Bis-biguanide compounds, pharmaceutical compositions and use in the management of cancer
阅读说明：本技术 双缩二胍化合物、药物组合物和在管理癌症中的用途 (Bis-biguanide compounds, pharmaceutical compositions and use in the management of cancer ) 是由 亚当·马库斯 杰西卡·科尼恩 雷切尔·科曼达 杰米·阿恩斯特 托塔·甘内什 于 2020-02-28 设计创作，主要内容包括：本公开内容涉及使用双缩二胍化合物诸如阿来西定来管理癌症的方法和包含双缩二胍化合物的药物组合物。在某些实施方案中,本公开内容涉及治疗肺癌的方法,该方法包括向有相应需要的受试者施用有效量的双缩二胍化合物。在某些实施方案中,本公开内容涉及治疗小细胞肺癌的方法,该方法包括向有相应需要的受试者施用有效量的双缩二胍化合物。在某些实施方案中,受试者被诊断患有肺癌。在某些实施方案中,受试者被诊断患有小细胞肺癌。在某些实施方案中,受试者是人类受试者。(The present disclosure relates to methods of managing cancer using bis-biguanide compounds such as alexidine and pharmaceutical compositions comprising bis-biguanide compounds. In certain embodiments, the present disclosure relates to methods of treating lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound. In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound. In certain embodiments, the subject is diagnosed with lung cancer. In certain embodiments, the subject is diagnosed with small cell lung cancer. In certain embodiments, the subject is a human subject.)
1. A method of treating cancer, the method comprising administering a bis-biguanide compound or derivative to a subject in need thereof.
2. The method of claim 1, wherein the subject is diagnosed with lung cancer.
3. The method of claim 1, wherein the bis-biguanide compound is alexidine or a salt thereof.
4. The method of claim 1, wherein the bis-biguanide compound is AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt thereof.
5. The method of claim 1, wherein the bis-biguanide compound is AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt thereof.
6. The method of claim 1, wherein the bis-biguanide compound is AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt thereof.
7. The method of claim 2, wherein the bis-biguanide compound has formula I or a salt thereof:
wherein the content of the first and second substances,
l is a linking group;
n is 1 to 22;
R1is a hydrocarbyl, aryl or lipid, wherein R1Optionally substituted with one or more substituents, and
R2is a hydrocarbyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents.
8. The method of claim 7, wherein L is individually and independently selected at each occurrence from O, NH, C-O, CH2、OCH2、CH2O、NHCH2、CH2NH、OCH2CH2、CH2CH2O、NHCH2CH2Or CH2CH2NH。
9. The method of claim 7, wherein L is (CH)2) And n is 2 to 12.
10. The method of claim 7, wherein R1Is a branched hydrocarbon group and n is 2 to 22.
11. The method of claim 7, wherein R2Is a branched hydrocarbon group and n is 2 to 22.
12. The method of claim 1, wherein the bis-biguanide compound is administered in combination with a second chemotherapeutic agent.
13. The method of claim 12, wherein the subject is diagnosed with lung cancer and the second therapeutic agent is selected from bevacizumab, ramucirumab, crizotinib, erlotinib, gefitinib, afatinib maleate, ceritinib, ramucirumab, nivolumitumumab, palboceprizumab, ocitinib, tolituzumab, altertib, brigatinib, trametinib, dabrafenib, duvatuzumab, dacoveritinib, loratidinib, or a combination thereof.
14. The method of claim 1, wherein the subject is a human.
15. A bis-biguanide compound having the formula I or a salt thereof:
Wherein the content of the first and second substances,
l is a linking group;
n is 1 to 22;
R1is a hydrocarbyl, aryl or lipid, wherein R1Optionally substituted with one or more substituents, and
R2is a hydrocarbyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents.
16. The compound of claim 1, wherein the bis-biguanide compound is AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt thereof.
17. The compound of claim 1, wherein the bis-biguanide compound is AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt thereof.
18. The compound of claim 1, wherein the bis-biguanide compound is AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt thereof.
19. A pharmaceutical composition comprising a compound according to claims 15-18 and a pharmaceutically acceptable excipient.
Background
Non-small cell lung cancer is a broad term for several types of lung cancer that behave similarly, such as squamous cell epithelial carcinoma, adenocarcinoma, and large cell epithelial carcinoma. Severe smokers often develop Small Cell Lung Cancer (SCLC). The outcome of patients with SCLC is still unpredictable. Although many SCLC patients respond to first-line chemotherapy, disease recurrence is common. Relapse after initial first-line therapy is associated with a higher risk of tolerance to available remedial treatment options. Thus, there is a need to identify improved therapies.
Konen et al reported an image-guided genomics technique called spatio-temporal genomics and cellular analysis (SaGA) that allows for the precise selection and expansion of both living and rare cells. Nat Comm,2017,8: 15078. SaGA was used on a population of generally aggressive 3D cancer cells to create purified leader cell lines and follower cell lines. Lead cell cultures are phenotypically stable and highly invasive compared to follow-up cultures that show phenotypic plasticity over time.
Yip et al reported the potential use of alexidine dihydrochloride as a pro-apoptotic anticancer agent. Mol Cancer Ther,2006,5(9): 2234-40. See also Graber et al, Oral diagnostics, which inhibit protein-protein interactions, mediated by the anti-adaptive protein Bcl-xL and index apoptosis in human organ cells, eds., 2013,52: 4487-; niemi et al Downcorrelation of the Mitochondrial Phosphoptase PTPMT1 Is minor to promoter Cell Death, PLoS ONE,2013,8(1): e 53803; and Lo et al, computerized cell cycle profiling of cancer cells for printing FDA-improved drugs with reproducing potential, Sci Rep,2017,7(1): 11261.
The references cited herein are not an admission of prior art.
SUMMARY
The present disclosure relates to methods of managing cancer using bis-biguanide compounds such as alexidine and pharmaceutical compositions comprising bis-biguanide compounds. In certain embodiments, the present disclosure relates to methods of treating lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound. In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound. In certain embodiments, the subject is diagnosed with lung cancer. In certain embodiments, the subject is diagnosed with small cell lung cancer. In certain embodiments, the subject is a human subject.
The present disclosure relates to bis-biguanide compounds and pharmaceutical compositions comprising the same. In certain embodiments, the bis-biguanide compound is alexidine, a derivative or salt thereof. In certain embodiments, the bis-biguanide compound is chlorhexidine. In certain embodiments, the bis-biguanide or alexidine derivative has formula I or a salt thereof:
Wherein L is a linking group; n is 1 to 22; r1Is a hydrocarbyl, aryl or lipid, wherein R1Optionally substituted with one or more substituents, and R2Is a hydrocarbyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents.
In certain embodiments, L is selected, individually and independently at each occurrence, from O, NH, C ═ O, CH2、OCH2、CH2O、NHCH2、CH2NH、OCH2CH2、CH2CH2O、NHCH2CH2Or CH2CH2NH。
In certain embodiments, L is (CH)2) And n is 2 to 8. In certain embodiments, L is (CH)2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R1Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R1Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R1Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 22.
In certain embodiments, L is (CH)2) And n is 2 to 8. In certain embodiments, L is (CH)2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R2Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R 2Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R2Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 22.
In certain embodimentsL is (CH)2) And n is 2 to 8. In certain embodiments, L is (CH)2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R1Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R1Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R1Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 22.
In certain embodiments, L is (CH)2) And n is 2 to 8. In certain embodiments, L is (CH)2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R2Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R2Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R 2Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 22.
In certain embodiments, the bis-biguanide compound is administered in combination with a second chemotherapeutic agent. In certain embodiments, the subject is diagnosed with lung cancer and the second chemotherapeutic agent is selected from bevacizumab (bevacizumab), ramucirumab (ramucirumab), crizotinib (crizotinib), erlotinib (erlotinib), gefitinib (gefitinib), afatinib dimaleate (afatinib), ceritinib (ceritinib), ramucirumab, nivolumab (nivolumab), palbociclumab (pembroglizumab), oxifinib (ositinib), tolitumumab (necitumumab), alitinib (alectinib), alemtuzumab (atezumab), bregatinib (brigatinib), trametinib (trametinib), darafenib (dabigatran), metribulizumab (atex), or ibritumomab (erlotinib), or a combination thereof.
In certain embodiments, the present disclosure relates to the use of a bis-biguanide compound disclosed herein for the production of a medicament for the treatment or prevention of a cancer as reported herein.
In certain embodiments, the present disclosure relates to a method of making a bis-biguanide compound disclosed herein, comprising mixing the starting materials and reagents disclosed herein under conditions such that the compound is formed.
Brief description of several views of the drawings
Figure 1A illustrates certain bis-biguanide compounds of the present disclosure. Alexidine has the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylhexyl) biguanide). AX-1 has the chemical name 1- (2-ethylhexyl) -5-propylbiguanide. AX-2 has the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (methyl) biguanide). AX-3 has the chemical name 1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide). AX-4 has the chemical name 1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide).
Figure 1B illustrates certain bis-biguanide compounds of the present disclosure. TG-AX5 has the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-butylhexyl) biguanide). TG-AX7 has the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide). TG-AX10 has the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (4-methoxybutyl) biguanide).
FIG. 2A shows data for dose-dependent viability of H1299 (human lung cells derived from metastatic lymph nodes) lead cells (leader cells) isolated by spatio-temporal genomics and cell analysis (SaGA) after 72H treatment with alexidine and analogs AX-2, AX-4 and AX-7.
Fig. 2B shows data for following cells (follower cells) isolated by SaGA.
Figure 2C shows data for parental cells isolated by SaGA.
Figure 3 shows inhibition of 3D invasion of H1299 leader cells into Matrigel at 48H.
Fig. 4A illustrates a method of making an embodiment of the present disclosure.
Fig. 4B illustrates a method of making an embodiment of the present disclosure.
Fig. 4C illustrates a method of making an embodiment of the present disclosure.
Figure 5 illustrates certain bis-biguanide compounds and derivatives of the present disclosure. Compound a has the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide). TG-AX12 has the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinyl urea). TG-AX13 has the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide). TG-AX14 has the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-propylpentyl) biguanide). TG-AX15 has the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide).
Detailed discussion
Before the present disclosure is described in more detail, it is to be understood that this disclosure is not limited to the described embodiments and, thus, may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
Unless defined otherwise, 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 disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.
All publications and patents cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and were set forth in its entirety herein to disclose and describe the methods and/or materials in connection with which the publications were cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any mentioned methods may be performed in the order of events mentioned or in any other order that is logically possible.
Unless otherwise indicated, embodiments of the present disclosure will employ techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings unless an intention to the contrary is apparent.
By "subject" is meant any animal, preferably a human patient, livestock, rodent, monkey, or domestic pet.
By "subject" is meant any animal, preferably a human patient, livestock or domestic pet.
As used herein, the terms "preventing" and "preventing" include preventing relapse, spread, or seizures. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity is reduced.
As used herein, the terms "treatment" and "treating" are not limited to situations in which a subject (e.g., a patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatments that merely alleviate symptoms and/or delay disease progression.
As used herein, the term "in combination with … …" when used to describe administration with an additional treatment means that the agent can be administered prior to, concurrently with, or after the additional treatment, or a combination thereof.
"cancer" refers to any of a variety of cellular diseases having malignant neoplasms characterized by cell proliferation. This does not mean that diseased cells (diseased cells) must actually invade surrounding tissues and metastasize to new body sites. Cancer can involve any tissue of the body and has many different forms in each body region. In the context of certain embodiments, the presence or absence of a "reduction in cancer" can be identified by a variety of diagnostic means known to those of skill in the art, including but not limited to observing a reduction in the size or number of tumor masses (tumor masses), or whether an increase in cancer cell apoptosis is observed, for example, if more than a 5% increase in cancer cell apoptosis is observed for the sample compound compared to a control without the compound. Can also be identified by changes in relevant biomarkers or gene expression profiles, such as PSA for prostate cancer, HER2 for breast cancer, or others.
In the context of the present disclosure, the cancer to be treated may be any type of cancer or tumor. These tumors or cancers include, but are not limited to, hematopoietic and lymphoid tissue tumors or hematopoietic and lymphoid malignancies, tumors affecting the blood, bone marrow, lymphoid and lymphoid systems. Hematological malignancies can be derived from two major blood cell lineages: myeloid cell lines and lymphoid cell lines. Myeloid cell lines typically produce granulocytes, erythrocytes, platelets, macrophages and mast cells; lymphocyte cell lines produce B cells, T cells, NK cells and plasma cells. Lymphomas, lymphoblastic leukemias, and myelomas are derived from the lymphoid lineage, while acute and chronic myelogenous leukemias, myelodysplastic syndromes, and myeloproliferative diseases originate in the bone marrow.
Also contemplated are malignancies located in the colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testis, ovary, thymus, thyroid), eye, head and neck, nervous system (central and peripheral), lymphatic system, pelvis, skin, soft tissues, spleen, chest and genitourinary (genetic-genitalia) and more particularly childhood acute lymphoblastic leukemia, acute myelogenous leukemia, adrenocortical carcinoma, adult (primary) hepatocellular carcinoma, adult (primary) liver cancer, adult acute lymphoblastic leukemia, adult acute myelogenous leukemia, adult Hodgkin's disease, adult Hodgkin's lymphoma, adult lymphocytic leukemia, adult non-Hodgkin's lymphoma, human hepatoma, human primary liver cancer, human acute lymphoblastic leukemia, human non-Hodgkin's lymphoma, human lymphomas, and human genitalia, Adult primary liver cancer, adult soft tissue sarcoma, AIDS-related lymphoma, AIDS-related malignancy, anal cancer, astrocytoma, biliary tract cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, renal pelvis and ureter cancer, primary central nervous system lymphoma, cerebellar astrocytoma, brain astrocytoma, cervical cancer, childhood (primary) hepatocellular carcinoma, childhood (primary) liver cancer, childhood acute lymphoblastic leukemia, childhood acute myelogenous leukemia, childhood brain stem glioma, childhood cerebellar astrocytoma, childhood brain astrocytoma, childhood extracranial germ cell tumor, childhood Hodgkin's disease, childhood Hodgkin's lymphoma, childhood visual pathway and hypothalamic glioma, childhood lymphoblastic leukemia, childhood medulloblastoma, childhood non-Hodgkin's lymphoma, human cancer, cancer of the liver, cancer of the brain stem and cell, cancer of the kidney, cancer of the brain stem and the kidney, and the like, Primary neuroectodermal and pineal tumors in the child's supratentorial, childhood, primary liver cancer, childhood rhabdomyosarcoma, childhood soft tissue sarcoma, childhood visual pathway and hypothalamic gliomas, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, cutaneous T-cell lymphoma, endocrine islet cell carcinoma, endometrial cancer, ependymoma, epithelial cancer, esophageal cancer, ewing's sarcoma and related tumors, exocrine pancreatic cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic biliary tract cancer, ocular cancer, female breast cancer, gaucher's disease, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor (gastointestinal carcinoid tumor), gastrointestinal tumor, germ cell tumor, gestational trophoblastic tumor, head and neck cancer, hepatocellular carcinoma, hodgkin's disease, hodgkin's lymphoma, hypercholesterolemia, hypopharyngeal cancer, intestinal cancer, intraocular melanoma, islet cell carcinoma, pancreatic carcinoma, neuroblastoma tumor, hemangioblastoma, hemangiocarcinoma, carcinoma, hemangiocarcinoma, carcinoma of the head and others, carcinoma of the like, carcinoma of the head and others, carcinoma of the body of the head and others, carcinoma of the body of the head, Pancreatic islet cell carcinoma, kaposi's sarcoma, kidney cancer, larynx cancer, lip and oral cancer, liver cancer, lung cancer, lymphoproliferative disorders, macroglobulinemia, male breast cancer, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, mesothelioma, occult primary metastatic squamous neck cancer, multiple myeloma/plasmacytoma, myelodysplastic syndrome, myeloid leukemia, myelogenous leukemia, myeloproliferative disorders, paranasal sinus and nasal cavity cancer, nasopharyngeal cancer, neuroblastoma, gestational non-hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, metastatic squamous neck cancer with occult primary, oropharyngeal cancer, malignant fibrosarcoma/osteocyte, Epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, paraproteinemia (paraproteinemia), purpura, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, plasmacytoma/multiple myeloma, primary central nervous system lymphoma, primary liver cancer, prostate cancer, kidney cancer, renal cell carcinoma, carcinoma of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoidosis, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous neck cancer, gastric cancer (stomach cancer), pineal and supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, carcinoma of the renal pelvis and ureter, transitional renal pelvis and ureter cancer, trophoblastic tumor, renal pelvis and ureter cell cancer, urethral cancer, uterine cancer, thyroid cancer, and ureter cell cancer, cervical cancer, prostatic cancer, cervical cancer, prostatic cancer, renal carcinoma, and ureter cancer, cervical cancer, Uterine sarcoma, vaginal cancer, optic nerve pathway and hypothalamic glioma, vulvar cancer, Waldenstrom's macroglobulinemia, nephroblastoma and any other hyperproliferative diseases as well as tumor formation in the aforementioned organ systems.
"chemotherapeutic agent", "anti-cancer agent" and the like refer to molecules that are believed to contribute to the treatment of cancer. Contemplated examples include the following molecules, prodrugs or derivatives thereof. In certain embodiments, it is contemplated that the additional chemotherapeutic agent or combination is selected from the group consisting of abelcitonin (abemaciclib), abiraterone acetate, methotrexate, paclitaxel, doxorubicin, alcalitinib (acalaburtinib), weibull kept mab, ado-enrietuzumab (ado-trastuzumab emtansine), aflibercept, afatinib, netupitant, palonosetron, imiquimod, aldeskin, alexanib, alemtuzumab, pemetrexed disodium, copulisib, melphalan, bucatinib, chlorambucil, amifostine, aminoacetylpropionic acid, anastrozole, apatamide (aparitamide), apitansine (aprepitant), mirtazumab disodium, exemestane, nelarabine, arsenic trioxide, mellitinib, bevacizumab, azalide, azacitib, azalide, bevacizumab, fluvastatin, bevacizumab, fluvastatin, or a, Imidazemab ozogamicin, bevacizumab, bexarotene, bicalutamide, bleomycin, belinostoc, bortezomib, bosutinib, vebutuximab, bocetinib, busulfan, irinotecan, capecitabine, fluorouracil, carboplatin, carfilzomib, ceritinib, daunorubicin, cetuximab, cisplatin, cladribine, cyclophosphamide, clofarabine, cobicistinib, cabozantinib malate (cabozantinib-S-malalate), dactinomycin, crizotinib, ifosfamide, ramucirumab, cytarabine, dalafenib, dacarbazine, decitabine, dareutuzumab, daltepuzumab, dasatinib, degareliximab, digaegliclarubicin (doxin), dexrazin, dexrazoxane, doxin, dexrazin, doxetacin, gazeocin, doxin, doxorubicin, valrubicin, trexatin, doxycycline, clofibrate, doxycycline, clofibrate, bexaprop-b, bexaglibenezetil, bexaprop-b, bexaglibenfurin, bexaprop-b, bexaglibenezetil, bexaprop-b, bexa, Labyrinthic, epirubicin, eltamizumab, oxaliplatin, eltrombopagolamine (eltrombopag olamine), enzipine, enzalutamide, eribulin, vismodegib (vismodegib), erlotinib, etoposide, everolimus, raloxifene, toremifene, panobinostat, fulvestrant, letrozole, filgrastim, fludarabine, flutamide, pralatrexate, otuzumab, gefitinib, gemcitabine, gemtuzumab ozolomide, goukapapidase (glucarpidadase), goserelin, propranolol, trastuzumab, topotecan, piperacillin, ibritumomab (ibritumomitantetan), ibrutinib, linaglipizide, idarubicin, elalisisib, imatinib (itacilazalide), ibrinolide, tamide, gazepine, docetaxel, rituximab, valcanicillin, gefitinib, idarubicin, etamine, etamol, valnemadefovir, valnemadelomib, paclitaxel, valnemadefovir, valdecoxib, paclitaxel, valnemadefovir, valnemadelomib, valdecoxib, paclitaxel, valdecoxib, valnemadefovir, valnemadelomicrotretamine, valnemadevicitabine, valnemadelomicronel, valnemadelomib, valnemadelomicron, valnemadevicitabine, valnemadelomicron, paclitaxel, valnemadelomicron, valnemadelomib, paclitaxel, valnemadelomib, valnemadelomicron, valnemadelomib, paclitaxel, and a, valnemadelomicron, valnemadelomib, a, Ribociclib, tisagenleceucel, lanreotide, lapatinib, olaratumab, lenalidomide, ranvatinib, calcium folinate, leuprolide, lomustine, trifluridine, olaparide, vincristine, procarbazine (procarbazine), mechlothiamine, megestrol, trimetinib, temozolomide, methylnaltrexone bromide, midodrine, mitomycin C, mitoxantrone, prasuxaforte, vinorelbine, netoruzumab, neratinib, sorafenib, nilutamide, nilotinib, nilapanib, niboletuzumab, tamoxifen, tamiflavine, donigutib (sonidegigb), reacetaxine, pemetrexenase (pegasragomalizumab), ondansetrexen, oxepirubicin, palentinostoc, paparipiprolipramipeline, peruviorelbine (peruviorelbine), papovanib (peganufactol), papovanib (papovanib), papovanib), papovanib (papovanib), papovanib (papova), papova (papova), papovanib), papova (papova), papova), papova (papova), papova (papova, cetuximab, sunitinib, thioguanine, temsirolimus (temsirolimus), thalidomide, thiotepa, trabectedin, valrubicin, vandetanib (vandetanib), vinblastine, vemurafenib (vemurafenib), vorinostat, zoledronic acid (zoledronic acid), or combinations thereof, such as the following: cyclophosphamide, methotrexate, 5-fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); nitrogen mustard, vincristine, procarbazine, prednisolone (MOPP); doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (RCHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); and methotrexate, vincristine, doxorubicin, cisplatin (MVAC).
As used herein, the term "small cell lung cancer" refers to small cell carcinoma (oat cell carcinoma) or a combined small cell carcinoma identified in lung tissue. The tests and procedures can be used for detection (discovery), diagnosis and staging of small cell lung cancer. A subject may be diagnosed with small cell lung cancer by laboratory testing, sputum cytology, lung biopsy, such as a fine-needle aspiration (FNA) biopsy of the lung, bronchoscopy, thoracoscopy, thoracocentesis, mediastinoscopy, CT scan (CAT scan), or chest x-ray. Test samples of lung tissue or fluid, blood, urine, or other substances in the body may be used. These tests can be used to plan and examine treatment or to monitor disease over time.
As used herein, "bis-biguanide compound" refers to a compound having two bridged biguanide groups, i.e., (— NH (C ═ NH) NH —), connected by a linking group. In certain embodiments, the bis-biguanide compounds are alexidine [1,1'- (hexane-1, 6-diyl) bis (5- (2-ethylhexyl) biguanide) ] and derivatives and chlorhexidine [1,1' - (hexane-1, 6-diyl) bis (3- (4-chlorophenyl) biguanide) ] and derivative salts thereof, including digluconate and diacetate, especially digluconate. Other salts include dipropionate, diformate, dilactate, dihydrochloride, dihydrofluoride, dihydrobromide, sulfate, phosphate, succinate, pivalate, citrate, tartrate and maleate salts.
As used herein, the term "derivative" refers to a structurally similar compound that retains sufficient functional attributes of the identified analog. Derivatives may be structurally similar in that the derivative lacks one or more atoms, e.g., hydrogen in place of an amino group, a hydroxyl group, or a thiol group; substituted; salt; in different hydration/oxidation states; or because one or more atoms within the molecule are converted, such as, but not limited to, replacing an oxygen atom with a sulfur atom or replacing an amino group with a hydroxyl group or a hydrogen saturated carbon. The derivatives may be prodrugs including lipids, polyethylene glycol, sugars, polysaccharides. A derivative may be two or more compounds linked together by a linking group. It is contemplated that the linking group may be biodegradable. Derivatives may be prepared by a variety of synthetic methods or appropriate modifications as provided in textbooks of synthetic Chemistry or Organic Chemistry, such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6 th edition (2007) Michael B.Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F.Tietze, incorporated herein by reference.
The term "prodrug" refers to an agent that is converted in vivo to a biologically active form. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent compound. For example, they can be bioavailable by oral administration, whereas the parent compound cannot. The solubility of the prodrug in the pharmaceutical composition may also be improved over the parent drug. Prodrugs can be converted to the parent drug by a variety of mechanisms, including enzymatic processes and metabolic hydrolysis. Typical prodrugs are pharmaceutically acceptable esters. Prodrugs include compounds wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the active compounds, or acetamide, formamide, and benzamide derivatives of amine functionality, and the like.
As used herein, a "lipid" group refers to a naturally or non-naturally occurring hydrophobic group that is highly insoluble in water. As used herein, a lipid group is considered to be highly insoluble in water when the point of attachment on the lipid is replaced by hydrogen, and the resulting compound has less than 0.63 x 10 in water-4% w/w solubility (at 25 ℃), which is the percentage solubility by weight of octane in water. See the Solvent Recovery Handbook of Blackwell Science, second edition, Smallwood,2002, page 195. Examples of naturally occurring lipids include saturated or unsaturated hydrocarbon chains present in fatty acids, glycerolipids, cholesterol, steroids, polyketides and derivatives. Non-naturally occurring lipids include derivatives of naturally occurring lipids, acrylic polymers, aromatic and alkylated compounds and derivatives thereof.
"linking group" refers to a wide variety of molecular arrangements that can be used to bridge molecular moieties together. An exemplary formula may be-Rm-, wherein R is individually and independently selected at each occurrence as: -CRmRm-、-CHRm-、-CH-、-C-、-CH2-、-C(OH)Rm、-C(OH)(OH)-、-C(OH)H、-C(Hal)Rm-、-C(Hal)(Hal)-、-C(Hal)H-、-C(N3)Rm-、-C(CN)Rm-、-C(CN)(CN)-、-C(CN)H-、-C(N3)(N3)-、-C(N3)H-、-O-、-S-、-N-、-NH-、-NRm-、-(C＝O)-、-(C＝NH)-、-(C＝S)-、-(C＝CH2) -, which may individually and independently comprise single, double or triple bonds between the R groups. If R is RmBranch, then it can be used such as-CH 3、-H、-CH＝CH2、-CCH、-OH、-SH、-NH2、-N3The radical of-CN or-Hal terminates, or the two branched Rs may form a cyclic structure. It is contemplated that in some instances, the total R or "m" may be less than 100 or 50 or 25 or 10. Examples of linking groups include bridging hydrocarbyl and hydrocarbyloxy hydrocarbyl.
The term "substituted" refers to a molecule in which at least one hydrogen atom is replaced with a substituent. When substituted, one or more groups are "substituents". The molecule may be multiply substituted. In the case of an oxo substituent ("═ O"), two hydrogen atoms are replaced. Exemplary substituents herein may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, heterocarbocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb、-NRaC(＝O)Rb、-NRaC(＝O)NRaNRb、-NRaC(＝O)ORb、-NRaSO2Rb、-C(＝O)Ra、-C(＝O)ORa、-C(＝O)NRaRb、-OC(＝O)NRaRb、-ORa、-SRa、-SORa、-S(＝O)2Ra、-OS(＝O)2Raand-S (═ O))2ORa. R in this textaAnd RbMay be the same or different and are independently hydrogen, halogen, hydroxy, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, heterocarbocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
As used herein, "hydrocarbyl" means acyclic straight or branched chain, unsaturated or saturated hydrocarbons, such as those containing 1 to 10 carbon atoms. Representative saturated straight chain hydrocarbyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and the like; and the saturated branched alkyl group includes isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl and the like. Unsaturated hydrocarbon groups contain at least one double or triple bond between adjacent carbon atoms (referred to as "alkenyl" or "alkynyl", respectively). Representative straight and branched chain alkenyls include ethenyl, propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2, 3-dimethyl-2-butenyl, and the like; and representative straight and branched alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.
Non-aromatic monocyclic or polycyclic hydrocarbon groups are referred to herein as "carbocyclyl" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and unsaturated carbocyclic rings include cyclopentenyl, cyclohexenyl, and the like.
A "heterocarbocycle" or "heterocarbocyclyl" group is a carbocycle containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the carbocycle may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl (pyrrolidinonyl), pyrrolidinyl, piperidinyl, hydantoinyl (hydantoinyl), valerolactanyl (valerolactamyl), oxiranyl, oxetanyl (oxolanyl), tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, etc.
The term "aryl" refers to an aromatic homocyclic (i.e., hydrocarbon) containing monocyclic, bicyclic, or tricyclic groups, preferably having 6-to 12-members, such as phenyl, naphthyl, and biphenyl. Phenyl is a preferred aryl group.
As used herein, "heteroaryl" or "heteroaromatic" refers to an aromatic heterocarbocyclic ring having from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom, including both monocyclic and polycyclic ring systems. The polycyclic ring system can, but is not required to, comprise one or more non-aromatic rings, provided that one ring is aromatic. Representative heteroaryl groups are furyl, benzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl and quinazolinyl. It is envisaged that the use of the term "heteroaryl" includes N-alkylated derivatives such as 1-methylimidazol-5-yl substituents.
As used herein, "heterocycle" or "heterocyclyl" refers to monocyclic and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom. The monocyclic and polycyclic ring systems can be aromatic rings, non-aromatic rings or mixtures of aromatic and non-aromatic rings. Heterocycles include heterocarbocycles, heteroaryls, and the like.
Bis-biguanide or alexidine derivatives
In certain embodiments, the bis-biguanide compound is alexidine, a derivative or salt thereof. In certain embodiments, the bis-biguanide compound is chlorhexidine. In certain embodiments, the bis-biguanide or alexidine derivative has formula I or a salt thereof:
wherein L is a linking group; n is 1 to 22; r1Is a hydrocarbyl, aryl or lipid, wherein R1Optionally substituted with one or more substituents, and R2Is a hydrocarbyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents.
In certain embodiments, the bis-biguanide or alexidine derivative has formula II or a salt thereof:
wherein L is a linking group; n is 1 to 22; r1Is a hydrocarbyl, aryl or lipid, wherein R1Optionally substituted with one or more substituents, and R2Is a hydrocarbyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents.
In certain embodiments, the bis-biguanide or alexidine derivative has formula III or a salt thereof:
wherein L is a linking group; n is 1 to 22; r1Is a hydrocarbyl, aryl or lipid, wherein R1Optionally substituted with one or more substituents, and R 2Is a hydrocarbyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents.
In certain embodiments, the bis-biguanide or alexidine derivative has formula IV or a salt thereof:
wherein L is a linking group; n is 1 to 22; r1Is a hydrocarbyl, aryl or lipid, wherein R1Optionally is covered withOne or more substituents, and R2Is a hydrocarbyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents. R3Is hydrogen, alkyl, aryl or lipid, wherein R3Optionally substituted with one or more substituents.
In certain embodiments, the bis-biguanide or alexidine derivative has formula V or a salt thereof:
wherein L is a linking group; n is 1 to 22; r1Is a hydrocarbyl, aryl or lipid, wherein R1Optionally substituted with one or more substituents, and R2Is hydrogen, alkyl, aryl or lipid, wherein R2Optionally substituted with one or more substituents. R3Is a hydrocarbyl, aryl or lipid, wherein R3Optionally substituted with one or more substituents.
In certain embodiments, L is selected, individually and independently at each occurrence, from O, NH, C ═ O, CH2、OCH2、CH2O、NHCH2、CH2NH、OCH2CH2、CH2CH2O、NHCH2CH2Or CH2CH2NH。
In certain embodiments, L is (CH) 2) And n is 2 to 8. In certain embodiments, L is (CH)2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R1Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R1Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R1Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 22.
In certain embodiments, L is (CH)2) And n is 2 to 8. In thatIn certain embodiments, L is (CH)2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R2Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R2Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R2Is a branched hydrocarbon group optionally substituted with one or more substituents and n is 2 to 22.
In certain embodiments, L is (CH)2) And n is 2 to 8. In certain embodiments, L is (CH) 2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R1Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R1Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R1Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 22.
In certain embodiments, L is (CH)2) And n is 2 to 8. In certain embodiments, L is (CH)2) And n is 2 to 12. In certain embodiments, L is (CH)2) And n is 2 to 22. In certain embodiments, R2Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 8. In certain embodiments, R2Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 12. In certain embodiments, R2Is a branched phenyl group optionally substituted with one or more substituents and n is 2 to 22.
Application method
In certain embodiments, the present disclosure relates to a method of treating cancer or lung cancer, the method comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound or derivative disclosed herein. In certain embodiments, the subject is diagnosed with small cell lung cancer. In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound. In certain embodiments, the subject is diagnosed with lung cancer. In certain embodiments, the subject is a human subject.
In certain embodiments, the present disclosure relates to methods of treating or preventing cancer comprising administering a pharmaceutical composition disclosed herein to a subject diagnosed with, exhibiting symptoms of, or at risk of cancer. In certain embodiments, the cancer is selected from the group consisting of: leukemia, melanoma, cervical cancer, ovarian cancer, colon cancer, breast cancer, gastric cancer, lung cancer, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, head cancer, neck cancer, and renal cancer. In certain embodiments, the pharmaceutical composition is administered in combination with a second chemotherapeutic agent.
In certain embodiments, the present disclosure relates to the methods of treatment disclosed herein, wherein the pharmaceutical composition is administered before, after, or during radiation therapy.
In certain embodiments, the subject is a human subject. In certain embodiments, the present disclosure contemplates use as a first line therapy and as a second line therapy, e.g., following the recovery of growth of small cell lung cancer after remission. In certain embodiments, the subject has previously received a first chemotherapy treatment, such as a schedule of administration of etoposide, cisplatin, carboplatin, irinotecan, or a combination thereof.
In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound in combination with etoposide.
In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound in combination with carboplatin.
In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of a bis-biguanide compound in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of alexidine, a derivative, or a salt in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of alexidine, a derivative, or a salt in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of alexidine, a derivative, or a salt in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of alexidine, a derivative, or a salt in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer comprising administering to a subject in need thereof an effective amount of alexidine, a derivative or a salt in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of alexidine, a derivative or salt thereof, in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of alexidine, a derivative, or a salt in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with irinotecan.
In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer, comprising administering to a subject in need thereof an effective amount of AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-3[1,1' - (butane-1, 4-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer, comprising administering to a subject in need thereof an effective amount of AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with irinotecan.
In certain embodiments, the present disclosure relates to methods of treating small cell lung cancer, comprising administering to a subject in need thereof an effective amount of AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-4[1,1' - (octane-1, 8-diyl) bis (5- (2-ethylhexyl) biguanide) ] or a salt in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt thereof in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of AX-7[1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) biguanide) ] or a salt in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of compound a or a salt having the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide) in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of compound a or a salt having the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide) in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of compound a or a salt having the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide) in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of compound a or a salt having the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide) in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of compound a or a salt having the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide) in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of compound a or a salt having the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide) in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of compound a or a salt having the chemical name 1,1' - (hexane-1, 6-diyl) bis (guanidino) bis (3- (4-ethyl) hexanamide) in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX12 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinium urea) or a salt in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX12 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinium urea) or a salt in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX12 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinium urea) or a salt in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX12 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinium urea) or a salt in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX12 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinium urea) or a salt in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX12 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinium urea) or a salt in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX12 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-ethylbutyl) guanidinium urea) or a salt in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX13 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide) or a salt thereof in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX13 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide) or a salt thereof in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX13 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide) or a salt thereof in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX13 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide) or a salt thereof in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX13 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide) or a salt thereof in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX13 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide) or a salt thereof in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX13 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (2-ethyl-4-ethyl-5- (2-ethylbutyl) biguanide) or a salt thereof in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX14 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-propylpentyl) biguanide) or a salt thereof in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX14 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-propylpentyl) biguanide) or a salt thereof in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX14 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-propylpentyl) biguanide) or a salt thereof in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX14 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-propylpentyl) biguanide) or a salt thereof in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX14 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-propylpentyl) biguanide) or a salt thereof in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX14 having the chemical name 1,1' - (hexane-1, 6-diyl) bis (5- (2-propylpentyl) biguanide) or a salt thereof in combination with carboplatin and irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX15 having the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide) or a salt thereof in combination with cisplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX15 having the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide) or a salt thereof in combination with etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX15 having the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide) or a salt thereof in combination with irinotecan.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX15 having the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide) or a salt thereof in combination with carboplatin.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX15 having the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide) or a salt thereof in combination with cisplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX15 having the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide) or a salt thereof in combination with carboplatin and etoposide.
In certain embodiments, the present disclosure relates to a method of treating small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of TG-AX15 having the chemical name 3,3' - (hexane-1, 6-diyl) bis (N- (2-ethylbutyl) -2-iminotetrahydropyrimidine-1 (2H) -carboximidamide) or a salt in combination with carboplatin and irinotecan.
In certain embodiments, the method contemplates administration in a cycle with a daily treatment period of 1 day to 3 days followed by a rest period of at least one, two, three or more days. In certain embodiments, a cycle typically lasts about 2 to 4 weeks, and/or 2 to 6 cycles, 2 to 7 cycles, or 2 to 8 cycles.
In certain embodiments, the present disclosure contemplates methods wherein a subject is administered one cycle of a bis-biguanide compound disclosed herein, optionally in combination with other chemotherapeutic agents, if during initial treatment, the cancer progresses during treatment or recurs after treatment with etoposide, cisplatin, irinotecan, or a combination thereof.
Pharmaceutical composition
In certain embodiments, the present disclosure contemplates pharmaceutical compositions comprising the bis-biguanide compounds disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure contemplates the production of medicaments comprising the compounds disclosed herein and the use of the compounds for the methods disclosed herein.
Pharmaceutical compositions generally comprise an effective amount of the compound and a suitable pharmaceutically acceptable carrier. The formulations may be prepared in a manner known per se, which generally comprises mixing a compound according to the present disclosure with one or more pharmaceutically acceptable carriers and, if desired, in combination with other pharmaceutically active compounds under sterile conditions. Reference is made to U.S. patent No. 6,372,778, U.S. patent No. 6,369,086, U.S. patent No. 6,369,087 and U.S. patent No. 6,372,733 and other references mentioned above, as well as to standard manuals such as the latest edition of Remington's pharmaceutical Sciences.
In certain embodiments, the present disclosure relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pill or in a capsule, or the composition is an aqueous buffer, e.g., having a pH between 6 and 8. In certain embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of fillers, glidants (glidants), binders, disintegrants, lubricants, and sugars. Optionally, the pharmaceutical composition further comprises a secondary coagulant, such as aminocaproic acid (epsilon-aminocaproic acid), tranexamic acid, fibrinogen and vitamin K.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or sterile non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluent solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil, sesame oil) and injectable organic esters such as ethyl oleate.
Prevention of the action of microorganisms can be controlled by adding various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, and the like). It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the compound may be mixed with at least one inert conventional excipient (or carrier) such as sodium citrate or dicalcium phosphate or: (a) fillers or extenders, such as, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) wetting agents (humectant), such as, for example, glycerol, (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, such as, for example, paraffin, (f) absorption promoters, such as, for example, quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, such as, for example, kaolin and bentonite, and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
In certain embodiments, methods of production are contemplated wherein two components, a bis-biguanide compound disclosed herein and a pharmaceutical carrier, have been provided in a combined dry form, ready for reconstitution together. In other embodiments, it is contemplated that the bis-biguanide compounds disclosed herein and a pharmaceutical carrier are admixed to provide a pharmaceutical composition.
The pharmaceutical composition may be provided in a one-step process simply by adding a suitable pharmaceutically acceptable diluent to the composition in the container. In certain embodiments, the container is preferably a syringe for administering the pharmaceutical composition reconstituted after contact with a diluent. In certain embodiments, the coated compound can be filled into a syringe, and the syringe can then be closed with a stopper. The diluent is used in an amount to achieve the desired final concentration. The pharmaceutical compositions may contain other useful components such as ions, buffers, excipients, stabilizers and the like.
A "dried" pharmaceutical composition typically has only a residual moisture content, which may correspond approximately to the moisture content of a comparable commercial product, e.g., about 12% moisture as a dried product. Generally, the dried pharmaceutical composition according to the invention has a residual moisture content preferably below 10% moisture, more preferably below 5% moisture, in particular below 1% moisture. The pharmaceutical composition may also have a lower moisture content, e.g. 0.1% or even lower. In certain embodiments, the pharmaceutical composition is provided in a dry form to prevent degradation and achieve storage stability.
The container may be any container suitable for containing (and storing) a pharmaceutical composition, such as a syringe, vial, tube, or the like. The pharmaceutical composition may then preferably be administered via a specific needle of a syringe or via a suitable catheter. Typical diluents include water for injection, NaCl (preferably 50mM to 150mM, especially 110mM), CaCl2(preferably 10mM to 80mM, especially 40mM), sodium acetate (preferably 0 to 50mM, especially 20mM), and mannitol (preferably up to 10% w/w, especially 2% w/w). Preferably, the diluent may also comprise a buffer or a buffering system in order to buffer the pH of the reconstituted dry composition at a pH of preferably 6.2 to 7.5, in particular at a pH of 6.9 to 7.1.
In certain embodiments, the diluent is provided in a separate container. The separate container may preferably be a syringe. The diluent in the syringe can then be easily applied to the container for reconstitution of the dry composition. If the container is also a syringe, both syringes may be packaged together. Thus, it is preferred to provide the dry composition in a syringe that is completed with a diluent syringe having a pharmaceutically acceptable diluent for reconstituting the dry and stable composition.
In certain embodiments, the present disclosure contemplates kits comprising a pharmaceutical composition disclosed herein and a container containing a suitable diluent. Other components of the kit may be instructions for use, administration devices (means), such as syringes, catheters, brushes, etc., if the composition is not already provided in the administration device, or other components required for use in medical (surgical) practice, such as replacement needles or catheters, additional vials or further wound covering devices. In certain embodiments, the kit includes a syringe containing the dry and stable hemostatic composition and a syringe containing the diluent (or provided to draw the diluent from another diluent container).
Examples
Identification of alexidine hydrochloride
Scientific data suggests that rare and phenotypically heterogeneous cancer cells hidden in a larger patient tumor cell population are the primary cause of patient relapse and poor clinical outcome. See, for example, Burrell et al, Nature,2013,501: 338-. Spatiotemporal genomics and cellular analysis (SaGA) is a technology that involves the combination of microscopy and genomics to isolate rare cells. See Konen et al Nat Comm,2017,8: 15078. Dendra2 is a photoconverted fluorophore that emits green fluorescence. However, when excited by light at 405nm, green fluorescence is converted to red fluorescence due to cleavage of histidine. Thus, with single cell precision, any cancer cell expressing Dendra2 could be optically highlighted (turned red) using a point-scan confocal microscope. Regions of interest are drawn around the cells of interest based on transmitted light or fluorescent protein tags. This region can be exposed to a 405nm laser, resulting in near instantaneous light conversion by Dendra2 and light labeling (photomark) the cells red. A single cell can be phototransformed without causing any measurable phototransformation of neighboring cells. Cells were extracted from the 3-D environment using dispase for 15 minutes (collagenase for collagen). The cells were then sorted using FACS to separate red light transformed cells from green cells. The isolated cells are cultured in culture medium using standard cell culture techniques. Spatiotemporal genomics and cellular analysis (SaGA) were used to identify rare lung cancer cells, which were then used for drug screening. The compound alexidine (fig. 1A) was identified as disrupting metastasis by targeting rare cell types in an aggressive cell population (i.e., a subset of lead cells). See fig. 2A.