 110 mg d8; clinical diagnosis: connective and soft tissue malignancy (stage IV uterine leiomyosarcoma), target lesion: abdominal and pelvic cavity (101 mm in the hepatic cyst, 104 mm in the pelvic cavity), total diameter 205 mm.

[0135] Multiple metastases were discovered approximately two years after the resection of the uterine leiomyosarcoma. The PET / CT results from June 11, 2019, are as follows: After combination therapy for uterine leiomyosarcoma: 1. Evidence suggesting multiple metastases in the abdomen and pelvic cavity based on PET / MRI images; 2. Multiple gallstones; abdominal and pelvic effusion; 3. Possibility of lymph nodes in the left clavicular region; bilateral pulmonary bronchiectasis accompanied by infection; calcification of the left breast. The table below shows the results of the therapy and efficacy evaluation.

[0136] Evaluation date Target lesion Validity evaluation First cycle regimen: Anlotinib 12 mg po qd d1-d14 + Epirubicin 140 mg civ 48 h (90 mg / m²) 2 ), q3w 2019-07-25 Total diameter 148 mm (84 mm in the liver sac, 64 mm in the pelvic cavity) SD Therapy after start of second cycle: Anlotinib 12 mg po qd d1-d14 + Epirubicin 110 mg civ 48 h (72 mg / m²) 2 ), q3w 2019-09-05 Total diameter 116 mm (63 mm in the liver sac, 53 mm in the pelvic cavity) PR 2019-10-17 Total diameter 115 mm (59 mm in the liver sac, 56 mm in the pelvic cavity) PR 2019-11-28 Total diameter 97 mm (47 mm in the liver sac, 50 mm in the pelvic cavity) PR

[0137] As a result of the efficacy evaluation, a total of 25 patients met the criteria, including 13 patients for SD, 1 patient for PR, 9 patients for PD, 1 patient who dropped out of the study, and 1 patient whose efficacy was not evaluated, and the DCR was 56%.

[0138] According to the contents disclosed in this application, the compositions and methods of this application have been described in terms of preferred embodiments. However, it will be apparent to those skilled in the art that, without departing from the concept, intent, and scope of this application, the compositions and / or methods and steps or the order of steps of said method described herein may be modified and applied.

[0139] All documents cited herein are incorporated by reference to the extent that they provide exemplary, procedural, and other details that supplement what is described herein.

Claims

Claim 1 (i) a compound of Formula I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical composition for concomitant administration for use in treating soft tissue sarcoma comprising epirubicin as an active ingredient.[Formula I] In the above, (i) a compound of formula I or a pharmaceutically acceptable salt thereof; and (ii) epirubicin are administered simultaneously, individually, or sequentially. Claim 2 A pharmaceutical composition according to claim 1, wherein the soft tissue sarcoma is selected from the group consisting of undifferentiated sarcoma, angiosarcoma, fibrosarcoma, gastrointestinal stromal tumor, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberance, malignant peripheral nerve sheath tumor, alveolar soft-part sarcoma, clear cell sarcoma, malignant mesenchymal sarcoma, and epithelioid sarcoma. Claim 3 A pharmaceutical composition according to claim 1, characterized in that the soft tissue sarcoma is an undifferentiated polymorphic sarcoma or an alveolar soft-part sarcoma. Claim 4 In claim 1, the soft tissue sarcoma is a desmoid tumor, Kaposi's sarcoma, neurodermal tumor, alveolar soft tissue sarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, mixed liposarcoma, low-grade fibromyxoid sarcoma, hyalinizing spindle cell tumor, sclerosing epithelioid fibrosarcoma, pericellular tumor, glomus tumor, glomus angioma, perimyoma, myofibroma, vascular leiomyoma, embryonic rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, spindle-shaped / sclerosing rhabdomyosarcoma, epithelioid hemangioma, epithelioid malignant peripheral neurodermal tumor, malignant Triton tumor, malignant granular cell tumor, synovial sarcoma, clear cell sarcoma of soft tissue, connective tissue-forming small cell tumor, extrarenal rhabdomyosarcoma, neoplasm with perivascular epithelioid differentiation, endometrial sarcoma, A pharmaceutical composition characterized by being selected from the group consisting of undifferentiated sarcoma, undifferentiated spindle cell sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid cell sarcoma, connective tissue-forming small cell tumor, and borderline fibrous tissue tumor. Claim 5 A pharmaceutical composition according to any one of claims 1 to 4, wherein the soft tissue sarcoma is selected from recurrent soft tissue sarcoma and / or metastatic soft tissue sarcoma and / or refractory soft tissue sarcoma and / or unresectable soft tissue sarcoma and / or progressive soft tissue sarcoma; or the soft tissue sarcoma is locally advanced soft tissue sarcoma; or the soft tissue sarcoma is primary soft tissue sarcoma or secondary soft tissue sarcoma. Claim 6 A pharmaceutical composition according to any one of claims 1 to 4, wherein the soft tissue sarcoma is a soft tissue sarcoma that has progressed or relapsed after receiving at least one chemotherapy; or the soft tissue sarcoma is a soft tissue sarcoma that is not resistant to chemotherapy; or the soft tissue sarcoma is a soft tissue sarcoma that has not received prior systemic treatment. Claim 7 A pharmaceutical composition according to any one of claims 1 to 4, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as an intermittent therapy during the replacement therapy and discontinuation period, and the ratio of the treatment period (days) to the discontinuation period is one of the following ratios: 2:0.5 to 2:5, 2:0.5 to 2:3, 2:0.5 to 2:2, and 2:0.5 to 2:

1. Claim 8 A pharmaceutical composition according to claim 7, characterized in that the intermittent therapy is one of the following cycles, and the cycle may be repeated multiple times: 2 weeks of discontinuation after 2 consecutive weeks of treatment, 1 week of discontinuation after 2 consecutive weeks of treatment, and 2 days of discontinuation after 5 consecutive days of treatment. Claim 9 A pharmaceutical composition according to any one of claims 1 to 4, characterized in that the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of 3 mg to 30 mg, 5 mg to 20 mg, 8 mg to 16 mg, or 10 mg to 14 mg. Claim 10 A pharmaceutical composition according to any one of claims 1 to 4, characterized in that the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 8 mg, 10 mg, or 12 mg. Claim 11 In any one of claims 1 to 4, (i) a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in doses of 6 mg, 8 mg, 10 mg and / or 12 mg; and (ii) 50-150 mg / m² 2 A pharmaceutical composition comprising a dose of epirubicin; or (i) a pharmaceutical composition comprising a dose of 6 mg, 8 mg, 10 mg and / or 12 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof; and (ii) 50, 54, 60, 72, 80, 90, 100, 110, 120, 135 and / or 150 mg / m² 2 A pharmaceutical composition comprising a dose of epirubicin; or (i) a pharmaceutical composition comprising a dose of 12 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof; and (ii) 90 mg / m² 2 A pharmaceutical composition characterized by comprising a pharmaceutical composition containing a dose of epirubicin. Claim 12 A kit for treating soft tissue sarcoma comprising a pharmaceutical composition according to any one of claims 1 to 4, wherein the kit comprises (a) epirubicin; and (b) a secondary pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient. Claim 13 A pharmaceutical composition according to claim 4, characterized in that the above-mentioned synovial film sarcoma is synovial film sarcoma NOS. Claim 14 delete

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