Compounds for the treatment of triple negative breast and ovarian cancer
阅读说明：本技术 用于三阴性乳腺癌和卵巢癌的治疗的化合物 (Compounds for the treatment of triple negative breast and ovarian cancer ) 是由 李伟 D·D·米勒 S·邓 R·克鲁蒂里娜 T·西格罗夫斯 J·越 G·赵 W·清辉 于 2019-05-15 设计创作，主要内容包括：本发明涵盖使用治疗有效量的由式I的结构表示的化合物来治疗三阴性乳腺癌和/或卵巢癌的方法。(The present invention encompasses methods of treating triple negative breast and/or ovarian cancer using a therapeutically effective amount of a compound represented by the structure of formula I.)
1. A method of treating triple negative breast and/or ovarian cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by the structure of formula XI:
wherein
X is a bond, NH or S;
q is O, NH or S; and
a is a substituted or unsubstituted monocyclic, fused or polycyclic aryl or (hetero) ring system; substituted or unsubstituted, saturated or unsaturated N-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated S-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated O-heterocycle; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or a substituted or unsubstituted or saturated or unsaturated mixed heterocycle;
wherein the A ring is optionally substituted with 1-5 substituents independently being O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2(ii) a And
i is an integer between 0 and 5;
wherein if Q is S, then X is not a bond.
2. The method of claim 1, wherein the compound is represented by the structure of formula VIII:
R4、R5and R6Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
Q is S, O or NH;
i is an integer between 0 and 5; and
n is an integer between 1 and 3.
3. The method of claim 1, wherein the compound is represented by the structure of formula xi (b):
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) OAlkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
4. The method of claim 1, wherein the compound is represented by the structure of formula xi (c):
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
5. The method of claim 4, wherein the compound is compound 55 represented by the following structure:
6. the method of claim 2, wherein the compound is (2- (phenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5a), (2- (p-tolylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5b), (2- (p-fluorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5c), (2- (4-chlorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5d), or (2- (phenylamino) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5 e).
7. The method of claim 1, wherein the compound is combined with a pharmaceutically acceptable carrier.
8. The method of claim 1, further comprising administering an additional cancer therapy.
9. A method of treating triple negative breast and/or ovarian cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by the structure of formula xi (e), or an isomer, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, or combination thereof, to treat the triple negative breast and/or ovarian cancer:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
10. The method of claim 9, wherein the compound is compound 17ya represented by the structure:
11. the method of claim 9, further comprising an additional cancer therapy.
Technical Field
The present invention relates to novel methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof, optionally comprising a pharmaceutically acceptable excipient.
Statement regarding research or development supported by the Federal government
The invention described herein is made with government support under grant number CA148706 issued by the National Institutes of Health. The government has certain rights in the invention.
Background
Cancer is the second most common cause of death in the united states, second only to heart disease. In the united states, 1in every 4 deaths is cancer. The 5-year relative survival rate for all Cancer patients diagnosed between 1996 and 2003 was 66% higher than 50% between 1975 and 1977 (Cancer Facts & Figures American Cancer Society: Atlanta, GA (2008)). The improved survival rate reflects the progress of early diagnosis and improved treatment. The discovery of highly potent anticancer agents with low toxicity is a major goal in cancer research.
Microtubules are cytoskeletal filaments composed of α and β -tubulin heterodimers and are involved in a variety of cellular functions including shape maintenance, vesicle trafficking, cell movement and division. Tubulin is the major structural component of microtubules and a reliable target for many very successful anticancer drugs. Compounds that interfere with the microtubule-tubulin balance in cells are effective in treating cancer. Anticancer drugs that interfere with the microtubule-tubulin balance in cells (such as paclitaxel and vinblastine) are widely used in cancer chemotherapy. There are three main classes of antimitotic agents. Representative of microtubule stabilizing agents are taxanes and epothilones, which bind to intact formed microtubules and prevent depolymerization of tubulin subunits. Two other classes of agents are microtubule destabilizers, which bind to tubulin dimers and inhibit the polymerization of tubulin dimers into microtubules. Vinca alkaloids (such as vinblastine) bind to the vinca site and are representative of one of these classes. Colchicine and colchicine site binding agents interact at different sites on tubulin and define a third class of antimitotic agents.
Both taxanes and vinca alkaloids are widely used in the treatment of human cancers, and colchicine site-binding agents are not currently approved for cancer chemotherapy. However, colchicine binding agents such as combretastatin A-4(CA-4) and ABT-751 are currently in clinical research as potential novel chemotherapeutic agents (Luo et al, ABT-751, "A novel tubulin-binding agent, cultures and dispersions tissue, Anticancer Drugs 2009,20(6), 483-92; Mauer et al," A Phase II study of ABT-751in tissues with adsorbed non-soluble cancer, "J.Thorac.Oncol.,2008,3(6), 6; Rustin et al," A Phase of CA4P (branched A-4 phosphor), carboplatin, tissue, 631 and 13, tissue J.2010, 1355, 102, W.S.A. A.A. 894 (R.A-4 phosphor) and cancer tissue, W.S.A. A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.
Unfortunately, clinically used microtubule-interacting anticancer drugs suffer from two major problems, namely drug resistance development and neurotoxicity. The common mechanism of resistance is because Multidrug resistance protein (MDR), i.e., ATP Binding Cassette (ABC) transporter mediated drug efflux, limits the efficacy of these drugs (Green et al, "Beta-Tubulin proteins in individual using strand and compatibility analysis-real of failure porous drugs," Cancer Letters,2006,236(1), 148-54; Wang et al, "Paclite resistance in cells with reduced Beta-Tubulin," Biochemical Acta, Molecular Research,2005,1744(2), 245-255; Leslie et al, "Multi drug resistance: protein of MRroll, 24-8652, Biochemical CG, 3676 CG, 3652, Biochemical CG).
The P-glycoprotein (P-gp protein encoded by the MDR1 gene) is an important member of the ABC superfamily. P-gp prevents the intracellular accumulation of many cancer drugs by actively shedding them out of the cancer cells and contributes to the normal hepatic, renal, or intestinal clearance pathways. Attempts to co-administer P-gp modulators or inhibitors to increase cell availability by blocking The effects of P-gp have met with limited success (Gottesman et al, "The multidugtransport, a double-injected sword," J.biol. chem.,1988,263(25), 12163-6; Fisher et al, "Clinical students with modulators of multiduger resistance," Hematology/Oncology Clinics of North America,1995,9(2), 363-82).
Another major problem with taxanes, as with many biologically active natural products, is their lipophilicity and insolubility in aqueous systems. The result of this problem is the use of emulsifiers (such as Cremophor EL and Tween 80) in clinical preparations. Many biological effects involving these pharmaceutical formulation vehicles, including acute hypersensitivity and peripheral neuropathy, have been described (Hennenfet et al, "Novel formulations of taxanes: a review. old wires in a new bottle.
Colchicine binding agents generally exhibit a relatively simple structure compared to compounds that bind to the paclitaxel binding site or the vinca alkaloid binding site. Thus, improved solubility and Pharmacokinetic (PK) parameters via structural optimization provide better opportunities for oral bioavailability. In addition, many of these drugs appear to circumvent P-gp mediated resistance. Therefore, these novel colchicine binding site-targeting compounds have broad prospects as therapeutic agents, especially because they have improved water solubility and overcome P-gp mediated drug resistance.
It was found that 15% of all breast cancer cases in the united states were triple negative breast cancer. Triple negative breast cancer is defined as tumors that lack the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor (HER-2). Triple negative breast cancer is characterized by aggressive clinical behavior and poor prognosis due to rapid resistance to multiple chemotherapeutic drugs and lack of appropriate targets. Currently, no targeted therapy is approved. Classical microtubule-targeted drugs (MTDs), such as paclitaxel and its semi-synthetic derivatives, have met with considerable success in the clinical control of breast cancer neoplasms. Anthracycline and taxane-based chemotherapy is the standard of care for triple negative breast cancer. However, eventually most triple negative breast cancer patients will develop resistance, tumor recurrence and/or metastasis after a brief response to the first few rounds of therapy. There is an urgent need to develop innovative and more effective treatments to achieve a more durable response to treatment of triple negative breast cancer.
Metastatic ovarian cancer is the most lethal gynaecological malignancy in women, and chemotherapy is one of the standard treatment options. Although there are several FDA approved anti-tubulin agents (primarily taxanes) that have been included in the effective control of ovarian cancer, resistance to taxanes often develops as the disease progresses.
With the rising incidence of triple negative breast and ovarian cancer and the high resistance to current therapeutic agents, the development of more effective drugs for treating such cancers that can effectively circumvent MDR would provide significant beneficial effects for cancer patients.
Disclosure of Invention
In one embodiment, the present invention encompasses methods of treating triple negative breast and/or ovarian cancer in a subject by administering to the subject a therapeutically effective amount of a compound of formula XI, and pharmaceutically acceptable salts thereof, wherein formula XI is represented by the formula:
wherein
X is a bond, NH or S;
q is O, NH or S; and
a is a ring and is a substituted or unsubstituted saturated or unsaturated monocyclic, fused or polycyclic, aryl or (hetero) cyclic ring system; an N-heterocycle; an S-heterocycle; an O-heterocycle; a cyclic hydrocarbon; or a mixed heterocycle;
wherein ring A is optionally substituted with 1-5 substituents independently selected from O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, -CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer between 0 and 5;
wherein if Q is S, then X is not a bond.
Another embodiment of the present invention encompasses methods of treating triple negative breast and/or ovarian cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of formula VIII, and pharmaceutically acceptable salts thereof, wherein formula VIII is represented by the structure:
(VIII)
R4、R5and R6Each independently is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, -CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
Q is S, O or NH;
i is an integer between 0 and 5; and
n is an integer between 1 and 3.
Yet another embodiment of the present invention encompasses methods of treating triple negative breast and/or ovarian cancer in a subject in need thereof by administering to said subject a therapeutically effective amount of a compound of formula xi (b), and pharmaceutically acceptable salts thereof, wherein formula xi (b) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, -CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
One embodiment of the present invention encompasses methods of treating triple negative breast and/or ovarian cancer in a subject in need thereof by administering to said subject a therapeutically effective amount of a compound of formula xi (c), and pharmaceutically acceptable salts thereof, wherein the compound of formula xi (c) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, -CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
Another embodiment of the present invention encompasses methods of treating triple negative breast and/or ovarian cancer in a subject in need thereof by administering a compound of formula xi (e), and pharmaceutically acceptable salts thereof, wherein formula xi (e) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, -CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
Yet another embodiment of the present invention encompasses methods of treating triple negative breast and/or ovarian cancer in a subject in need thereof by administering to said subject a therapeutically effective amount of at least one of the following compounds: (2- (phenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5a), (2- (p-tolylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5b), (2- (p-fluorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5c), (2- (4-chlorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5d), (2- (phenylamino) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5e), 2- (1H-indol-3-yl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (17 ya); and (2- (1H-indol-5-ylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (55).
In another embodiment, the compound of the present invention is a stereoisomer, a pharmaceutically acceptable salt, a hydrate, an N-oxide, or a combination thereof, of the compound. The invention includes pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.
Drawings
The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, may best be understood by reference to the following detailed description when read in conjunction with the accompanying drawings in which:
FIGS. 1A-1B show two graphs of the in vitro anti-cancer activity of compound 17 ya. FIG. 1A shows compound 17ya tested with the MDA-MB-231 cell line, and compared to colchicine and paclitaxel. FIG. 1B shows compound 17ya tested with the MDA-MB-468 cell line, and compared to colchicine and paclitaxel.
Figures 2A-2B show a comparison of colchicine, paclitaxel and compound 17ya activity in MDS-MB-231 cell lines at concentrations of 0, 8, 16 and 32nM (figure 2A), and a bar graph representation of the results (figure 2B).
FIGS. 3A-3B show the anti-migration effect of compound 17 ya. FIG. 3A shows the anti-migratory effect of compound 17ya on TNBC cell lines compared to control, colchicine (16nM) and compound 17ya (16nM) in MDA-MB-231 and MDC-MB-468 cell lines. Fig. 3B shows the results of the test in bar graph form.
Figures 4A-4B show comparisons between control, colchicine, paclitaxel and compound 17ya at 0 hours, 12 hours and 24 hours using the MBA-MD-231(16nM) cell line, which is first shown in figure 4A. Figure 4B shows the numerical results in a histogram.
FIGS. 5A-5B show comparisons between control, colchicine, paclitaxel and compound 17ya at 0 hours, 24 hours and 48 hours using MBA-MD-468(16nM) cell line. Fig. 5A shows the anti-migration effect. Figure 5B shows the numerical results in a bar graph.
FIGS. 6A-6B show the anti-invasive effect of Compound 17 ya. FIG. 6A shows the anti-invasive effect of compound 17ya (40nM) on TNBC cell line in MDA-MB-231 versus control and 17ya (32nM) on TNBC cell line in MDC-MB-468 versus control and colchicine (32 nM). Fig. 6B shows the results of the test in bar graph form.
FIGS. 7A-7B show the apoptotic effect of compound 17ya (100nM) on TNBC cells. FIG. 7A shows the apoptotic effect of compound 17ya (100nM) on TNBC cells, cell line MDA-MB-231, compared to controls at 24 hours, 48 hours, and 72 hours. Fig. 7B shows the results of the comparison in the form of a bar graph.
FIG. 8 shows the apoptotic effect of compound 17ya on TNBC cells, cell line MDA-MB-231, in a dose and time dependent manner after 48 hours compared to 50nM, 100nM, 150nM and 200nM of control colchicine (200nM), and paclitaxel (200nM) and compound 17 ya. The graph also shows the results of the comparison in the form of a bar graph.
Figures 9A-9B show, in two panels, the inhibition of TNBC tumor growth by compound 17ya in a dose-dependent manner without interfering with mouse body weight. Figure 9A compares the percent tumor growth (volume) over time for administration of vehicle, 5mg/kg compound 17ya, and 10mg/kg compound 17 ya. Figure 9B shows the change in rat body weight over time (days) when vehicle, 5mg/kg compound 17ya and 10mg/kg compound 17ya were administered.
Figure 10 shows in bar graph form the tumor weight or final tumor weight (as shown in figure 9) and a comparison of the size due to compound 17ya inhibiting TNBC tumor growth in a dose-dependent manner.
Figures 11A-11B demonstrate the anticancer activity of compound 17ya compared to vehicle and paclitaxel. Figure 11A demonstrates the anticancer activity of compound 17ya compared to 12.5mg/kg vehicle and paclitaxel by measuring tumor weight. Figure 11B demonstrates the anticancer activity of compound 17ya compared to 12.5mg/kg vehicle and paclitaxel by measuring the final tumor volume.
FIG. 12 shows the anti-metastatic effect of compound 17ya using lung-derived H & E sections compared to control, 10mg/kg paclitaxel and 10mg/kg compound 17ya in vivo.
Fig. 13A-B show the effect of compound 17ya on ovarian cancer cells, demonstrating a significant inhibition of cell survival. Figure 13A shows cell viability as determined by colonies/field of 350 SKOV3 cells treated with 0, 1.25, 2.5, 5,10 and 30nM of compound 17ya, where p <0.01 and p < 0.001. Figure 13B shows cell survival as determined by colony/field of OVCAR3 cells treated with 0, 1.25, 2.5, 5,10 and 30nM of compound 17ya, where p <0.01 and p < 0.001.
FIGS. 14A-14B show the inhibition of migration and invasion of ovarian cancer cells by Compound 17 ya. Figure 14A shows the results of cell migration of SKOV3 and OVCAR3 cells treated with compound 17ya (20nM) and control (vehicle) using Transwell plates. Migrated cells were stained and counted with crystal violet, where p <0.01 and p < 0.001. Figure 14B shows the results of invasion of SKOV3 and OVCAR3 cells treated with compound 17ya (20nM) and control (vehicle) 5h using Matrigel coated plates (h.e. stained and counted cells), and p <0.01 and p < 0.001.
FIGS. 15A-15C show the inhibition of ovarian tumor growth and metastasis by Compound 17ya in vivo. Figure 15A demonstrates the effect of compound 17ya on 2-month-old NSG female mice injected intravesicularly with 5x 105 wild-type SKOV3-Luc2 cells five days per week for 4 weeks. Figure 15B shows the tumor weight of compound 17ya and control treated ovaries graphically. Figure 15c shows that tumors were not visible in ovaries, liver and spleen of mice treated with compound 17 ya.
FIGS. 16A-B show, in a schematic way, the cell viability after treatment with colchicine, paclitaxel and compound 17 ya. FIG. 16A shows MDA-MD-231 cell viability, IC, after treatment with colchicine, paclitaxel and Compound 17ya50(nM) 17.46, 3.05 and 8.23, respectively, and SEM 3.40, 0.42 and 1.34, respectively. FIG. 16B shows MDA-MD-468 cell viability, IC, after treatment with colchicine, paclitaxel and Compound 17ya50(nM) 9.80, 4.61 and 9.59, respectively, and SEM 1.45, 0.63 and 1.78, respectively.
FIGS. 17A-B show the inhibition of cell migration by compound 17ya and colchicine. Figure 17A demonstrates the effect of colchicine or compound 17ya on cell migration compared to controls. Figure 17B demonstrates the effect of colchicine, PTX, compound 17ya on cell migration by Matrigel coated membranes.
FIG. 18 shows immunofluorescence staining of MDA-MB-231 and MDA-MB-468 cells used to show a microtubule network comparison between control, colchicine, paclitaxel and Veru-111 (compound 17ya) (all 32 nM).
Figure 19 shows the effect of compound 17ya (VERU-111) on apoptosis induction in TNBC cells, where MDA-MB-231 cells were treated with 100nM compound 17ya in a time-dependent manner and induced apoptosis at different times and concentrations at 24h, 48h and 72h compared to control.
Figure 20 demonstrates the anti-cancer activity of compound 17ya (VERU-111) in an in situ TNBC mouse model to determine whether the in vivo observed potent effect of compound 17ya can be determined over time (including after 33 days of treatment), wherein compound 17ya inhibits TNBC tumor growth in a dose-dependent manner without interfering with the body weight of the mouse.
Figure 21 shows a comparison of the efficacy of compound 17ya (VERU-111) with paclitaxel in the model, since paclitaxel is one of the standard care measures for clinical TNBC treatment, compound 17ya and paclitaxel significantly reduced tumor size and tumor weight.
Figure 22 demonstrates H & E staining of tumors in a comparative study of compound 17ya (VERU-111) and paclitaxel in inducing TNBC tumor necrosis in lung tissue, with complete metastasis (indicated by yellow arrows) in the vehicle group and little metastasis in the lungs in compound 17ya and paclitaxel groups, indicating that compound 17ya significantly reduced TNBC metastasis.
Figure 23 demonstrates IHC staining of tumors in a comparative study of compound 17ya (VERU-111) and paclitaxel in inducing TNBC tumor necrosis in lung tissue, with complete metastasis (indicated by yellow arrows) in the vehicle group and little metastasis in the lungs in compound 17ya and paclitaxel groups, indicating that compound 17ya significantly reduced TNBC metastasis.
Figure 24 shows a brief summary of compounds showing that compound VERU-111 (compound 17ya) is a novel, oral, next generation tubulin inhibitor targeting the alpha and beta subunits of microtubules, has low nanomolar tubulin polymerization inhibition, high oral bioavailability, high brain permeability, and has efficacy against prostate, breast and other cancers both in vivo and in vitro.
Figure 25 demonstrates that VERU-111 (compound 17ya) inhibits microtubule assembly based on a validated mechanism and compares microtubules isolated from spindle (control) and sphere (compound 17 ya).
Fig. 26A-B show molecular modeling of VERU-111 (compound 17ya) with tubulin complex (compound 17ya ═ 6A). Figure 26A shows molecular modeling of compound 17ya with a colchicine binding site, where the compound binds to TN-16 more closely than it binds to colchicine itself. Figure 26B demonstrates that compound 17ya is more linear than TN-16, penetrates deeper into the binding pocket of β -tubulin monomer than TN-16, and has hydrogen bonding, which results in differential and stronger binding to α and β tubulin.
FIG. 27 shows the drug-like properties of VERU-111 (Compound 17ya) and VERU-112 (Compound 55).
FIG. 28 shows the pharmacokinetic parameters of VERU-111 (Compound 17ya) and VERU-112 (Compound 55) in mice, rats and dogs.
Figure 29 demonstrates the metabolic pathway of VERU-111 (compound 17ya) in humans and dogs, where a large number of metabolites M +34 are present only in canine liver microsomes, resulting in high clearance in vivo in dogs.
FIG. 30 shows brain penetration rates for VERU-111 (Compound 17ya) and VERU-112 (Compound 55). VERU-112 (Compound 55) exhibited high brain penetration. The brain/plasma concentration ratio was about 20% 4h after oral treatment. The brain/plasma concentration ratio of VERU-111 (compound 17ya) and VERU-112 (compound 55) remained relatively constant over time, indicating that the brain concentration and plasma concentration were within the same pharmacokinetic compartment and did not accumulate in the brain; perhaps reducing the potential for neurotoxicity.
FIG. 31 shows the activity of compounds on p-glycoprotein ATPase (Pgp ATPase). VERU-111 (Compound 17ya) is not a substrate for p-glycoprotein, where p < 0.05.
Figure 32 shows a summary of the in vitro and in vivo cytotoxic activity of VERU-111 (compound 17ya) showing similar or higher potency as paclitaxel and docetaxel in the parental cell lines; whereas paclitaxel and docetaxel lost activity in taxane-resistant cell lines, VERU-111 (compound 17ya) had potent antiproliferative activity; and the compounds are cytotoxic to a variety of cancer types: prostate cancer, taxane-resistant prostate cancer, breast cancer, triple negative breast cancer, lung cancer, melanoma, glioma, colon cancer, uterine cancer, ovarian cancer, and pancreatic cancer.
FIG. 33 shows the in vitro cytotoxicity (IC) of VERU-111 (Compound 17ya) after 96 hours50value-nM). VERU-111 (Compound 17ya) had similar potency in the parental PC-3 cell line as paclitaxel and docetaxel. VERU-111 (Compound 17ya) maintained its potency in paclitaxel-resistant PC-3 cells, while paclitaxel and docetaxel lost potency.
FIGS. 34A-D show that VERU-111 (Compound 17ya) (II) and VERU-112(IAT) inhibit the growth of paclitaxel-resistant prostate cancer xenografts. FIG. 34A shows the tolerance to PC-3, when the tumor reached 150-300mm3The process is started. FIG. 34B shows tolerance to TxR (PC-3/TxR is taxane-resistant), when tumors reached 150-300mm3The process is started. FIG. 34C shows tolerance to TxR (PC-3/TxR is taxane-resistant), when tumors reached 150-300mm3The process is started. FIG. 34D shows tolerance to TxR (PC-3/TxR is taxane-resistant), when tumors reached 150-300mm3The process is started.
FIG. 35 shows the antitumor activity of VERU-111 (compound 17ya) and VERU-112 with docetaxel in vivo. VERU-111 (Compound 17ya) was administered orally with a TGI > 100% and had no effect on body weight compared to the lack of efficacy of docetaxel in PC-3/TxR tumors.
Figure 36 shows VERU-111 (compound 17ya) tested in an additional xenograft model.
FIG. 37 shows the in vitro anti-cancer activity of VERU-111 (Compound 17ya) in Triple Negative Breast Cancer (TNBC), where the IC of colchicine is in MDA-MB-2315017.46(SE 0.05); IC of paclitaxel503.05(SE 0.04); and IC of VERU-111 (Compound 17ya)50It was 8.23(SE 0.05). IC of colchicine in MDA-MB-468509.80(SE 0.02); IC of paclitaxel50Is 4.61(SE 0.03)(ii) a IC of VERU-111 (Compound 17ya)50It was 22.96(SE 0.02).
FIG. 38 shows the in vivo anti-tumor activity of VERU-111 (compound 17ya) in TNBC, wherein VERU-111 (compound 17ya) inhibits TNBC tumor growth in a dose-dependent manner without interfering with mouse body weight.
FIG. 39 shows that VERU-111 (Compound 17ya) inhibits triple negative breast cancer xenografts in mice.
FIG. 40 shows that VERU-111 (Compound 17ya) inhibits triple negative breast cancer metastasis in mice.
FIG. 41 shows that VERU-111 (Compound 17ya) inhibits ovarian cancer in the orthotopic ovarian cancer model (tx 5X/week for 4 weeks).
FIGS. 42A-D show that VERU-111 (Compound 17ya) inhibits pancreatic cancer. FIG. 42A (i-II) shows the dose-dependent effect of VERU-111 (Compound 17ya) on the cell lines Panc-1, AsPC-1 and HPAF-II (expressed as a percentage of cell viability). FIG. 42B (i-ii) shows the time-dependent effect of VERU-111 (compound 17ya) at 5nM, 10nM and 20nM compared to control. FIG. 42C shows the effect of VERU-111 (Compound 17ya) at 1.25nM, 2.5nM and 5nM, compared to Panc-1 (FIG. C (i)), AsPC-1 (FIG. C (II)), or HPAF-II (FIG. C (iii)) cell line controls. FIG. 42D shows, in bar graph form, the effect of VERU-111 (Compound 17ya) at 1.25nM, 2.5nM and 5nM, as compared to Panc-1 (Panel D (i)), AsPC-1 (Panel D (II)) or HPAF-II (Panel D (iii)) cell line controls.
FIG. 43 shows that VERU-111 (Compound 17ya) inhibits pancreatic cancer.
Fig. 44 shows preclinical safety (less myelosuppression, less neurotoxicity, maintenance of body weight) of VERU-111 (compound 17ya), where fig. 44 shows toxicity testing of liver weight and white blood cell count (WBC) in mice in the use of VERU-111(3.3mpk or 6.7mpk) and VERU-112(10mpk and 30mpk) compared to control and DTX (10mpk and 20 mpk).
Figure 45 demonstrates the preclinical safety (less bone marrow suppression, less neurotoxicity, maintenance of body weight) of VERU-111 (compound 17ya), wherein figure 45 demonstrates neurotoxicity testing (hot plate test at 5 ℃ -52.5 ℃ and time required to lick paw recorded as latency to pain threshold) in mice in use of VERU-111(3.3mpk or 6.7mpk) and VERU-112(10mpk and 30mpk) compared to control and DTX (10mpk and 20 mpk).
FIG. 46 demonstrates that VERU-111 (Compound 17ya) has antiproliferative effects and maintains body weight, with > 100% TGI administered orally, and no effect on body weight, compared to the lack of efficacy of docetaxel in PC-3/Txr tumors.
FIG. 47 shows the blockade assessment of HERG potassium channels stably expressed in HEK293 cells and non-clinical results of central nervous system safety studies in rats (IC)209.23nM) and oral administration of VERU-111 (compound 17ya) at doses up to 10mg/kg, including 10mg/kg, was not associated with any adverse effects on neurobehavioral function in rats.
Fig. 48 shows non-clinical results of VERU-111 (compound 17ya) in a beagle cardiovascular and respiratory assessment study in which VERU-111 (compound 17ya) was administered to beagle dogs at doses of 2, 4 and 8mg/kg and did not cause death or effect on blood pressure, heart rate or assessment of electrocardiogram or respiratory parameters. An increase in body temperature (max. change. ltoreq.0.7 ℃) was observed in VERU-111 (compound 17ya) at all doses within about 3.5 to 11 hours after administration. Emesis was recorded between 4 and 24 hours after the 8mg dose. Oral administration of VERU-111 (compound 17ya) at doses up to 8mg/kg (including 8mg/kg) was not associated with any adverse effects on the cardiovascular or respiratory function of the dog.
FIG. 49 shows that canine VERU-111 (compound 17ya) pharmacokinetics are the mean (. + -. SD) and CV% of the VERU-111 (compound 17ya) pharmacokinetic parameters on days 1 and 7 after oral capsules of 5 and 10mg/kg VERU-111 were administered to male dogs.
FIG. 50 shows a VERU-111 (Compound 17ya)28 day oral capsule toxicity study on beagle dogs, where VERU-111 was found not to affect dog survival and was not abnormal by ophthalmoscopy; hematological, coagulation and urinalysis parameters were unchanged; no abnormality is found in clinical or macroscopic pathological observation; at 4 and 8mg/kg, mild anorexia, vomiting and diarrhea were observed; at 8 mg/kg/dayIn case of weight loss in dogs; changes with QTc prolongation over 10%; and thymic organ weight loss and thymic lymphocyte depletion; no visible adverse events level (NOAEL) was 4 mg/kg/day; mean C28 days after 4 mg/kg/day dosingmaxAnd AUC0-12hValues were 23.2ng/mL and 71.7h ng/mL, respectively.
FIGS. 51A and 51B show VERU-111 (Compound 17ya)28 day oral capsule toxicity study-body weight on dogs. Fig. 51A shows the average body weight of male dogs relative to the time (week) from the start date. Fig. 51B shows the average body weight of dogs with respect to time (week) from the start date.
FIG. 52 shows VERU-111 (Compound 17ya)28 day oral capsule toxicity study-QT interval for dogs.
FIG. 53 shows VERU-111 (Compound 17ya)28 day oral capsule toxicity study-hematology performed on dogs.
FIG. 54 shows VERU-111 (Compound 17ya)28 day oral capsule toxicity study-hematology performed on dogs.
Figure 55 shows VERU-111 (compound 17ya)28 day oral capsule toxicity study-liver function test on dogs.
Figure 56 shows VERU-111 (compound 17ya)28 day oral capsule toxicity study-liver function test on dogs.
FIGS. 57A-B show the compound 17ya 28 day oral capsule pharmacokinetic study on beagle dogs. Figure 57A shows single and average compound 17ya C on days 1 and 28 after daily oral capsule administration of 2, 4 and 8mg/kg compound 17ya to dogs (male and female combination)maxThe value is obtained. Figure 57B shows single and averaged compound 17ya AUC at day 1 and day 28 after daily oral capsule administration of 2, 4, and 8mg/kg compound 17ya for dogs (male and female combination)0-12hThe value is obtained.
FIGS. 58A-B show the effect of compound 17ya with the tubulin destabilizing agent colchicine and the tubulin stabilizing agent paclitaxel. FIG. 58A shows the effect of compound 17ya, colchicine and paclitaxel in the MDA-MB-231 cell line. FIG. 58B shows the effect of compound 17ya, colchicine and paclitaxel in the MDA-MB-486 cell line.
FIGS. 59A-B show the effect of compound 17ya compared to colchicine and paclitaxel in a colony formation assay. FIG. 59A shows the effect of compound 17ya, colchicine and paclitaxel on MDA-MB-231. FIG. 59B shows the effect of compound 17ya, colchicine and paclitaxel on MDA-MB-486.
Figure 60 shows immunofluorescence staining of the microtubule network compared to controls, compound 17ya, colchicine and paclitaxel.
FIG. 61 shows the effect of compound 17ya on the ability to inhibit TNBC cell migration through the membrane pores in the presence of 16nM concentration, as indicated by a mean mobility of 40% in MDA-MB-231 cells and 34% in MDA-MB-468 cells compared to the control group.
FIG. 62 shows the effect of compound 17ya on reducing the ability of TNBC cells to invade a Matrigel-coated membrane, with mean invasion rates of 55% and 36% in MDA-MB-231 and MDA-MB-468 cells compared to controls.
FIGS. 63A-B show the results of a scratch assay performed on MDA-MB-231 and MDA-MB-486 cell lines using compound 17ya, paclitaxel and colchicine (as positive controls). For MDA-MB-231, compound 17ya, colchicine and paclitaxel showed effective inhibition of cell migration at 16nM dose, as shown in FIG. 63A. The effect of the same compound and dose for MDA-MB-486 is shown in FIG. 63B.
FIGS. 64A-B show the effect of compound 17ya, colchicine and paclitaxel on the accumulation of G2 and M phase MDA-MB-231 and MDA-MB-486 cells. FIG. 64A shows the effect of compound 17ya, colchicine and paclitaxel (used as positive controls) on G1 and S phase cell populations in a dose-dependent manner for G2/M phase MDA-MB-231 cells. FIG. 64B shows the effect of compound 17ya, colchicine and paclitaxel (used as positive controls) on G1 and S phase cell populations in a dose-dependent manner for G2/M phase MDA-MB-486 cells.
Figures 65A-B demonstrate the ability of compound 17ya, colchicine and paclitaxel to trigger apoptotic cell death in a dose-dependent manner. FIG. 65A shows the effect on MDA-MB-231 cell line. FIG. 65B shows the effect on the MDA-MB-486 cell line.
FIGS. 66A-B show the efficacy of compound 17ya, colchicine and paclitaxel in inducing TNBC apoptosis. FIG. 66A shows the results of MDA-MB-231 cell lines when treated with 100nM of compound 17ya for 24, 48, and 72 hours. FIG. 66B shows the results of MDA-MB-486 cell lines when treated with 100nM of compound 17ya for 24, 48 and 72 hours.
FIGS. 67A-B show the effect of compound 17ya, colchicine and paclitaxel on apoptotic cell death by modulating the caspase-3/PARP pathway, expression of cleaved caspase-3, and cleaved PARP in TNBC cells. FIG. 67A shows the effect on MDA-MB-231 cells after 24 hours treatment by Western blot analysis. FIG. 67B shows the effect on MDA-MB-486 cells after 24 hours treatment by Western blot analysis.
FIG. 68 shows the increased effect of compound 17ya and controls on cleaved caspase-3 and cleaved PARP of MDA-MB-231 and MDA-MB-486 in a time-dependent manner.
FIG. 69 shows the assessment of the effect of compound 17ya and controls on the expression of caspase 3/7 activity on MDA-MB-231 and MDA-MB-468 cells using the caspase Glo 3/7 assay system.
Figure 70 shows the effect of vehicle, compound 17ya and paclitaxel on the percent increase in tumor volume after treatment.
Figure 71 shows the effect of vehicle, compound 17ya and paclitaxel on mouse body weight after treatment.
Figure 72 shows the final tumor volume after treatment with 10mg/kg compound 17 ya.
Figure 73 shows the final tumor weight after treatment with 10mg/kg compound 17 ya.
Figure 74 shows the effect of compound 17ya, control and paclitaxel on the percentage of necrotic cells.
Figure 75 shows the effect of control, compound 17ya and paclitaxel on Ki 67.
Figure 76 shows the effect of control, compound 17ya and paclitaxel on CD 31.
Figure 77 demonstrates the effect of control, compound 17ya and paclitaxel on cleaved PARP.
FIG. 78 shows the effect of control, compound 17ya and paclitaxel on cleaved caspase-3.
It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.
Detailed Description
The present invention encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (I), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (I) has the formula:
wherein
A and C are each independently a substituted or unsubstituted monocyclic, fused or polycyclic aryl or (hetero) ring system; substituted or unsubstituted, saturated or unsaturated N-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated S-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated O-heterocycle; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or a substituted or unsubstituted, saturated or unsaturated mixed heterocycle;
b is
R10And R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
X is a bond, NH, C1To C5A hydrocarbon, O or S;
y is a bond, -C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S;
wherein said A and C rings are optionally substituted with 1-5 substituents independently selected from O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl; alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer between 0 and 5;
l is an integer between 0 and 2;
wherein
If B isA benzene, thiophene, furan or indole ring, then X is not a bond or CH2And A is not indole; and
if B is indole, X is not O.
Triple negative breast cancer may be taxane-resistant TNBC, taxane-sensitive TNBC and/or metastasis.
In one embodiment, if B of formula I is a thiazole ring, X is not a bond.
In one embodiment, a in the compound of formula I is indolyl. In another embodiment, A is 2-indolyl. In another embodiment, a is phenyl. In another embodiment, a is pyridinyl. In another embodiment, a is naphthyl. In another embodiment, a is isoquinoline. In another embodiment, C in the compound of formula I is indolyl. In another embodiment, C is 2-indolyl. In another embodiment, C is 5-indolyl. In another embodiment, B in the compound of formula I is thiazole. In another embodiment, B in the compound of formula I is thiazole; y is CO and X is a bond. Non-limiting examples of compounds of formula I are selected from: (2- (1H-indol-2-yl) thiazol-4-yl) (1H-indol-2-yl) methanone (8) and (2- (1H-indol-2-yl) thiazol-4-yl) (1H-indol-5-yl) methanone (21).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer in a subject in need thereof by administering to the subject at least one compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (Ia) has the structure
Wherein
A is a substituted or unsubstituted monocyclic, fused or polycyclic aryl or (hetero) ring system; substituted or unsubstituted, saturated or unsaturated N-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated S-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated O-heterocycle; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or a substituted or unsubstituted, saturated or unsaturated mixed heterocycle;
b is
R1、R2And R3Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
R10And R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
X is a bond, NH, C1To C5A hydrocarbon, O or S;
y is a bond, -C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S;
wherein the A ring is optionally substituted with 1-5 substituents independently being O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl; alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer between 0 and 5;
l is an integer between 0 and 2;
m is an integer between 1 and 3;
wherein
If B is a benzene, thiophene, furan or indole ring, X is not a bond or CH2And A is not indole; and
if B is indole, X is not O.
In one embodiment, if B of formula Ia is a thiazole ring, X is not a bond.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (II) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (II) has the formula:
wherein
B is
R1、R2、R3、R4、R5And R6Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
R10And R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
X is a bond, NH, C1To C5A hydrocarbon, O or S;
y is a bond, -C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S;
i is an integer between 0 and 5;
l is an integer between 0 and 2;
n is an integer between 1 and 3; and
m is an integer between 1 and 3;
wherein
If B is indole, X is not O.
In one embodiment, if B of formula II is a thiazole ring, X is not a bond.
The invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (III) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof in a therapeutically effective amount, wherein the compound of formula (III) has the general formula of the compound of formula (III)
Wherein
B is
R4、R5And R6Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2(ii) a And
R10and R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
X is a bond, NH, C1To C5A hydrocarbon, O or S;
y is a bond, -C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S;
i is an integer between 0 and 5;
l is an integer between 0 and 2; and
n is an integer between 1 and 3;
wherein
If B is indole, X is not O.
In one embodiment, if B of formula III is a thiazole ring, X is not a bond.
The present invention encompasses methods of treating triple negative breast cancer by administering to a subject in need thereof at least one compound of formula (IV), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (IV) has the following formula:
wherein ring a is indolyl;
b is
R1And R2Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
R10And R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
X is a bond, NH, C1To C5A hydrocarbon, O or S;
y is a bond, C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S;
wherein said a is optionally substituted with: o-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl; alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2(ii) a And
i is an integer between 0 and 5;
l is an integer between 0 and 2; and
m is an integer between 1 and 4;
wherein
If B is a benzene, thiophene, furan or indole ring, X is not a bond or CH2。
In one embodiment, if B of formula IV is a thiazole ring, X is not a bond.
In another embodiment, the indolyl group of ring a of formula IV is attached to one of the 1-7 positions of X, or, if X is a bond (i.e., no group), directly to B.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula iv (a), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula iv (a) has the following formula:
b is
R1、R2、R4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2(ii) a And
R10and R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
X is a bond, NH, C1To C5A hydrocarbon, O or S;
y is a bond or C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S;
i is an integer between 0 and 5;
l is an integer between 0 and 2;
n is an integer between 1 and 2; and
m is an integer between 1 and 4;
wherein
If B is a benzene, thiophene, furan or indole ring, X is not a bond or CH2。
In one embodiment, if B of formula IVa is a thiazole ring, X is not a bond.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (V), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (V) has the formula:
b is
R4、R5And R6Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
R10And R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer between 1 and 5;
l is an integer between 0 and 2; and
n is an integer between 1 and 3.
In another embodiment, B of formula V is not thiazoleIn another embodiment, B of formula V is not oxazole. In another embodiment, B of formula V is not oxazoline. In another embodiment, B of formula V is not imidazole. In another embodiment, B of formula V is not thiazole, oxazole, oxazoline or imidazole.
The compounds encompassed by the methods of the present invention include the following:
the present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (VI) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof in a therapeutically effective amount, wherein the compound of formula (VI) has the formula:
wherein
R4、R5And R6Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2(ii) a And
y is a bond or C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S;
n is an integer between 1 and 3; and
i is an integer of 1 to 5.
The present invention encompasses methods of using the following compounds:
in one embodiment, the present invention relates to compound 3 a:
in one embodiment, the present invention relates to compound 3 b:
in one embodiment, the present invention relates to a compound of formula (VII) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer thereof
Wherein
Y is a bond or C ═ O, -C ═ S, -C ═ N-NH2、-C＝N-OH、-CH-OH、-C＝CH-CN、
-C＝N-CN、-CH＝CH-、-C＝C(CH3)2、-C＝N-OMe、-(C＝O)-NH、-NH-(C＝O)、–(C＝O)-O、-O-(C＝O)、-(CH2)1-5-(C＝O)、(C＝O)-(CH2)1-5、-(SO2)-NH-、-NH-(SO2)-、SO2SO or S.
In one embodiment, the present invention relates to the following compounds:
in one embodiment, the present invention relates to a compound of formula (VIII) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer thereof
Wherein
R4、R5And R6Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
Q is S, O or NH;
i is an integer between 0 and 5; and
n is an integer between 1 and 3.
In one embodiment, the present invention relates to the following compounds:
the invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (IX), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (IX):
wherein
R4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、
-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, - (O) NH2Or NO2；
A' is halogen; substituted or unsubstituted monocyclic, fused or polycyclic, aryl or (hetero) ring systems; substituted or unsubstituted, saturated or unsaturated N-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated S-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated O-heterocycle; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or a substituted or unsubstituted, saturated or unsaturated mixed heterocycle; wherein the A' ring is optionally substituted with 1-5 substituents independently selected from O-alkyl, O-haloalkyl, F, Cl, Br,I. Haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer between 1 and 5; and
n is an integer between 1 and 3.
In one embodiment, the compound of formula IX is represented by the structure of:
in another embodiment, a' of formula IX is halogen. In one embodiment, a' of formula IX is phenyl. In another embodiment, a' of formula IX is a substituted phenyl. In another embodiment, the substitution of a' is halogen. In another embodiment, the substitution is 4-F. In another embodiment, the substitution is 3,4,5- (OCH)3)3. In another embodiment, A' of formula IX is a substituted or unsubstituted 5-indolyl group. In another embodiment, A' of formula IX is a substituted or unsubstituted 2-indolyl group. In another embodiment, A' of formula IX is a substituted or unsubstituted 3-indolyl group.
The invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (IXa), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (IXa):
wherein
R4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、
-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, - (O) NH2Or NO2；
A' is halogen; substituted or unsubstituted monocyclic, fused or polycyclic, aryl or (hetero) ring systems; substituted or unsubstituted, saturated or unsaturated N-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated S-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated O-heterocycle; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or a substituted or unsubstituted, saturated or unsaturated mixed heterocycle; wherein the A' ring is optionally substituted with 1-5 substituents independently being O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer between 1 and 5; and
n is an integer between 1 and 3.
In another embodiment, a' of formula IXa is halogen. In one embodiment, a' of formula IXa is phenyl. In another embodiment, a' of formula IXa is substituted phenyl. In another implementationIn the schemes, the substitution of a' is halogen. In another embodiment, the substitution is 4-F. In another embodiment, the substitution is 3,4,5- (OCH)3)3. In another embodiment, A' of formula IXa is a substituted or unsubstituted 5-indolyl group. In another embodiment, A' of formula IXa is a substituted or unsubstituted 2-indolyl group. In another embodiment, A' of formula IXa is a substituted or unsubstituted 3-indolyl group.
In another embodiment, the compound of formula IXa is 1-chloro-7- (4-fluorophenyl) isoquinoline. In another embodiment, the compound of formula IXa is 7- (4-fluorophenyl) -1- (1H-indol-5-yl) isoquinoline. In another embodiment, the compound of formula IXa is 7- (4-fluorophenyl) -1- (3,4, 5-trimethoxyphenyl) isoquinoline. In another embodiment, the compound of formula IXa is 1, 7-bis (4-fluorophenyl) isoquinoline (40). In another embodiment, the compound of formula IXa is 1, 7-bis (3,4, 5-trimethoxyphenyl) isoquinoline. In another embodiment, the compound of formula IXa is 1- (4-fluorophenyl) -7- (3,4, 5-trimethoxyphenyl) isoquinoline. In another embodiment, the compound of formula IXa is 1- (1H-indol-5-yl) -7- (3,4, 5-trimethoxyphenyl) isoquinoline. In another embodiment, the compound of formula IXa is 1-chloro-7- (3,4, 5-trimethoxyphenyl) isoquinoline.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XI), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XI) is represented by the following structure:
wherein
X is a bond, NH or S;
q is O, NH or S; and
a is a substituted or unsubstituted monocyclic, fused or polycyclic, aryl or (hetero) cyclic system; substituted orUnsubstituted, saturated or unsaturated N-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated S-heterocyclic ring; substituted or unsubstituted, saturated or unsaturated O-heterocycle; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or a substituted or unsubstituted, saturated or unsaturated mixed heterocycle; wherein said A ring is optionally substituted with 1-51-5 substituents independently selected from O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2(ii) a And
i is an integer of 0 to 5.
In one embodiment, if Q of formula XI is S, X is not a bond.
In one embodiment, a of the compound of formula XI is Ph. In another embodiment, a of the compound of formula XI is substituted Ph. In another embodiment, the substitution is 4-F. In another embodiment, the substitution is 4-Me. In another embodiment, Q of the compound of formula XI is S. In another embodiment, X of the compound of formula XI is NH. Non-limiting examples of compounds of formula XI are selected from: (2- (phenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5a), (2- (p-tolylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5b), (2- (p-fluorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5c), (2- (4-chlorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5d), (2- (phenylamino) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (5e), (2- (phenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone hydrochloride (5Ha), (2- (p-tolylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone hydrochloride (5Hb), (2- (p-fluorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone hydrochloride (5Hc), (2- (4-chlorophenylamino) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone hydrochloride (5Hd), (2- (phenylamino) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone hydrochloride (5 He).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula xi (a), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula xi (a) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula xi (b), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula xi (b) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula xi (c), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula xi (c) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula xi (d), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula xi (d) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula xi (e), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula xi (e) is represented by the structure:
wherein R is4And R5Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2；
i is an integer of 0 to 5; and
n is an integer between 1 and 4.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering compound 55 to a subject in need thereof in a therapeutically effective amount, wherein compound 55 is represented by the following structure:
the present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering compound 17ya in a therapeutically effective amount to a subject in need thereof, wherein compound 17ya is represented by the structure:
the present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound having the structure:
it is to be understood that in the structures provided by the present invention, wherein the nitrogen atom has fewer than 3 bonds, an H atom is provided to complete the valence of the nitrogen.
In one embodiment, the A, A' and/or C groups of formulas I, I (a), IV, IX (a), and XI are independently substituted and unsubstituted furyl, indolyl, pyridyl, phenyl, biphenyl, triphenyl, diphenylmethane, adamantyl, fluorenyl, and other heterocyclic analogs, such as pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, isoquinolyl, quinolyl, isoquinolyl, benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, oxacyclopropane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furyl, pyrylium, benzofuranyl, benzodioxazolyl, thiacyclopropyl, thiacyclobutyl, tetrahydrothienyl, tetrahydrofuranyl, substituted and unsubstituted furyl, Dithiolyl, tetrahydrothiopyranyl, thienyl, thianylA group selected from the group consisting of thiaindenyl, oxathiolanyl, morpholinyl, thialkyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and oxadiazolyl.
In one embodiment, the A, A' and/or C groups are substituted and unsubstituted phenyl groups. In another embodiment, the A, A' and/or C groups are phenyl substituted with Cl, F, or methyl. In one embodiment, the A, A' and/or C groups are substituted and unsubstituted isoquinolinyl groups. In one embodiment, the A, A' and/or C groups include substituted and unsubstituted indolyl groups; most preferably, substituted and unsubstituted 3-indolyl and 5-indolyl groups.
In one embodiment, the A, A' and/or C groups of formulas I, I (a), IV, IX (a), and XI can be substituted or unsubstituted. Thus, while the exemplary groups recited in the preceding paragraphs are unsubstituted, those skilled in the art will appreciate that these groups may be substituted with one or more, two or more, three or more, and even up to five substituents (other than hydrogen).
In one embodiment, the most preferred A, A' and/or C groups are substituted with 3,4, 5-trimethoxyphenyl. In another embodiment, A, A' and/or the C group are substituted with alkoxy. In another embodiment, the A, A' and/or C groups are substituted with methoxy. In another embodiment, A, A' and/or the C group are substituted with alkyl groups. In another embodiment, A, A' and/or the C group are substituted with methyl. In another embodiment, A, A' and/or the C group are substituted with a halogen. In another embodiment, A, A' and/or the C group is substituted with F. In another embodiment, A, A' and/or the C group are substituted with Cl. In another embodiment, ring A, A' and/or C is substituted with Br.
Substituents for these A, A' and/or C groups of formulae I, I (a), IV, IX (a), and XI are independently selected from the following groups: hydrogen (e.g., unsubstituted at a particular position), hydroxy, aliphatic straight or branched C1To C10Hydrocarbons, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halogenElements (e.g., F, Cl, Br, I), haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C (O) Ph, C (O) -alkyl, C (O) O-alkyl, C (O) H, C (O) NH2、-OC(O)CF3、OCH2Ph, amino group, aminoalkyl group, alkylamino group, methanesulfonylamino group, dialkylamino group, arylamino group, amino group, NHC (O) -alkyl group, urea, alkylurea, alkylamido group (e.g., acetamide), haloalkylamido group, arylamido group, aryl group, and C5To C7Cycloalkyl, arylalkyl, and combinations thereof. The individual substituents may be present in ortho, meta or para positions. When two or more substituents are present, one of them is preferably, although not necessarily, located at the para position.
In one embodiment, the B groups of formulas I, I (a), II, III, IV, IVa and V are selected from substituted or unsubstituted thiazoles, thiazolidines, oxazoles, oxazolines, oxazolidines, benzenes, pyrimidines, imidazoles, pyridines, furans, thiophenes, isoxazoles, piperidines, pyrazoles, indoles, and isoquinolines, wherein the B ring is attached to X and Y via any two positions of the ring or directly to the a and/or C rings.
In one embodiment, the B groups of formulas I, I (a), II, III, IV, IVa, and V are unsubstituted. In another embodiment, the B groups of formulas I, I (a), II, III, IV, IVa, and V are:
in another embodiment, the B groups of formulas I, I (a), II, III, IV, IVa, and V are substituted. In another embodiment, the B groups of formulas I, I (a), II, III, IV, IVa, and V are:
wherein R is10And R11Independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3、C1-C5Straight or branched chain alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH2Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH2Or NO2。
In another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn a further embodiment of the process of the present invention,the B group beingIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group is In another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group isIn another embodiment, the B group is
In one embodiment, the B groups of formulas I, I (a), II, III, IV, IVa and V are substituted with R10And R11And (4) substitution. In another embodiment, R10And R11Are all hydrogen. In another embodiment, R10And R11Independently is an O-alkyl group. In another embodiment, R10And R11Independently is an O-haloalkyl. In another embodiment, R10And R11Independently F. In another embodiment, R10And R11Independently Cl. In another embodiment, R10And R11Independently is Br. In another embodiment, R10And R11Independently is I. In another embodiment, R10And R11Independently a haloalkyl group. In another embodiment, R10And R11Independently is CF3. In another embodiment, R10And R11Independently CN. In another embodiment, R10And R11Independently is-CH2And (C) CN. In another embodiment, R10And R11Independently is NH2. In another embodiment, R10And R11Independently a hydroxyl group. In another embodiment, R10And R11Independently is- (CH)2)iNHCH3. In another embodiment, R10And R11Independently is- (CH)2)iNH2. In another embodiment, R10And R11Independently is- (CH)2)iN(CH3)2. In another embodiment, R10And R11Independently is-OC (O) CF3. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain alkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain haloalkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched alkylamino. In another embodiment, R10And R11Independently is C1-C5Straight or branched aminoalkyl groups. In another embodiment, R10And R11Independently is-OCH2Ph. In another embodiment, R10And R11Independently is-NHCO-alkyl. In another embodiment, R10And R11Independently COOH. In another embodiment, R10And R11Independently, -C (O) Ph. In another embodiment, R10And R11Independently is C (O) O-alkyl. In another embodiment, R10And R11Independently C (O) H. In another embodiment, R10And R11Independently is-C (O) NH2. In another embodiment, R10And R11Independently is NO2。
In another embodiment, the B group of formulas I, I (a), II, III, IV, IVa and V isWherein R is10And R11Independently is H, and l is 1. In another embodiment, R10And R11Independently is an O-alkyl group. In another embodiment, R10And R11Independently is an O-haloalkyl. In another embodiment, R10And R11Independently F. In another embodiment, R10And R11Independently Cl. In another embodiment, R10And R11Independently is Br. In another embodiment, R10And R11Independently is I. In another embodiment, R10And R11Independently a haloalkyl group. In another embodiment, R10And R11Independently is CF3. In another embodiment, R10And R11Independently CN. In another embodiment, R10And R11Independently is-CH2And (C) CN. In another embodiment, R10And R11Independently is NH2. In another embodiment, R10And R11Independently a hydroxyl group. In another embodiment, R10And R11Independently is- (CH)2)iNHCH3. In another embodiment, R10And R11Independently is- (CH)2)iNH2. In another embodiment, R10And R11Independently is- (CH)2)iN(CH3)2. In another embodiment, R10And R11Independently is-OC (O) CF3. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain alkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain haloalkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched alkylamino. In another embodiment, R10And R11Independently is C1-C5Straight or branched aminoalkyl groups. In another embodiment, R10And R11Independently is-OCH2Ph. In another embodiment, R10And R11Independently is-NHCO-alkyl. In another embodiment, R10And R11Independently COOH. In another embodiment, R10And R11Independently, -C (O) Ph. In another embodiment, R10And R11Independently is C (O) O-alkyl. In another embodiment, R10And R11Independently C (O) H. In another embodiment, R10And R11Independently is-C (O) NH2. In another embodiment, R10And R11Independently is NO2。
In another embodiment, the B group of formulas I, I (a), II, III, IV, IVa and V isWherein R is10And R11Independently is H, and l is 1. In another embodiment, R10And R11Independently is an O-alkyl group. In another embodiment, R10And R11Independently is an O-haloalkyl. In another embodiment, R10And R11Independently F. In another embodiment, R10And R11Independently Cl. In another embodiment, R10And R11Independently is Br. In another embodiment, R10And R11Independently is I. In another embodiment, R10And R11Independently a haloalkyl group. In another embodiment, R10And R11Independently is CF3. In another embodiment, R10And R11Independently CN. In another embodiment, R10And R11Independently is-CH2And (C) CN. In another embodiment, R10And R11Independently is NH2. In another embodiment, R10And R11Independently a hydroxyl group. In another embodiment, R10And R11Independently is- (CH)2)iNHCH3. In another embodiment, R10And R11Independently is- (CH)2)iNH2. In another embodiment, R10And R11Independently is- (CH)2)iN(CH3)2. In another embodiment, R10And R11Independently is-OC (O) CF3. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain alkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain haloalkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched alkylamino. In another embodiment, R10And R11Independently is C1-C5Straight or branched aminoalkyl groups. In another embodiment, R10And R11Independently is-OCH2Ph. In another embodiment, R10And R11Independently is-NHCO-alkaneAnd (4) a base. In another embodiment, R10And R11Independently COOH. In another embodiment, R10And R11Independently, -C (O) Ph. In another embodiment, R10And R11Independently is C (O) O-alkyl. In another embodiment, R10And R11Independently C (O) H. In another embodiment, R10And R11Independently is-C (O) NH2. In another embodiment, R10And R11Independently is NO2。
In another embodiment, the B group of formulas I, I (a), II, III, IV, IVa and V is Wherein R is10And R11Independently is H, and l is 1. In another embodiment, R10And R11Independently is an O-alkyl group. In another embodiment, R10And R11Independently is an O-haloalkyl. In another embodiment, R10And R11Independently F. In another embodiment, R10And R11Independently Cl. In another embodiment, R10And R11Independently is Br. In another embodiment, R10And R11Independently is I. In another embodiment, R10And R11Independently a haloalkyl group. In another embodiment, R10And R11Independently is CF3. In another embodiment, R10And R11Independently CN. In another embodiment, R10And R11Independently is-CH2And (C) CN. In another embodiment, R10And R11Independently is NH2. In another embodiment, R10And R11Independently a hydroxyl group. In another embodiment, R10And R11Independently is- (C)H2)iNHCH3. In another embodiment, R10And R11Independently is- (CH)2)iNH2. In another embodiment, R10And R11Independently is- (CH)2)iN(CH3)2. In another embodiment, R10And R11Independently is-OC (O) CF3. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain alkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched chain haloalkyl. In another embodiment, R10And R11Independently is C1-C5Straight or branched alkylamino. In another embodiment, R10And R11Independently is C1-C5Straight or branched aminoalkyl groups. In another embodiment, R10And R11Independently is-OCH2Ph. In another embodiment, R10And R11Independently is-NHCO-alkyl. In another embodiment, R10And R11Independently COOH. In another embodiment, R10And R11Independently, -C (O) Ph. In another embodiment, R10And R11Independently is C (O) O-alkyl. In another embodiment, R10And R11Independently C (O) H. In another embodiment, R10And R11Independently is-C (O) NH2. In another embodiment, R10And R11Independently is NO2。
In one embodiment, the X bridge of formulae I, Ia, II, III, IV, IVa and XI is a bond. In another embodiment, the X bridge is NH. In another embodiment, the X bridge is C1To C5A hydrocarbon. In another embodiment, the X bridge is CH2. In another embodiment, the X bridge is-CH2-CH2-. In another embodiment, the X bridge is O. In another embodiment, the X bridge is S.
In one embodiment, the Y bridge of formulae I, Ia, II, III, IV, IVa, VI and VII is C ═ O. In another embodiment, the Y bridge is C ═ S. In another embodiment, the Y bridge is C ═ N (NH)2) -. In another embodiment, the Y bridge is — C ═ NOH. In another embodiment, the Y bridge is-CH-OH. In another embodiment, the Y bridge is-C ═ CH- (CN). In another embodiment, the Y bridge is-C ═ n (cn). In another embodiment, the Y bridge is-C ═ C (CH)3)2. In another embodiment, the Y bridge is-C ═ N-OMe. In another embodiment, the Y bridge is- (C ═ O) NH-. In another embodiment, the Y bridge is — NH (C ═ O) -. In another embodiment, the Y bridge is- (C ═ O) -O. In another embodiment, the Y bridge is — O- (C ═ O). In another embodiment, the Y bridge is- (CH)2)1-5- (C ═ O). In another embodiment, the Y bridge is- (C ═ O) - (CH)2)1-5. In another embodiment, the Y bridge is S. In another embodiment, the Y bridge is SO. In another embodiment, the Y bridge is SO2. In another embodiment, the Y bridge is-CH ═ CH-. In another embodiment, the Y bridge is- (SO)2) -NH-. In another embodiment, the Y bridge is-NH- (SO)2)-。
In one embodiment, R of formulae Ia, II, III, IV (a), V, VI, VIII, IX (a), XI (b), XI (c), XI (d), and XI (e)1、R2、R3、R4、R5And R6Independently hydrogen. In another embodiment, R1、R2、R3、R4、R5And R6Independently is an O-alkyl group. In another embodiment, R1、R2、R3、R4、R5And R6Independently is an O-haloalkyl. In another embodiment, R1、R2、R3、R4、R5And R6Independently F. In another embodiment, R1、R2、R3、R4、R5And R6Independently Cl. In another embodiment, R1、R2、R3、R4、R5And R6Independently is Br. In another embodiment, R1、R2、R3、R4、R5And R6Independently is I. In another embodiment, R1、R2、R3、R4、R5And R6Independently a haloalkyl group. In another embodiment, R1、R2、R3、R4、R5And R6Independently is CF3. In another embodiment, R1、R2、R3、R4、R5And R6Independently CN. In another embodiment, R1、R2、R3、R4、R5And R6Independently is-CH2And (C) CN. In another embodiment, R1、R2、R3、R4、R5And R6Independently is NH2. In another embodiment, R1、R2、R3、R4、R5And R6Independently a hydroxyl group. In another embodiment, R1、R2、R3、R4、R5And R6Independently is- (CH)2)iNHCH3. In another embodiment, R1、R2、R3、R4、R5And R6Independently is- (CH)2)iNH2. In another embodiment, R1、R2、R3、R4、R5And R6Independently is- (CH)2)iN(CH3)2. In another embodiment, R1、R2、R3、R4、R5And R6Independently is-OC (O) CF3. In another embodiment, R1、R2、R3、R4、R5And R6Independently is C1-C5Straight or branched chain alkyl. In another embodiment, R1、R2、R3、R4、R5And R6Independently a haloalkyl group. In another embodiment, R1、R2、R3、R4、R5And R6Independently is an alkylamino group. In another embodiment, R1、R2、R3、R4、R5And R6Independently, an aminoalkyl group. In another embodiment, R1、R2、R3、R4、R5And R6Independently is-OCH2Ph. In another embodiment, R1、R2、R3、R4、R5And R6Independently is-NHCO-alkyl. In another embodiment, R1、R2、R3、R4、R5And R6Independently COOH. In another embodiment, R1、R2、R3、R4、R5And R6Independently, -C (O) Ph. In another embodiment, R1、R2、R3、R4、R5And R6Independently is C (O) O-alkyl. In another embodiment, R1、R2、R3、R4、R5And R6Independently C (O) H. In another embodiment, R1、R2、R3、R4、R5And R6Independently is-C (O) NH2. In another embodiment, R1、R2、R3、R4、R5And R6Independently is NO2。
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula XII, or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula XII is represented by the structure:
wherein the content of the first and second substances,
p and Q are independently H or
W is C-O, C-S, SO2Or S ═ O;
wherein at least one of Q or P is not hydrogen;
R1and R4Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2(ii) a C (O) O-alkyl or C (O) H; wherein R is1And R4Is not hydrogen;
R2and R5Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
m is an integer between 1 and 4;
i is an integer between 0 and 5; and
n is an integer between 1 and 4.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula XIII, or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula XIII is represented by the structure:
wherein
Z is O or S;
R1and R4Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph、OH、CN、NO2-NHCO-alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2(ii) a COOH, C (O) O-alkyl or C (O) H; wherein R is1And R4Is not hydrogen;
R2and R5Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2；OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
m is an integer between 1 and 4;
i is an integer between 0 and 5; and
n is an integer between 1 and 4.
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XIV), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XIV) is represented by the following structure:
wherein R is1And R4Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2PH、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H; wherein R is1And R4Is not hydrogen;
R2and R5Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
m is an integer between 1 and 4;
i is an integer between 0 and 5; and
n is an integer between 1 and 4.
In one embodiment, R of compounds of formulas XII, XIII and XIV1Is OCH3. In another embodiment, R of compounds of formulas XII, XIII and XIV1Is 4-F. In another embodiment, R of compounds of formulas XII, XIII and XIV1Is OCH3And m is 3. In another embodiment, R of compounds of formulas XII, XIII and XIV4Is 4-F. In another embodiment, R of compounds of formulas XII, XIII and XIV4Is OCH3. In another embodiment, R of the compound of formula XIV4Is CH3. In another embodiment, R of compounds of formulas XII, XIII and XIV4Is 4-Cl. In another embodiment, R of compounds of formulas XII, XIII and XIV4Is 4-N (Me)2. In another embodiment, R of compounds of formulas XII, XIII and XIV4Is OBn. In another embodiment, R of compounds of formulas XII, XIII and XIV4Is 4-Br. In another embodiment, R of compounds of formulas XII, XIII and XIV4Is 4-CF3. Non-limiting examples of compounds of formula XIV are selected from: (2-phenyl-1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12aa), (4-fluorophenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12af), (2- (4-fluorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ba), (2- (4-methoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ca), and (4-fluorophenyl) (2- (4-methoxyphenyl) -1H-imidazol-4-yl) methanone (1 ca)2cb), (2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12da), (4-fluorophenyl) (2- (p-tolyl) -1H-imidazol-4-yl) methanone (12db), (4-hydroxy-3, 5-dimethoxyphenyl) (2- (p-tolyl) -1H-imidazol-4-yl) methanone (12dc), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12fa), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12fb), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (4-hydroxy-3, 5-dimethoxyphenyl) methanone (12fc), (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ga); (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12gb), (2- (3, 4-dimethoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ha), (2- (4- (benzyloxy) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12jb), (2- (4-bromophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12la), (2- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone 12 pa).
The invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XIVa), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XIVa) is represented by the structure:
wherein R is1And R4Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2PH、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H; wherein R is1And R4Is not hydrogen;
R2and R5Independently H, O-alkyl, I, Br, Cl, F, alkyl,Haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
R9is H, linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, CH2Ph, substituted benzyl, haloalkyl, aminoalkyl, OCH2Ph, substituted or unsubstituted SO2-aryl, substituted or unsubstituted- (C ═ O) -aryl or OH;
wherein the substituents are independently selected from the group consisting of: hydrogen (e.g., unsubstituted at a particular position), hydroxy, aliphatic straight or branched C1To C10Hydrocarbons, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halogen (e.g., F, Cl, Br, I), haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C (O) Ph, C (O) -alkyl, C (O) O-alkyl, C (O) H, C (O) NH2、-OC(O)CF3、OCH2Ph, amino group, aminoalkyl group, alkylamino group, methanesulfonylamino group, dialkylamino group, arylamino group, amino group, NHC (O) -alkyl group, urea, alkylurea, alkylamido group (e.g., acetamide), haloalkylamido group, arylamido group, aryl group, and C5To C7Cycloalkyl, arylalkyl, and combinations thereof;
m is an integer between 1 and 4;
i is an integer between 0 and 5; and
n is an integer between 1 and 4.
In one embodiment, R of the compound of formula XIVa9Is CH3. In another embodiment, R of the compound of formula XIVa9Is CH2Ph. In another embodiment, R of the compound of formula XIVa9Is (SO)2) Ph. In another embodiment, R of the compound of formula XIVa9Is (SO)2)-Ph-OCH3. In another embodiment, R of the compound of formula XIVa9Is H. In another embodimentR of a compound of formula XIVa4Is H. In another embodiment, R of the compound of formula XIVa4Is CH3. In another embodiment, R of the compound of formula XIVa4Is OCH3. In another embodiment, R of the compound of formula XIVa4Is OH. In another embodiment, R of the compound of formula XIVa4Is 4-Cl. In another embodiment, R of the compound of formula XIVa4Is 4-N (Me)2. In another embodiment, R of the compound of formula XIVa4Is OBn. In another embodiment, R of the compound of formula XIVa1Is OCH3(ii) a m is 3 and R2Is H. In another embodiment, R of the compound of formula XIVa1Is F; m is 1 and R2Is H. Non-limiting examples of compounds of formula XIVa are selected from: (4-fluorophenyl) (2-phenyl-1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11af), (4-fluorophenyl) (2- (4-methoxyphenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11cb), (4-fluorophenyl) (1- (phenylsulfonyl) -2- (p-tolyl) -1H-imidazol-4-yl) methanone (11db), (2- (4-chlorophenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11fb), (2- (4- (dimethylamino) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11af) -4-yl) (3,4, 5-trimethoxyphenyl) methanone (11ga), (2- (4- (dimethylamino) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11gb), (2- (3, 4-dimethoxyphenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11ha), (2- (4- (benzyloxy) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11jb), (2- (4- (dimethylamino) phenyl) -1- ((4-methoxyphenyl) sulfonyl) -1 H-imidazol-4-yl) (4-fluorophenyl) methanone (12gba), (1-benzyl-2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12daa), (1-methyl-2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12dab), (4-fluorophenyl) (2- (4-methoxyphenyl) -1-methyl-1H-imidazol-4-yl) methanone (12 cba).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XV), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XV) is represented by the following structure:
wherein R is4And R5Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
i is an integer between 0 and 5; and
n is an integer between 1 and 4.
In one embodiment, R of the compound of formula XV4Is H. In another embodiment, R of the compound of formula XV4Is F. In another embodiment, R of the compound of formula XV4Is Cl. In another embodiment, R of the compound of formula XV4Is Br. In another embodiment, R of the compound of formula XV4Is I. In another embodiment, R of the compound of formula XV4Is N (Me)2. In another embodiment, R of the compound of formula XV4Is OBn. In another embodiment, R of the compound of formula XV4Is OCH3. In another embodiment, R of the compound of formula XV4Is CH3. In another embodiment, R of the compound of formula XV4Is CF3. Non-limiting examples of compounds of formula XV are selected from: (2-phenyl-1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12aa), (2- (4-fluorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ba), (2- (4-methoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ca), (2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12da), (3,4,5-Trimethoxyphenyl) (2- (3,4, 5-trimethoxyphenyl) -1H-imidazol-4-yl) methanone (12ea), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12fa), (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ga), (2- (3, 4-dimethoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ha), (2- (2- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ia), (2- (4- (benzyloxy) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ja), (2- (4-hydroxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ka), (2- (4-bromophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12la), (2- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone 12 pa).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XVI), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XVI) is represented by the following structure:
wherein R is4And R5Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
R3is I, Br, Cl or F;
i is an integer between 0 and 5; and
n is an integer between 1 and 4.
In one embodiment, R of the compound of formula XVI3Is a halogen. In another embodiment, R3Is F. In another embodimentIn the embodiment, R3Is Cl. In another embodiment, R3Is Br. In another embodiment, R3Is I. In another embodiment, R4Is H. In another embodiment, R4Is OCH3. In another embodiment, R4Is OCH3(ii) a n is 3 and R5Is H. In another embodiment, R4Is CH3. In another embodiment, R4Is F. In another embodiment, R4Is Cl. In another embodiment, R4Is Br. In another embodiment, R4Is I. In another embodiment, R4Is N (Me)2. In another embodiment, R4Is OBn. In another embodiment, R3Is F; r5Is hydrogen; n is 1 and R4Is 4-Cl. In another embodiment, R3Is F; r5Is hydrogen; n is 1 and R4Is 4-OCH3. In another embodiment, R3Is F; r5Is hydrogen; n is 1 and R4Is 4-CH3. In another embodiment, R3Is F; r5Is hydrogen; n is 1 and R4Is 4-N (Me)2. In another embodiment, R3Is F; r5Is hydrogen; n is 1 and R4Is 4-OBn. Non-limiting examples of compounds of formula XVI are selected from: (4-fluorophenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12af), (4-fluorophenyl) (2- (4-methoxyphenyl) -1H-imidazol-4-yl) methanone (12cb), (4-fluorophenyl) (2- (p-tolyl) -1H-imidazol-4-yl) methanone (12db), (4-fluorophenyl) (2- (3,4, 5-trimethoxyphenyl) -1H-imidazol-4-yl) methanone (12eb), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12fb), (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (4-fluoro phenyl) methanone (12fb), (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (4-fluoro methyl ether) Phenyl) methanone (12gb), (2- (4- (benzyloxy) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12 jb).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XVII), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XVII) is represented by the following structure:
wherein R is4Is H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
wherein R is1And R2Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
and
m is an integer between 1 and 4.
In one embodiment, R of a compound of formula XVII4Is a halogen. In another embodiment, R4Is F. In another embodiment, R4Is Cl. In another embodiment, R4Is Br. In another embodiment, R4Is I. In another embodiment, R4Is OCH3. In another embodiment, R4Is CH3. In another embodiment, R4Is N (Me)2. In another embodiment, R4Is CF3. In another embodiment, R4Is OH. In another embodiment, R4Is OBn. In another embodiment, R of a compound of formula XVII1Is a halogen. In another embodiment, R of a compound of formula XVII1Is F. In another embodiment, R of a compound of formula XVII1Is Cl. In another embodiment, R of a compound of formula XVII1Is Br. In another embodiment, R of a compound of formula XVII1Is I. In another embodiment, R of a compound of formula XVII1Is OCH3. In another embodiment, the compound of formula XVIIR of (A) A (B)1Is OCH3M is 3 and R2Is H. In another embodiment, R of a compound of formula XVII1Is F, m is 1 and R2Is H. In another embodiment, R4Is F; r2Is hydrogen; n is 3, and R1Is OCH3. In another embodiment, R4Is OCH3；R2Is hydrogen; n is 3 and R1Is OCH3. In another embodiment, R4Is CH3；R2Is hydrogen; n is 3 and R1Is OCH3. In another embodiment, R4Is Cl; r2Is hydrogen; n is 3, and R1Is OCH3. In another embodiment, R4Is N (Me)2；R2Is hydrogen; n is 3 and R1Is OCH3. In one embodiment, R of a compound of formula XVII4Is halogen, R1Is H and R2Is a halogen. In one embodiment, R of a compound of formula XVII4Is halogen, R1Is halogen and R2Is H. In one embodiment, R of a compound of formula XVII4Is alkoxy, XVII is halogen and R2Is H. In one embodiment, R of a compound of formula XVII4Is methoxy, R1Is halogen and R2Is H. Non-limiting examples of compounds of formula XVII are selected from: (2- (4-fluorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ba), (2- (4-methoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ca), (4-fluorophenyl) (2- (4-methoxyphenyl) -1H-imidazol-4-yl) methanone (12cb), (2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12da), (4-fluorophenyl) (2- (p-tolyl) -1H-imidazol-4-yl) methanone (12db), (4-hydroxy-3, 5-dimethoxyphenyl) (2- (p-tolyl) -1H-imidazol-4-yl) methanone (12dc), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12fa), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12fb), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (3,4, 5-trihydroxyphenyl) methanone (13fa), (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethylOxyphenyl) methanone (12ga), (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12gb), (2- (4- (benzyloxy) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12jb), (2- (4-hydroxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ka), (2- (4-bromophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12la), (2- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 pa).
In another embodiment, the compound of formula XVII is represented by the structure of formula 12 fb:
in another embodiment, the compound of formula XVII is represented by the structure of formula 12 cb:
the present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XVIII), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XVIII) is represented by the following structure:
wherein
W is C-O, C-S, SO2Or S ═ O;
R4and R7Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
R5and R8Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
n is an integer between 1 and 4;
i is an integer between 0 and 5; and
q is an integer between 1 and 4.
In one embodiment, W of the compound of formula XVIII is C ═ O. In another embodiment, W of the compound of formula XVIII is SO2. In another embodiment, R of a compound of formula XVIII4Is H. In another embodiment, R of a compound of formula XVIII4Is NO2. In another embodiment, R of a compound of formula XVIII4Is OBn. In another embodiment, R of a compound of formula XVIII7Is H. In another embodiment, R of a compound of formula XVIII7Is OCH3. In another embodiment, R of a compound of formula XVIII7Is OCH3And q is 3. Non-limiting examples of compounds of formula XVII are selected from: (4-methoxyphenyl) (2-phenyl-1H-imidazol-1-yl) methanone (12aba), (2-phenyl-1H-imidazol-1-yl) (3,4, 5-trimethoxyphenyl) methanone (12aaa), 2-phenyl-1- (phenylsulfonyl) -1H-imidazole (10a), 2- (4-nitrophenyl) -1- (phenylsulfonyl) -1H-imidazole (10x), 2- (4- (benzyloxy) phenyl) -1- (phenylsulfonyl) -1H-imidazole (10 j).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XIX), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XIX) is represented by the following structure:
wherein
W is C-O, C-S, SO2、S＝O；
R1、R4And R7Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
R2、R5and R8Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
m is an integer between 1 and 4;
n is an integer between 1 and 4;
i is an integer between 0 and 5; and
q is 1 to 4.
In one embodiment, R of formula XIX1、R4And R7Independently is H. In another embodiment, R of formula XIX1、R4And R7Independently is an O-alkyl group. In another embodiment, R of formula XIX1、R4And R7Independently a halogen. In another embodiment, R of formula XIX1、R4And R7Independently CN. In another embodiment, R of formula XIX1、R4And R7Independently is OH. In another embodiment, R of formula XIX1、R4And R7Independently an alkyl group. In another embodiment, R of formula XIX1、R4And R7Independently is OCH2Ph. In one embodiment, R of formula XIX2、R5And R8Independently is H. In another embodiment, R of formula XIX2、R5And R8Independently is an O-alkyl group. In another embodiment, R of formula XIX2、R5And R8Independently a halogen. In another embodiment, R of formula XIX2、R5And R8Independently CN. In another embodiment, R of formula XIX2、R5And R8Independently is OH. In another embodiment, R of formula XIX2、R5And R8Independently an alkyl group. In another embodiment, R of formula XIX2、R5And R8Independently is OCH2Ph. In another embodiment, R of formula XIX5、R2And R8Is H, R4Is 4-N (Me)2，R1Is OCH3M is 3 and R7Is OCH3. In another embodiment, R of formula XIX5、R2、R7And R8Is H, R4Is 4-Br, R1Is OCH3And m is 3. In another embodiment, W is SO2. In another embodiment, W is C ═ O. In another embodiment, W is C ═ S. In another embodiment, W is S ═ O. Non-limiting examples of compounds of formula XIX are selected from: (2- (4- (dimethylamino) phenyl) -1- ((4-methoxyphenyl) sulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11 gaa); (2- (4-bromophenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11la), (4-fluorophenyl) (2- (4-methoxyphenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11cb), (2- (4-chlorophenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11fb), (4-fluorophenyl) (2-phenyl-1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11af), (4-fluorophenyl) (1- (phenylsulfonyl) -2- (p-tolyl) -1H-imidazol-4-yl) methanone (11db), (2- (4- (dimethylamino) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11ga), (2- (4- (dimethylamino) phenyl) methanone) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11gb), (2- (3, 4-dimethoxyphenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11ha), (2- (4- (benzyloxy) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11jb), (2- (4- (dimethylamino) phenyl) -1- ((4-methoxyphenyl) sulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12 gba).
In another embodiment, the compound of formula XIX is represented by the structure of formula 11 cb:
in another embodiment, the compound of formula XIX is represented by the structure of formula 11 fb:
the present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XX), or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof, in a therapeutically effective amount, wherein the compound of formula (XX) is represented by the following structure:
wherein
R4Is H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H; and
i is an integer between 0 and 5.
In one implementationIn scheme, R of a compound of formula XX4Is H. In another embodiment, R of the compound of formula XX4Is a halogen. In another embodiment, R4Is F. In another embodiment, R4Is Cl. In another embodiment, R4Is Br. In another embodiment, R4Is I. In another embodiment, R4Is an alkyl group. In another embodiment, R4Is methyl. Non-limiting examples of compounds of formula XX are selected from: (2-phenyl-1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12aa), (2- (4-fluorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ba), (2- (4-methoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ca), (2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12da), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12fa), (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ga), (2- (2- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ia), (2- (4- (benzyloxy) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ja), (2- (4-hydroxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12ka), (2- (4-bromophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12la), (2- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 pa).
In another embodiment, the compound of formula XX is represented by the structure of formula 12 da:
in another embodiment, the compound of formula XX is represented by the structure of formula 12 fa:
the present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XXI) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof in a therapeutically effective amount, wherein the compound of formula (XXI) is represented by the structure:
wherein
A is indolyl;
q is NH, O or S;
R1and R2Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H; and
wherein said a is optionally substituted with: substituted or unsubstituted O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3Substituted or unsubstituted-SO2Aryl, substituted or unsubstituted C1-C5Straight or branched chain alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkylamino, substituted or unsubstituted aminoalkyl, -OCH2Ph, substituted or unsubstituted-NHCO-alkyl, COOH, substituted or unsubstituted-C (O) Ph, substituted or unsubstituted C (O) O-alkyl, C (O) H, -C (O) NH2、NO2Or a combination thereof;
i is an integer between 0 and 5; and
m is an integer between 1 and 4.
In one embodiment, R of a compound of formula XXI1Is OCH3(ii) a m is 3 and R2Is hydrogen. In another embodiment, R1Is F; m is 1 and R2Is hydrogen. In one embodiment, Q of formula XXI is O. In another embodiment, Q of formula XXI is NH. In another embodiment, Q of formula XXI is S.
In one embodiment, the A ring of the compound of formula XXI is a substituted 5-indolyl. In another embodiment, the substitution is- (C ═ O) -aryl. In another embodiment, aryl is 3,4,5- (OCH)3)3-Ph。
In another embodiment, the A ring of the compound of formula XXI is 3-indolyl. In another embodiment, the A ring of the compound of formula XXI is 5-indolyl. In another embodiment, the A ring of the compound of formula XXI is 2-indolyl. Non-limiting examples of compounds of formula XXI are selected from: (5- (4- (3,4, 5-trimethoxybenzoyl) -1H-imidazol-2-yl) -1H-indol-2-yl) (3,4, 5-trimethoxyphenyl) methanone (15 xaa); (1- (phenylsulfonyl) -2- (3,4, 5-trimethoxybenzoyl) -1H-indol-5-yl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (16 xaa); 2- (1H-indol-3-yl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (17 ya); (2- (1H-indol-2-yl) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (62 a); and (2- (1H-indol-5-yl) thiazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (66 a).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XXIa) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof in a therapeutically effective amount, wherein the compound of formula (XXIa) is represented by the following structure:
wherein
W is C-O, C-S, SO2、S＝O；
A is indolyl;
R1and R2Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
R7and R8Independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、OCH2Ph、OH、CN、NO2-NHCO-alkyl, COOH, C (O) O-alkyl or C (O) H;
wherein said a is optionally substituted with: substituted or unsubstituted O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3Substituted or unsubstituted-SO2Aryl, substituted or unsubstituted C1-C5Straight or branched chain alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkylamino, substituted or unsubstituted aminoalkyl, -OCH2Ph, substituted or unsubstituted-NHCO-alkyl, COOH, substituted or unsubstituted-C (O) Ph, substituted or unsubstituted C (O) O-alkyl, C (O) H, -C (O) NH2、NO2Or a combination thereof;
i is an integer between 0 and 5; and
m is an integer between 1 and 4;
q is an integer between 1 and 4.
In one embodiment, R of a compound of formula XXIa1Is OCH3(ii) a m is 3 and R2Is hydrogen. In another embodiment, R1Is F; m is 1 and R2Is hydrogen. In another embodiment, the A ring of the compound of formula XXIa is a substituted 5-indolyl. In another embodiment, the A ring of the compound of formula XXIa is 3-indolyl. Non-limiting examples of compounds of formula XXIa are selected from: (1- (phenylsulfonyl) -2- (3,4, 5-trimethoxybenzoyl) -1H-indol-5-yl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (16 xaa); (1- (phenylsulfonyl) -2- (1- (phenylsulfonyl) -1H-indol-3-yl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (17 yaa).
The present invention also encompasses methods of treating triple negative breast and/or ovarian cancer by administering to a subject in need thereof at least one compound of formula (XXII) or a pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer, or isomer thereof in a therapeutically effective amount, wherein the compound of formula (XXII) is represented by the following structure:
wherein
A is indolyl;
wherein said a is optionally substituted with: substituted or unsubstituted O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3、CN、-CH2CN、NH2Hydroxy, - (CH)2)iNHCH3、-(CH2)iNH2、-(CH2)iN(CH3)2、-OC(O)CF3Substituted or unsubstituted-SO2Aryl, substituted or unsubstituted C1-C5Straight or branched chain alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkylamino, substituted or unsubstituted aminoalkyl, -OCH2Ph, substituted or unsubstituted-NHCO-alkyl, COOH, substituted or unsubstituted-C (O) Ph, substituted or unsubstituted C (O) O-alkyl, C (O) H, -C (O) NH2、NO2Or a combination thereof;
i is an integer between 0 and 5.
In one embodiment, the A ring of the compound of formula XXII is a substituted 5-indolyl group. In another embodiment, the substitution is- (C ═ O) -aryl. In another embodiment, aryl is 3,4,5- (OCH)3)3-Ph。
In another embodiment, the A ring of the compound of formula XXII is 3-indolyl. Non-limiting examples of compounds of formula XXII are selected from: (5- (4- (3,4, 5-trimethoxybenzoyl) -1H-imidazol-2-yl) -1H-indol-2-yl) (3,4, 5-trimethoxyphenyl) methanone (15 xaa); (2- (1H-indol-3-yl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (17ya),
in another embodiment, the compound of formula XXI or XXII is represented by the structure of formula 17 ya:
in one embodiment, Q of the compound of formula XII is H and P isIn another embodiment, P of the compound of formula XII is H and Q isIn another embodiment, P of the compound of formula XII isAnd Q is SO2-Ph. In one embodiment. Q of the compound of formula XII is H and P isWherein W is C ═ O. In another embodiment, W of a compound of formula XII, XVIII, XIX, or XXIa is C ═ O. In another embodiment, W of a compound of formula XII, XVIII, XIX or XXIa is SO2. In another embodiment, W of a compound of formula XII, XVIII, XIX, or XXIa is C ═ S. In another embodimentIn the formula XII, XVIII, XIX or XXIa, W is S ═ O.
In one embodiment, Z of the compound of formula XIII is oxygen. In another embodiment, Z of the compound of formula XIII is sulfur.
In one embodiment, R5 of a compound of formula XII-XVI, XVIII or XIX is hydrogen, n is 1 and R is4In the para position.
In one embodiment, R of a compound of formula XII-XX4Is an alkyl group. In another embodiment, R of a compound of formula XII-XX4Is H. In another embodiment, R of a compound of formula XII-XX4Is methyl (CH)3). In another embodiment, R of a compound of formula XII-XX4Is an O-alkyl group. In another embodiment, R of a compound of formula XII-XX4Is OCH3. In another embodiment, R of a compound of formula XII-XX4Is I. In another embodiment, R of a compound of formula XII-XX4Is Br. In another embodiment, R of a compound of formula XII-XX4Is F. In another embodiment, R of a compound of formula XII-XX4Is Cl. In another embodiment, R of a compound of formula XII-XX4Is N (Me)2. In another embodiment, R of a compound of formula XII-XX4Is OBn. In another embodiment, R of a compound of formula XII-XX4Is OH. In another embodiment, R of a compound of formula XII-XX4Is CF3。
In one embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa2Is hydrogen; r1Is OCH3And m is 3. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa2Is hydrogen; m is 1 and R1In the para position. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa2Is hydrogen; m is 1 and R1Is Br. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa2Is hydrogen; m is 1 and R1Is I. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa2Is hydrogen; m is 1 and R1Is F. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa2Is hydrogen; m is 1 and R1Is Cl. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa1Is I. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa1Is Br. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa1Is Cl. In another embodiment, R of a compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa1Is F.
In one embodiment, Q of the compound of formula XII is H and P isWherein WC ═ O. Non-limiting examples of compounds of formulas XII-XVII and XX-XXII are selected from (2-phenyl-1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 aa); (4-methoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ab); (3-methoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ac); (3, 5-dimethoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ad); (3, 4-dimethoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ae); (4-fluorophenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 af); (3-fluorophenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ag); (2-phenyl-1H-imidazol-4-yl) (p-tolyl) methanone (12 ah); (2-phenyl-1H-imidazol-4-yl) (m-tolyl) methanone (12 ai); (2- (4-fluorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ba); (2- (4-methoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ca); (4-fluorophenyl) (2- (4-methoxyphenyl) -1H-imidazol-4-yl) methanone (12 cb); (2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 da); (4-fluorophenyl) (2- (p-tolyl) -1H-imidazol-4-yl) methanone (12 db); (4-fluorophenyl) (2- (p-toluene)Yl) -1H-imidazol-4-yl) methanone hydrochloride (12 db-HCl); (4-hydroxy-3, 5-dimethoxyphenyl) (2- (p-tolyl) -1H-imidazol-4-yl) methanone (12 dc); (3,4, 5-trimethoxyphenyl) (2- (3,4, 5-trimethoxyphenyl) -1H-imidazol-4-yl) methanone (12 ea); (4-fluorophenyl) (2- (3,4, 5-trimethoxyphenyl) -1H-imidazol-4-yl) methanone (12 eb); (2- (4-chlorophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 fa); (2- (4-chlorophenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12 fb); (2- (4-chlorophenyl) -1H-imidazol-4-yl) (4-hydroxy-3, 5-dimethoxyphenyl) methanone (12 fc); (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ga); (2- (4- (dimethylamino) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12 gb); (2- (3, 4-dimethoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ha); (2- (3, 4-dimethoxyphenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12 hb); (2- (2- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ia); (4-fluorophenyl) (2- (2- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) methanone (12 ib); (2- (4- (benzyloxy) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ja); (2- (4- (benzyloxy) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12 jb); (2- (4-hydroxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 ka); (2- (4- (hydroxyphenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (12kb), (2- (4-bromophenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12la), (2- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12pa), (3,4, 5-trihydroxyphenyl) (2- (3,4, 5-trihydroxyphenyl) -1H-imidazol-4-yl) methanone (13ea), (2- (4-chlorophenyl) -1H-imidazol-4-yl) (3,4, 5-trihydroxyphenyl) methanone (13 fa); and 2- (3, 4-dihydroxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trihydroxyphenyl) methanone (13 ha).
In one embodiment, P of the compound of formula XII isAnd Q is SO2-Ph. A compound of formula XII (wherein P of the compound of formula XII isAnd Q is SO2-Ph) is selected from: (4-methoxyphenyl) (2-phenyl-1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11 ab); (3-methoxyphenyl) (2-phenyl-1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11 ac); (2-phenyl-1- (phenylsulfonyl) -1H-imidazol-4-yl) (p-tolyl) methanone (11 ah); (4-fluorophenyl) (2-phenyl-1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11 af); (3-fluorophenyl) (2-phenyl-1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11 ag); (4-fluorophenyl) (2- (4-methoxyphenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) methanone (11 cb); (1- (phenylsulfonyl) -2- (p-tolyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone 11 da); (4-fluorophenyl) (1- (phenylsulfonyl) -2- (p-tolyl) -1H-imidazol-4-yl) methanone (11 db); (1- (phenylsulfonyl) -2- (3,4, 5-trimethoxyphenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11 ea); (4-fluorophenyl) (1- (phenylsulfonyl) -2- (3,4, 5-trimethoxyphenyl) -1H-imidazol-4-yl) methanone (11 eb); (2- (4-chlorophenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11 fb); (2- (4- (dimethylamino) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11 ga); (2- (4- (dimethylamino) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11 gb); (2- (3, 4-dimethoxyphenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11 ha); (2- (3, 4-dimethoxyphenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11 hb); (1- (phenylsulfonyl) -2- (2- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11 ia); (1- (phenylsulfonyl) -2- (2- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11 ib); and (2- (4- (benzyloxy) phenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (4-fluorophenyl) methanone (11 jb); (2- (4-bromophenyl) -1- (phenylsulfonyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11 la); (1- (phenylsulfonyl) -2- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (11 pa).
In one embodiment, R of the compounds of formulas XIII-XVI4And R5Is hydrogen. Compounds of formula XIII-XVI (wherein R is4And R5Is hydrogen) are selected from: (2-phenyl-1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (12 aa); (4-methoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ab); (3-methoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ac); (3, 5-dimethoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ad); (3, 4-dimethoxyphenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ae); (4-fluorophenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 af); (3-fluorophenyl) (2-phenyl-1H-imidazol-4-yl) methanone (12 ag); (2-phenyl-1H-imidazol-4-yl) (p-tolyl) methanone (12 ah); and (2-phenyl-1H-imidazol-4-yl) (m-tolyl) methanone (12 ai).
In one embodiment, P of the compound of formula XII is H and Q isIn another embodiment, W is C ═ O. In another embodiment, W of the compound of formula XVIII is C ═ O. Non-limiting examples of compounds of formula XVIII, wherein W is C ═ O, are selected from (4-methoxyphenyl) (2-phenyl-1H-imidazol-1-yl) methanone (12aba) and (2-phenyl-1H-imidazol-1-yl) (3,4, 5-trimethoxyphenyl) methanone (12aaa)
In another embodiment, W of the compound of formula XVIII is SO2. A compound of formula XVIII (wherein W is SO2) Are selected from 2-phenyl-1- (phenylsulfonyl) -1H-imidazole (10 a); 2- (4-nitrophenyl) -1- (phenylsulfonyl) -1H-imidazole (10x) and 2- (4- (benzyloxy) phenyl) -1- (phenylsulfonyl) -1H-imidazole (10 j).
The invention also encompasses methods of treating prostate cancer, taxane-resistant prostate cancer, breast cancer, triple negative breast cancer, lung cancer, melanoma, glioma, colon cancer, uterine cancer, ovarian cancer, and pancreatic cancer using compounds as described herein, e.g., compounds of formulas VIII, XI (b), XI (c), XI (e), and compounds 5a, 5b, 5c, 5d, 5e, 17ya, and 55. The invention also encompasses methods of treating prostate cancer, taxane-resistant prostate cancer, breast cancer, triple negative breast cancer, lung cancer, melanoma, glioma, colon cancer, uterine cancer, ovarian cancer, and pancreatic cancer using a compound as described herein. The invention also encompasses methods of treating prostate cancer using compounds as described herein. The invention also encompasses methods of treating taxane-resistant prostate cancer using compounds as described herein. The invention also encompasses methods of treating lung cancer using compounds as described herein. The invention also encompasses methods of treating breast cancer using compounds as described herein. The invention also encompasses methods of treating melanoma using compounds as described herein. The invention also encompasses methods of treating gliomas using compounds as described herein. The invention also encompasses methods of treating colon cancer using compounds as described herein. The invention also encompasses methods of treating prostate cancer, taxane-resistant prostate cancer, breast cancer, triple negative breast cancer, lung cancer, melanoma, glioma, colon cancer, uterine cancer, ovarian cancer, and pancreatic cancer using a compound as described herein. The invention also encompasses methods of treating uterine cancer using compounds as described herein. The invention also encompasses methods of treating pancreatic cancer using compounds as described herein. In one embodiment, the compound is of formulae VIII, XI (b), XI (c), and XI (e) and compounds 5a, 5b, 5c, 5d, 5e, 17ya, and 55. In one embodiment, the compound is a compound of formula XI. In one embodiment, the compound is a compound of formula xi (e). In one embodiment, the compound is compound 17 ya. In another embodiment, the compound is compound 55.
As used herein, a "monocyclic, fused or polycyclic, aryl or (hetero) ring system" can be any such ring: the rings include, but are not limited to, phenyl, biphenyl, triphenyl, naphthyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, fluorene, adamantane, and the like.
The "saturated or unsaturated N-heterocycle" may be any such nitrogen-containing heterocycle: the nitrogen-containing heterocycles include, but are not limited to, azacycloalkyl and diazacycloalkyl groups such as aziridinyl, azetidinyl, diazacyclobutylalkyl, pyrrolidinyl, piperidinyl, piperazinyl and azacyclooctyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, and the like.
The "saturated or unsaturated O-heterocycle" may be any oxygen-containing heterocycle including, but not limited to: oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium, benzofuranyl, benzodioxazolyl, and the like.
The "saturated or unsaturated S-heterocycle" may be any sulfur-containing heterocycle including, but not limited to, thiiranyl, thietanyl, tetrahydrothienyl, dithionyl, tetrahydrothiopyranyl, thienyl, thiaPhenyl, thioindenyl, and the like.
"saturated or unsaturated mixed heterocycle" can be any heterocycle containing two or more S-, N-, or O-heteroatoms including, but not limited to, oxathiolane, morpholinyl, thialkyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and the like.
As used herein, "aliphatic straight or branched chain hydrocarbon" refers to both an alkylene group containing a single carbon and up to a defined upper limit, and an alkenyl group and an alkynyl group containing two carbons up to the upper limit, whether the carbon atoms are present in a single chain or branched chain. Unless otherwise specified, the hydrocarbons may comprise up to about 30 carbons, or up to about 20 carbons, or up to about 10 carbons. Alkenyl and alkynyl groups may be mono-or polyunsaturated. In another embodiment, the alkyl group comprises C1-C6Carbon. In another embodiment, the alkyl group comprises C1-C8Carbon. In another embodiment, the alkyl group comprises C1-C10Carbon. In another embodiment, alkyl is C1-C12Carbon. In another embodiment, alkyl is C1-C5Carbon.
As used herein, unless otherwise indicated, the term "alkyl" can be any straight or branched chain alkyl group containing up to about 30 carbons. In another embodiment, the alkyl group comprises C1-C6Carbon. In another embodiment, the alkyl group comprises C1-C8Carbon. In another embodiment, the alkyl group comprises C1-C10Carbon. In another embodiment, alkyl is C1-C12Carbon. In another embodiment, alkyl is C1-C20Carbon. In another embodiment, the cyclic alkyl group has 3 to 8 carbons. In another embodiment, the branched alkyl is an alkyl substituted with an alkyl side chain of 1 to 5 carbons.
The alkyl group may be the only substituent or may be part of a larger substituent, such as in alkoxy, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, and the like. Preferred alkyl groups are methyl, ethyl and propyl, and thus are halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamido, ethylamido, propylamido, halomethylamido, haloethylamido, halopropylamido, methylurea, ethylurea, propylurea, and the like.
As used herein, the term "aryl" refers to any aromatic ring directly bonded to another group. The aryl group may be the only substituent or the aryl group may be part of a larger substituent, such as in arylalkyl, arylamino, arylamido, and the like. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, pyrrolyl, phenylmethyl, phenylethyl, phenylamino, phenylamido, and the like.
The term "aminoalkyl" as used herein refers to an amine group substituted with an alkyl group as defined above. Aminoalkyl refers to monoalkylamine, dialkylamine, or trialkylamine. Non-limiting examples of aminoalkyl groups are-N (Me)2、-NHMe、-NH3。
In another embodiment, a "haloalkyl" group refers to an alkyl group as defined above substituted with one or more halogen atoms (e.g., F, Cl, Br, or I). A non-limiting example of a haloalkyl group is CF3、CF2CF3、CH2CF3。
In one embodiment, the present invention provides a compound for use in the present invention or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph or crystal thereof, or a combination thereof. In one embodiment, the invention provides isomers of the compounds of the invention. In another embodiment, the invention provides a metabolite of a compound of the invention. In another embodiment, the invention provides a pharmaceutically acceptable salt of a compound of the invention. In another embodiment, the invention provides a pharmaceutical product of a compound of the invention. In another embodiment, the invention provides tautomers of the compounds of the invention. In another embodiment, the present invention provides a hydrate of the compound of the present invention. In another embodiment, the invention provides N-oxides of the compounds of the invention. In another embodiment, the present invention provides polymorphs of the compounds of the present invention. In another embodiment, the invention provides crystals of the compounds of the invention. In another embodiment, the invention provides a composition comprising a compound of the invention as described herein, or in another embodiment, a combination of isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, tautomers, hydrates, N-oxides, polymorphs, or crystals of a compound of the invention.
In one embodiment, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.
In one embodiment, the compounds of the invention are pure (E) -isomers. In another embodiment, the compounds of the invention are pure (Z) -isomers. In another embodiment, the compounds of the present invention are mixtures of (E) and (Z) isomers. In one embodiment, the compounds of the invention are pure (R) -isomers. In another embodiment, the compounds of the invention are pure (S) -isomers. In another embodiment, the compounds of the present invention are mixtures of the (R) and (S) isomers.
The compounds of the invention may also exist as racemic mixtures containing substantially equal amounts of the stereoisomers. In another embodiment, the compounds of the present invention can be prepared or isolated using known procedures to obtain stereoisomers that are substantially free of the corresponding stereoisomers (i.e., substantially pure). By substantially pure, it is meant that the stereoisomer is at least about 95% pure, more preferably at least about 98% pure, most preferably at least about 99% pure.
The compounds of the invention may also be in the form of hydrates, which means that the compounds also contain stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.
The compounds of the invention may exist in the form of one or more possible tautomers and, depending on the particular conditions, it may be possible to separate some or all tautomers into separate and distinct entities. It is to be understood that all possible tautomers are hereby encompassed, including all additional enol and keto tautomers and/or isomers. For example, the following tautomers are included, but not limited to these tautomers.
The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention, which may be produced by reaction of the compounds of the present invention with an acid or base. Certain compounds, especially those having acidic or basic groups, may also be in the form of salts, preferably pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, which are non-biological or undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, hydroxyacids, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Other salts are known to those skilled in the art and may be readily adapted for use in accordance with the present invention.
Suitable pharmaceutically acceptable salts of the amines of the compounds of the present invention may be prepared from inorganic acids or from organic acids. In one embodiment, examples of inorganic salts of amines are bisulfate, borate, bromide, chloride, hemisulfate, hydrobromide, hydrochloride, 2-isethionate (hydroxyethane sulfonate), iodate, iodide, isothiocyanate, nitrate, persulfate, phosphate, sulfate, sulfamate, sulfonic acid (alkyl sulfonate, aryl sulfonate, halogen-substituted alkyl sulfonate, halogen-substituted aryl sulfonate), sulfonate, and thiocyanate salts.
In one embodiment, examples of organic salts of amines may be selected from: aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of such salts being acetates, arginates, aspartates, ascorbates, adipates, anthranilates, alginates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium ethylenediaminetetraacetate, camphorsulfonates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochloride, caprates, heptanoates, ethanesulfonates, ethylenediaminetetraacetates, ethanedisulfonates, laurylsulfates, ethanesulfonates, fumarates, formates, Fluoride, galacturonic acid gluconate, glutamate, glycolate, gluconate, glucoheptonate, glycerophosphate, glucoheptonate, glycolylanilinate, glutarate, glutamate, heptanoate, hexanoate, hydroxymaleate, hydroxycarboxylate, hexylisophthalate, hydroxybenzoate, hydroxynaphthoate, hydrofluoride, lactate, lactobionate, laurate, malate, maleate, methylenebis (beta-oxynaphthoate), malonate, mandelate, methanesulfonate, methyl bromide, methyl nitrate methanesulfonate, monopotassium maleate, mucate, monocarboxylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, naphthoate, N-methylglucamine, oxalate, octanoate, Oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylacetate, pectinate, phenylpropionate, palmitate, pantothenate, polypyrolactobionate, pyruvate, quinite, salicylate, succinate, stearate, sulfa, subacetate, tartrate, theophylline acetate, p-toluenesulfonate (tosylate), trifluoroacetate, terephthalate, tannate, theachlorate, trihaloacetate, triiodoquaternary ammonium, tricarboxylate, undecanoate, and valerate.
In one embodiment, examples of inorganic salts of carboxylic acids or hydroxyl groups may be selected from ammonium salts, alkali metal salts (including lithium salts, sodium salts, potassium salts, cesium salts); alkaline earth metal salts (including calcium, magnesium, aluminum); zinc salt, barium salt, choline salt and quaternary ammonium salt.
In another embodiment, examples of organic salts of carboxylic acids or hydroxyl groups may be selected from: arginine salts, organic amines (including aliphatic organic amines, alicyclic organic amines, aromatic organic amines), benzylethylenediamine, tert-butylamine, phenethylamine (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine salts, methylamine, ergotamine, N-methyl-D-glucosamine, N' -dibenzylethylenediamine, nicotinamide, organic amines, ornithine salts, pyridine, picoline, piperazine, procaine, tris (hydroxymethyl) methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine, and urea.
In one embodiment, the salt may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of a suitable acid or base in a salt-insoluble solvent or medium or in a solvent such as water, which solvent or medium may be removed in vacuo or by freeze-drying or by ion-exchange of an existing salt for another ion or by a suitable ion-exchange resin.
The compounds used in the methods of the invention are synthesized according to the disclosed methods. In particular, the compounds are described according to PCT publication No. WO 2010/74776, published on 1/7/2010; and WO 2011/19059 published on 9.9.2010; and WO 2012/027481, published 3/1/2012, which are hereby incorporated by reference.
Pharmaceutical composition
Another aspect of the invention relates to a pharmaceutical composition for the treatment of triple negative breast and/or ovarian cancer comprising a pharmaceutically acceptable carrier and at least one compound described above. Typically, the pharmaceutical compositions of the invention will comprise a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvant, vehicle, excipient, or stabilizer, and may be in solid or liquid form, such as a tablet, capsule, powder, solution, suspension, or emulsion.
Typically, the compositions will comprise from about 0.01 to 99%, preferably from about 20 to 75% of the active compound, together with adjuvants, vehicles and/or excipients. While individual requirements may vary, it is within the skill of the art to determine the optimum range for effective amounts of each component. Typical dosages include about 0.01 to about 100mg/kg body weight. Preferred dosages include from about 0.1 to about 100mg/kg body weight. The most preferred dosage comprises from about 1 to about 100mg/kg body weight. One of ordinary skill in the art can also readily determine a treatment regimen for administering the compounds of the present invention. That is, the frequency of administration and the size of the dose can be determined by routine optimization, preferably while minimizing any side effects.
The solid unit dosage form may be of conventional type. Solid forms may be capsules and the like, such as the common gelatin type containing the compound and a vehicle, e.g., lubricants and inert fillers such as lactose, sucrose or corn starch. The compounds can be tableted with conventional tablet bases such as lactose, sucrose or corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch or alginic acid and lubricating agents such as stearic acid or magnesium stearate.
Tablets, capsules and the like may also contain binders such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. In addition to the active ingredient, the syrup may contain sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, dyes and flavors such as cherry or orange flavor.
For oral therapeutic administration, the active compounds may be combined with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. Of course, the percentage of compound in these compositions may vary, and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage is obtained. Preferred compositions according to the invention are prepared such that an oral dosage unit contains between about 1mg and 800mg of the active compound.
The active compounds or formulations thereof may be administered orally, for example, with an inert diluent or with an ingestible, edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be combined directly with the food in the diet.
Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy injection is possible. It should be stable under the conditions of manufacture and storage and should survive contamination by microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The compounds or pharmaceutical compositions of the invention may also be administered in injectable doses by solution or suspension of these substances in a physiologically acceptable diluent with a pharmaceutical adjuvant, vehicle or excipient. Such adjuvants, carriers and/or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of surfactants and other pharmaceutically and physiologically acceptable components. Exemplary oils are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
The active compounds or their formulations can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Exemplary oils are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
For use as an aerosol, the compound or formulation thereof in solution or suspension may be packaged in a pressurised aerosol container together with a suitable propellant, for example a hydrocarbon propellant such as propane, butane or isobutane, and conventional adjuvants. The materials of the present invention may also be applied in a non-pressurized form, such as in a nebulizer or atomizer.
The compounds used in the methods of the invention are administered in combination with an anti-cancer agent. In one embodiment, the anti-cancer agent is a monoclonal antibody. In some embodiments, the monoclonal antibody is used to diagnose, monitor, or treat cancer. In one embodiment, the monoclonal antibody is reactive against a specific antigen on the cancer cell. In one embodiment, the monoclonal antibody acts as a cancer cell receptor antagonist. In one embodiment, the monoclonal antibody enhances the immune response of the patient. In one embodiment, the monoclonal antibody acts on a cell growth factor, thereby blocking the growth of cancer cells. In one embodiment, the anti-cancer monoclonal antibody is conjugated or linked to an anti-cancer drug, radioisotope, other biological response modifier, other toxin, or combination thereof. In one embodiment, the anti-cancer monoclonal antibody is conjugated or linked to a compound as described above.
Another aspect of the invention relates to a method of treating triple negative breast and/or ovarian cancer, comprising selecting a subject in need of treatment for the cancer, and administering to the subject a pharmaceutical composition comprising at least one compound and a pharmaceutically acceptable carrier under conditions effective to treat the cancer.
When compounds are administered, they may be administered systemically, or they may be administered directly to a specific site where cancerous or precancerous cells are present. Thus, administration can be accomplished in any manner effective to deliver the compound or pharmaceutical composition to the cancerous or precancerous cells. Exemplary modes of administration include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal instillation, intracavitary or intravesical instillation, intraocular, intraarterial, intralesional or administration of the compound or composition by administration to mucous membranes such as the nose, throat and bronchi.
Biological activity
The present invention encompasses compounds and compositions for the treatment of triple negative breast and/or ovarian cancer. As will be appreciated by those skilled in the art, at least one compound or a composition comprising the compound will have utility in inhibiting, suppressing, enhancing or stimulating a desired response in a subject. The compositions may also contain additional active ingredients, the activity of which is useful for the particular application for which the compounds of the present invention are being administered.
Drug resistance is a major cause of cancer chemotherapy failure. Overexpression of P-glycoprotein (P-gp) is a major factor contributing to multidrug resistance. The protein is a clinically important transporter and belongs to the ATP binding cassette family of cell membrane transporters. It can excrete substrates including anticancer drugs from tumor cells through an ATP-dependent mechanism. The TNBC may be taxane-resistant TNBC, taxane-sensitive TNBC and/or metastasis.
Determination of the anticancer activity of compound 17ya by in vitro studies demonstrated a therapeutic approach to TNBC. The anti-TNBC activity of compound 17ya was compared to the activity of colchicine and paclitaxel on cell lines MDA-MB-231 and MDA-MB-468. IC of colchicine, paclitaxel and Compound 17ya in the MDA-MB-231 assay50(nM) was determined to be 17.46, 3.05 and 8.23, respectively, and SE was 0.05, 0.04 and 0.05, respectively. Colchicine, Taxus cuspidata in the MDA-MB-468 testIC of alcohol and Compound 17ya50(nM) was determined to be 9.80, 4.61 and 22.96, respectively, and SE was 0.02, 0.03 and 0.02, respectively. FIG. 1 shows diagrammatically the results of the anti-cancer activity of compound 17ya in vitro on the cell lines MDA-MB-231 and MDA-MB-468 in comparison with colchicine and paclitaxel. FIG. 2 shows the anti-migratory effect of compound 17ya (16nM) on TNBC cells compared to colchicine (16nM) and controls in cell lines MDA-MB-231 and MDA-MB-468. The anti-invasive properties of compound 17ya (40nM) were also determined in TNBC cell lines MDA-MB-231 and MDA-MB-468 compared to controls, colchicine (32nM) and paclitaxel (32 nM).
The apoptosis-inducing effect of compound 17ya on TNBC cells was also determined, compared to the study of 100nM compound 17ya at 24 hours, 48 hours and 72 hours. For illustration, see fig. 7. Compound 17ya induced TNBC apoptosis in a dose and time dependent manner compared to controls in which compound 17ya was studied at 50nM, 100nM, 150nM and 200nM for 48 hours and compared to colchicine (200nM, 48 hours) and paclitaxel (200nM, 48 hours). The results are shown in FIG. 8. The anticancer activity of compound 17ya was studied in vivo at 5mg/kg and 10mg/kg, and compared with a control, it was determined that compound 17ya inhibited TNBC tumor growth in a dose-dependent manner without interfering with body weight. FIG. 9 shows the percent tumor growth and body weight (g) of compound 17ya at 5mg/kg and 10mg/kg compared to controls. Fig. 10 shows a comparison of tumor sizes, as compound 17ya inhibited TNBC tumor growth in a dose-dependent manner.
Compound 17ya was compared to paclitaxel for anti-cancer activity. Compound 17ya has been determined to significantly inhibit TNBC tumor growth compared to control, similar to paclitaxel treatment. FIG. 11 shows vehicle, Compound 17ya (12.5g/kg) and paclitaxel (12.5g/kg) versus tumor weight (g) and final tumor volume (mm)3) A graphical comparison between the effects of (c).
Compound 17ya was also investigated for anti-metastatic activity in vivo. Compound 17ya (10mg/kg) was compared to control and paclitaxel (10mg/kg) activity in lung H7E sections. Figure 12 shows the results of this study in which compound 17ya was similar to paclitaxel, resulting in very few metastases, but was altered compared to the control group with many metastases.
The in vitro efficacy of compound 17ya was determined using an orthotopic ovarian cancer mouse model. Two weeks after transplantation of SKOV3 cells into the left ovaries of NSG female mice, mice were treated with oral vehicle or compound 17ya (10mg/kg) for 4 weeks (5 treatments per week). To test the activity of compound 17ya in SKOV3 and OVCAR3 cells, cell viability was investigated by performing a colony formation assay. Cell migration and invasion were examined by using a modified Transwell chamber. Pre-coated Matrigel on Transwell wells was used to test cell invasion capacity.
Compound 17ya used for treatment significantly inhibited SKOV3 ovarian tumor growth and metastasis to major organs in vivo (liver and spleen) compared to vehicle control (table 1). Cell growth was significantly reduced in both SKOV3 and OVCAR3 after 2 weeks of treatment with compound 17ya at concentrations of 10nM or 30 nM. Consistent with this finding, treatment with compound 17ya at 20nM substantially inhibited the migration and invasion capacity of ovarian cancer cells in SKOV3 and OVCAR3 cells. The results are summarized in table 1 below:
note that: for these data sets, the denominator is the number of mice tested and the numerator is the number of mice transferred.
The test results showed that orally available compound 17ya was effective in inhibiting tumor growth and metastasis in mouse models of orthotopic ovarian cancer without acute toxicity and reduced survival, migration and invasion ability of ovarian cancer cells, and it was concluded that compound 17ya is a tubulin inhibitor for the treatment of ovarian cancer.
In one embodiment, the present invention provides a method for treating triple negative breast cancer and/or ovarian cancer, comprising administering to a subject at least one compound described above and/or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph or crystal of said compound, or any combination thereof, in a therapeutically effective amount to treat said triple negative breast cancer.
The present invention includes a method of treating a subject having triple negative breast cancer and/or ovarian cancer, comprising administering to the subject at least one compound described above, or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystal, or any combination thereof, in an amount effective to treat the subject's triple negative breast cancer. In another embodiment, the compound is compound 12 db. In another embodiment, the compound is compound 11 cb. In another embodiment, the compound is compound 11 fb. In another embodiment, the compound is compound 12 da. In another embodiment, the compound is compound 12 fa. In another embodiment, the compound is compound 12 fb. In another embodiment, the compound is compound 12 cb. In another embodiment, the compound is compound 55. In another embodiment, the compound is compound 6 b. In another embodiment, the compound is compound 17 ya.
Yet another aspect of the invention relates to a method of treating or preventing a cancerous disease, the method comprising: providing at least one compound as described above and then administering an effective amount of the compound to the patient in a manner effective to treat or prevent the cancerous disease.
According to one embodiment, the patient to be treated is characterized by the presence of a pre-cancerous disease, and the administration of the compound is effective to prevent the pre-cancerous disease from progressing to a cancerous disease. This can be done by destroying the precancerous cells before or while they have further progressed to a cancerous state.
According to another embodiment, the patient to be treated is characterized by the presence of a cancerous disease, and the administration of the compound is effective to cause regression of the cancerous disease or to inhibit growth of the cancerous disease, i.e., to arrest its growth, or to reduce its rate of growth. Preferably, this is done by destroying the cancer cells, regardless of their location within the patient. That is, whether the cancer cells are located at the site of the primary tumor or whether the cancer cells have metastasized and produced a secondary tumor in the patient.
As used herein, a subject or patient refers to any mammalian patient, including but not limited to humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In one embodiment, the subject is male. In another embodiment, the subject is female. In some embodiments, the methods described herein can be used to treat males or females.
When compounds are administered, they may be administered systemically, or they may be administered directly to a specific site where cancerous or precancerous cells are present. Thus, administration can be accomplished in any manner effective to deliver the compound or pharmaceutical composition to the cancerous or precancerous cells. Exemplary modes of administration include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal instillation, intracavitary or intravesical instillation, intraocular, intraarterial, intralesional or administration of the compound or composition by administration to mucous membranes such as the nose, throat and bronchi.
The methods encompass administering a compound described herein alone, or in combination with other agents, in combination with at least one compound and an anti-cancer agent.
When a compound or pharmaceutical composition of the invention is administered to treat, inhibit, reduce severity, reduce risk of, or inhibit a cancerous disease, the pharmaceutical composition may also comprise or be administered with other therapeutic agents or treatment regimens now known or later developed for the treatment of various types of cancer. Examples of other therapeutic agents or treatment regimens include, but are not limited to, radiation therapy, immunotherapy, chemotherapy, surgical intervention, and combinations thereof.
The following examples are presented to more fully illustrate preferred embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.
Examples
The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
Materials and methods:
and (5) culturing the cells. Ovarian cancer cell lines SKOV3 and OVCAR3 were obtained from ATCC (American Type Culture Collection, Manassas, Va., USA) and cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS (MIDSCI; St. Louis, USA), 100U/ml penicillin and 100. mu.g/ml streptomycin (Invitrogen; Carlsbad, Calif.). Cells were maintained at 5% carbon dioxide (CO)2) And cultured in an incubator at 37 ℃.
Overview. All reagents were purchased from Sigma-Aldrich Chemical Co., Fisher Scientific (Pittsburgh, Pa.), AK Scientific (Mountain View, CA), Oakwood Products (West Columbia, SC), etc., and used without further purification. The humidity sensitive reaction was carried out under an argon atmosphere. ABT-751 according to Yoshino et al26The reported methods. Conventional Thin Layer Chromatography (TLC) was performed on an aluminum backed Uniplate (Analtech, Newark, DE). Melting points were measured using a Fisher-Johns melting point apparatus (uncorrected). NMR spectra were obtained on a Bruker AX 300(Billerica, MA) spectrometer or a Varian Inova-500(Vernon Hills, Illinois) spectrometer. Reported relative to CDCl3TMS in (1), chemical shifts are parts per million (ppm). Mass spectral data were collected in positive and negative ion modes on a Bruker ESQUIRE electrospray/ion trap instrument. Elemental analysis was performed by Atlantic Microlab Inc.
Example 1
Ovarian cancer tumor growth inhibition
The cell clones form a survival assay. 350 SKOV3 or OVCAR3 cells were seeded on 6-well plates and cultured in DMEM (i.e., growth medium) containing 10% FBS for 3 days. On the third day of culture, the medium was replaced with fresh growth medium containing compound 17ya at concentrations ranging from 0, 1.25, 2.5, 5,10 and 30 nM. Medium was replaced every 3 days with fresh growth medium containing compound 17ya until day 13 of culture. Cells were then fixed with 70% ethanol and stained with crystal violet. Colonies from triplicate wells were counted for statistical analysis.
Cell migration assay. Cell migration assays were performed using a modified Transwell chamber (BD FALCON, San Jose, CA). The chamber was inserted into a 24-well cell culture plate. 3 × 104 SKOV3 or OVCAR3 cells were added to the upper chamber with compound 17ya (20nM) and 300 μ l vehicle treatment in serum free DMEM. DMEM containing 10% FBS (used as a chemoattractant) was added to the lower chamber of each well and incubated for 8 hours. The medium and non-migrated cells in the upper chamber were removed while the migrated cells on the lower side of the membrane were fixed with methanol and stained with crystal violet. Photographs were taken at 10x magnification and cells were counted in at least three different fields of view.
Cell invasion assay. SKOV3 or OVCAR3 (5X 10)5) Cells were seeded with compound 17ya (20nM) and vehicle treatments in 300 μ l serum-free DMEM onto wells pre-coated with matrigel (BD biocoat) using a 24-well tumor invasion system (BD BioSciences, San Jose, CA). DMEM containing 10% FBS was added as a chemoattractant to the lower chamber of the invasive system and incubated for 24 hours. The medium and non-migrated cells in the upper chamber were removed while the migrated cells on the lower side of the membrane were fixed with methanol and stained with hematoxylin and eosin for 5 minutes. The photographs were taken at 10x magnification. The number of affected cells was counted in at least three different fields.
Mouse model of orthotopic ovarian cancer. 5X 105 SKOV3 cells labelled with a luciferase-expressing lentiviral vector (pLenti-UBC-Luc2-T2A-mKate) were injected intravesicularly into 10 two month old NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ severely immunocompromised female mice (NSG). Two weeks after transplantation of SKOV3 cells into the left ovaries of NSG female mice, mice were treated with oral vehicle or compound 17ya (10mg/kg) for 4 weeks (5 treatments per week). Five mice per group. Tumor development and metastasis were monitored once a week using a Xenogen imaging system. All mice were sacrificed at two months. Ovaries and metastatic organs were collected and imaged using a Xenogen imaging system. Tumors were weighed and treated tissues were H & E stained.
Treatment with compound 17ya inhibited the survival of ovarian cancer cells. To test the effect of compound 17ya on ovarian cancer cells, cell viability was examined by measuring cell colony formation, as described above. 350 SKOV3 and OVCAR3 ovarian cells were cultured in 6-well plates and treated with compound 17ya at six doses (0, 1.25, 2.5, 5,10, and 30 nM). On day 13, colonies were stained with crystal violet. As shown in figure 13, compound 17ya significantly inhibited cell survival both in SKOV3 and OVCAR3 cells (. p <0.01,. p < 0.001).
Treatment with compound 17ya inhibited migration and invasion of ovarian cancer cells. Cell migration assays were performed using Transwell plates against compound 17ya and vehicle treated cells. It was found that cell migration was significantly reduced in both SKOV3 and OVCAR3 cells with compound 17ya, as shown in figure 14A. Matrigel coated Transwell was used to assess cell invasion. As shown in figure 14B, treatment with compound 17ya significantly reduced cells compared to vehicle cells in SKOV3 and OVCAR 3.
Compound 17ya inhibited ovarian tumor growth and metastasis in vivo. An in situ ovarian cancer mouse model is established. 5X 105 wild-type SKOV3-Luc2 cells were injected intravesicularly into 2-month-old NSG female mice, and the mice were treated for 4 weeks for five days per week. Tumors were collected and imaged using the Xenogen system. SKOV3 cells transduced with a lentiviral luciferase vector were injected into the left ovary of two-month-old NSG mice, and the mice were treated with vehicle or compound 17ya (10mg/kg) for 4 weeks. As shown in fig. 15B, treatment with compound 17ya significantly inhibited the growth of SKOV3 ovarian tumor. Treatment with compound 17ya inhibited in vivo transfer to major organs (liver and spleen) compared to vehicle control shown in figure 15A. As shown in fig. 15C, HE staining of ovaries, tumors, and liver indicated that treatment with compound 17ya inhibited growth and metastasis of ovarian tumors. Tumors were not visible in ovaries, liver and spleen of mice treated with compound 17 ya.
Example 2
Materials and methods
Compounds and cell lines. Colchicine was purchased from Sigma (st. Taxol is purchased fromLC Laboratories (Woburn, MA). Compound 17ya (Chen et al, "Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) analogics targeting tubulin polymerization as antipolliative agents." J.Med.Chem.,2012,55.7285-7289 "), was synthesized in purity (. gtoreq.98%), and was verified by HPLC, HR-MS (Waters, Milford, MA), and proton nuclear magnetic resonance (Bruker, Billerica, MA). The study used two human Triple Negative Breast Cancer (TNBC) cell lines: MDA-MB-231 and MDA-MB-468 were purchased from ATCC (Manassas, Va.) and validated prior to use in this study. These cells were cultured in DMEM medium (Mediatech, inc., Manassas, VA) supplemented with 10% fetal bovine serum (Atlanta Biologicals, lawrence ville, GA) and 1% antibiotic-antimycotic solution (Sigma-Aldrich, st. louis, MO) in a humid environment (containing 5% CO) at 37 ℃2) And (5) culturing.
Cell viability assay. The antiproliferative effect of Compound 17ya in human melanoma (A375 and M14), human HER2 positive breast Cancer (MDA-MB-453 and SKBR3) and TNBC (MDA-MB-231 and MDA-MB-468) Cancer cells was studied, as described by Li et al, "A patent, metabolism Stable tubular Inhibitor Targets Binding Site and Overcomes Taxane Resistance," Cancer Res.,2018,78,265 Ash 277. IC was calculated by GraphPad Prism 7 software using non-linear regression50(50% inhibition of cell growth).
Colony formation assay. MDA-MB-231 or MDA-MB-468 cells were seeded into 12-well plates at a cell density of 200 cells/well and incubated for 24 hours. Cells were then treated with colchicine, paclitaxel and compound 17ya at various concentrations. The medium of each group was changed weekly. After 7 days of culture (MDA-MB-231) and 14 days of culture (MDA-MB-468), the cells were washed with PBS, fixed with methanol, and stained with 0.5% crystal violet. The morphology of the colonies was captured under a microscope and the colony area was quantified using ImageJ software (NIH, Bethesda, MD). Drug treatment was repeated three times.
Caspase 3/7 activity assay. Compound 17 ya-induced apoptosis was determined using the caspase Glo 3/7 assay system (Promega, Madison Wis.) according to the manufacturer's instructions, as described in Li et al, "Design, Synthesis and Structure-Activity Relationship students of Novel overview Inhibitors with Point-reactive Properties," PLoS One,2015,10, e 0129807. 5000 cells were seeded in each well of a 96-well plate and treated with compound 17ya at 20nM in triplicate for 24 h. Caspase 3/7 activity was normalized by the total protein content in each sample.
Cell migration and invasion assays. Chemotaxis cell migration assay was performed using Transwell 96-well plates containing membrane wells (pore size 8 μm) and trays (BD Biosciences, CA), and the effect of compound 17ya on cell invasion was performed using Matrigel invasion chamber (Corning, NY). In both assays, MDA-MB-231 and MDA-MB-468 cells in serum-free medium were starved for 24 hours, then the cells were suspended in serum-free medium containing 16nM colchicine and compound 17ya and plated in triplicate in the membrane wells or in the upper chamber of a Matrigel-coated membrane. Serum-containing medium was added as a chemotactic agent to the lower chamber. For MDA-MB-231 cells incubated for 24 hours, for MDA-MB-468 cells incubated for 48 hours, cells that did not migrate through the membrane or invaded Matrigel were removed with a cotton swab, while the migrated or invaded cells were on the bottom surface of the chamber, fixed in 4% phosphate-formalin buffer solution, stained with 0.5% crystal violet solution and imaged with a microscope. The number of migrated or invaded cells was counted manually using ImageJ software.
Cell migration was also analyzed by the scratch assay. Briefly, MDA-MB-231 cells (10)5One cell/well) and MDA-MB-468 (2X 10)5Individual cells/well) cells were seeded in 12-well plates and incubated overnight. The next day, the cell monolayer was scratched with 200 μ l sterile pipette tips. After washing off the floating cells, the cell culture medium is changed to a medium containing the specific concentration (e.g., 16nM) of the vehicle DMSO, colchicine, paclitaxel, or compound 17 ya. After 12 hours, 24 hours, and 48 hours, the wound width was determined and imaged with an Evos Fl imaging system (Life Technologies, Carlsbad, CA). The degree of wound closure is shown as the percentage reduction in the original scratch width at each measurement time point. Experiments were performed in triplicate.
And (4) performing immunofluorescence staining. Will 105MDA-MB-231 cells or 2X 105Individual MDA-MB-468 cells were seeded in 6-well plates on sterile coverslips for 24h, then treated with 32nM colchicine, paclitaxel and compound 17ya for 18 h. For tubulin visualization, cells were washed three times with PBS, fixed with 4% paraformaldehyde for 15 minutes, and then permeabilized with 0.2% Triton X-100 in PBS for 15 minutes. Cells were then blocked in 1.5% Bovine Serum Albumin (BSA), 0.1% Tween 20 in PBS for 1 hour and incubated in 1% Bovine Serum Albumin (BSA) with anti-a-tubulin antibody (Thermo Fisher Scientific, Waltham MA) in 0.1% Tween 20 in PBS overnight at 4 ℃. The next day, cells were washed and incubated with Alexa Fluor 647 goat anti-mouse IgG (Molecular Probes, Eugene OR) for 1 hour in the dark at room temperature, followed by addition of the locking Diamond anti-fade reagent with DAPI (Invitrogen, Carlsbad, CA) and mounting. The images depicted in the figure were obtained with a Keyence BZ-X700 microscope (Keyence, Osaka Japan).
And (4) detecting apoptosis. MDA-MB-231 and MDA-MB-468 cells were seeded in 6-well plates (2X 10)5One/well). After overnight incubation, cells were treated with 100nM compound 17ya for 24h, 48h and 72 h. Dose-dependent studies were performed by treating cells at increasing doses for 48 hours. The cells were then washed twice with PBS and 10 was added5Individual cells were suspended in 200ul annexin V-FITC binding buffer (eBioscience, Grand Island, NY). Mu.l annexin V-FITC and 10. mu.l propidium iodide cell suspension were added to 185. mu.l cell suspension, mixed and incubated at room temperature for 10 minutes before analysis with a Bio-Rad ZE5 cell analyzer (Bio-Rad, Hercules, Calif.).
Cell cycle analysis, western blot, in vivo orthotopic xenograft model.
All animal studies were conducted following NIH experimental animal care principles and protocols approved by the institutional animal care and use committee of the university of tennessee health science. Nod-Scid-gamma (NSG) female mice, 5-6 weeks old, were housed in a pathogen-free environment with 12:12 hours of light. The temperature is kept between 20 and 26 ℃, and the relative humidity is kept between 30 and 70 percent. Mu.l of 2.5X 10 in HBSS5MDA-MB-231 cellsThe left and right inguinal mammary fat pads of NSG mice were surgically inoculated as described by Pfeffer et al, "Comprehensive analysis of microRNA (miRNA) targets in Breast cancer cells," J.biol.chem.,2013,288,27480-27493, which is hereby incorporated by reference. Mice were examined weekly for tumor appearance until the mean tumor size reached 100mm3. The mice were then randomized into 3 groups (n-5 per group) and drug treatment was initiated. The control group was orally administered vehicle (PEG 300: water ratio 1:1) five times a week for drug treated groups, 5mg/kg compound 17ya or 10mg/kg compound 17ya, respectively. Primary tumor size was monitored twice weekly using digital calipers and mouse body weight was recorded during treatment. Using the formula volume ═ width2X length)/2 to calculate tumor volume. After 33 days of treatment, the tumor size in the vehicle group reached 1000mm3At the time, tumors and major organs were imaged and collected in 10% phosphate formalin buffer for histological analysis. Another similar orthotopic xenograft model was performed for comparing the efficacy of compound 17ya with paclitaxel as described above. The mice were randomly divided into 3 groups of 8 mice each. Similarly, control group was orally administered vehicle (PEG 300: water ratio 1:1), paclitaxel group was intraperitoneally injected once every other day with 12.5mg/kg paclitaxel, compound 17ya group was orally administered once 12.5mg/kg compound 17ya five times a week, when tumor size in vehicle group reached 1000mm3At this time, tumors and major organs were collected in 10% phosphate formalin buffer for histological analysis.
Experimental lung metastasis model: the efficacy of compound 17ya in inhibiting TNBC metastasis was studied using 7-8 week-old NSG mice. 2X 10 in 100. mu.l HBSS by tail vein injection5Each mouse was inoculated with MDA-MB-231 cells. Treatment with vehicle, 10mg/kg compound 17ya and 10mg/kg paclitaxel was started after 24 hours in an orthotopic xenograft model of the same dose frequency. Animal health and body weight were monitored weekly during treatment. After 23 days, the mice were sacrificed and all major organs were imaged and collected in 10% phosphate formalin buffer for subsequent histological and immunohistochemical analysis.
Histological and Immunohistochemical (IHC) analysis: fixed tumors and organs were embedded in paraffin and several slides of sections were cut for further hematoxylin/eosin (H & E) staining and IHC staining. H & E staining and IHC staining were performed as described above. Primary antibodies used in IHC staining included rabbit anti-Ki 67(1:400), rabbit anti-CD 31(1:100), rabbit anti-lytic Parp (1:50) and rabbit anti-lytic caspase 3(1:200) (# 9027; # 77699; # 5625; #9661, Cell Signal Technology, Danvers MA), and biotinylated horse anti-rabbit IgG antibody (BA-1100, Vector Laboratories Inc., Burlingame, CA) was used as the secondary antibody. Anti-mitochondrial IHC staining was performed to observe the metastasis of MDA-MB-231 cells in an experimental lung metastasis model. Images were taken with a Keyence BZ-X700 microscope.
Compound 17ya reduced proliferation of different breast cancer cells. Compound 17ya, IC was previously tested in a panel of melanoma cancer cell lines50At 10nM, as described in Li et al, "Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) antibodies targeting and transforming as anti-rolling agents," J.Med.chem.,2012, 557285-7289. Compound 17ya was evaluated using the MTS assay to determine if it could also inhibit the growth of breast cancer cells. Table 2 shows that compound 17ya has an anti-proliferative effect on breast cancer cell lines, especially in TNBC. This test combines the two well-known tubulin inhibitors colchicine and paclitaxel to compare the efficacy of compound 17ya on TNBC cell growth. The test results are shown in fig. 16. All three tubulin inhibitors were effective in inhibiting TNBC proliferation. Colony formation assays are consistently used to assess cell proliferation by determining colony growth from small to large colonies. Colony formation results indicate that compound 17ya attenuated the proliferative capacity of MDA-MB-231 and MDA-MB-468 cells in a dose-dependent manner.
Compound 17ya inhibited TNBC cell migration and invasion. The effect of compound 17ya on TNBC cell migration and invasion after 24 or 48 hours of drug treatment was investigated. Fig. 17 shows the results. Compound 17ya inhibited the ability of cells to migrate through the membrane pores at a concentration of 16nM, showing similar efficacy to colchicine. Also, compound 17ya reduced the ability of TNBC cells to invade through Matrigel coated membranes. To further confirm these results, scratch assays were performed using paclitaxel and colchicine as positive controls. At a dose of 16nM, compounds 17ya, colchicine and paclitaxel showed effective inhibition of cell migration. From these findings we conclude that: compound 17ya significantly inhibited cell migration, underscoring the potential role of compound 17ya in inhibiting TNBC metastasis.
Compound 17ya interfered with microtubule assembly and the organization of the mitotic spindle: immunofluorescent staining was performed using compound 17ya to reveal the microtubule network and compared to the known microtubule destabilizing agents colchicine and the microtubule stabilizing agent paclitaxel. TNBC cells of the negative control group showed intact microtubule fibers and microtubule organization. Fig. 18 shows these results. Treatment with paclitaxel produced multipolar spindles with highly condensed chromosomes due to the enhancement of tubulin polymerization in TNBC cells. As with colchicine treatment, cells treated with compound 17ya shrank and the cell shape changed from spindle to round and irregular, confirming that compound 17ya targets tubulin and interferes with tubulin polymerization.
Compound 17ya induced an increase in apoptosis of TNBC cells: since many tubulin inhibitors have been reported to have a pro-apoptotic effect on cancer cells, compound 17ya was studied to determine the induction of TNBC apoptosis. MDA-MB-231 cells were treated with 100nM compound 17ya in a time-dependent manner. Compound 17ya induced apoptosis as shown in figure 19. Cells were treated with increasing concentrations of compound 17ya for 48 hours. Compound 17ya promoted apoptotic cell death in a dose-dependent manner, resulting in TNBC cell apoptosis.
Compound 17ya inhibited TNBC tumor growth and metastasis in vivo. To validate the in vitro results, the anti-cancer activity of compound 17ya in the orthotopic TNBC mouse model was investigated to determine whether the in vitro potent effect of compound 17ya could be observed in vivo. Treatment with compound 17ya inhibited TNBC tumor growth in a dose-dependent manner without interfering with mouse body weight 33 days after treatment. The results are shown in FIG. 20. The reduced tumor size and tumor weight compared to control (vehicle-treated) mice showed the efficacy of compound 17ya in TNBC tumor-bearing mice. The shape of all tumors in these three groups further suggests that the size of the tumors decreased with increasing dose of compound 17 ya. H & E staining of tumor sections confirmed that compound 17ya induced TNBC tumor necrosis, similar to that observed in vitro. One study compared the efficacy of compound 17ya with paclitaxel in the same model, since paclitaxel is one of the standard of care for clinical TNBC treatment. Both compound 17ya and paclitaxel significantly reduced the size and weight of the tumor. The results are shown in FIG. 21. The overall tumor profile demonstrates that tumor size was reduced in both compound 17ya and paclitaxel treated mice. Although compound 17ya was less effective at inhibiting tumor growth than paclitaxel, it was better solubilized and administered in the treatment of cancer than paclitaxel. In a comparative study, H & E staining of tumors further indicated that both compound 17ya and paclitaxel induced TNBC tumor necrosis. A tail vein study determined the efficacy of compound 17ya in vivo against TNBC metastases. Fig. 22 and 23 show that the lungs of the vehicle group were filled with metastasis (indicated by yellow arrows), while the lungs of compound 17ya and paclitaxel had little metastasis, indicating that compound 17ya significantly reduced the metastasis of TNBC. Similar results were found in liver, kidney and spleen tissues, further indicating that compound 17ya inhibits TNBC metastasis.
Example 3
In addition to the materials and methods described above, the following procedures were used in the following examples.
And (4) analyzing the cell cycle. To determine the cell cycle profile in mitotic phase (especially G2 and M phase), cells were treated with colchicine, paclitaxel and compound 17ya, respectively. According to the manufacturer's protocol (# FCCH0225103, EMD Millipore Corp., Burlington MA)By trypsinization, immobilization, permeabilization, combined use of anti-phosphohistonesThe 488 antibody was stained on ice for 1 hour in the dark and then incubated with freshly prepared propidium iodide/rnase solution for 30 minutes at room temperature to harvest the cells. Stained cells were then analyzed by a Bio-Rad ZE5 cell analyzer (Bio-Rad, Hercules, Calif.). The data was processed and graphs were generated using FlowJo (FlowJo, LLC, Ashland, OR).
Western blotting. Cells were incubated with increasing doses of compound 17ya and 100nM colchicine and paclitaxel for 24h, or 100nM compound 17ya for 24h, 48h and 72h for time-dependent studies. The cells were then harvested, washed with ice cold PBS and washed in the presence of HaltTMProtease and phosphatase inhibitors (Thermo Fischer Scientific) in RIPA buffer (25nM Tris pH 7.6, 150nM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) were lysed and then centrifuged at 13000rpm for 10 min at 4 ℃. The protein in the supernatant was determined by BCA protein assay (Thermo Fischer Scientific). Equal amounts of each denatured protein sample were added and separated by SDS-PAGE gradient gel (Bio-Rad, # 456-1083). Proteins were transferred to PVDF membranes via wet cassettes. The membranes were then blocked in 5% skim milk in TBST solution at room temperature for 1 hour, incubated with primary antibody at 4 ℃ overnight, and then bound to secondary antibody for 1 hour. The following primary antibodies were used: rabbit anti-poly (ADP-ribose) polymerase (PARP, 1:1000), rabbit anti-lytic PARP (1:1000), rabbit anti-lytic caspase-3 (1:1000) and rabbit anti-GAPDH HRP conjugate (# 9532; # 5625; # 9661; #3683, Cell Signal Technology, Danvers, MA). Using ClarityTMThe bound proteins were detected by Western ECL substrate (Bio-Rad, #1705060) and visualized by the ChemiDoc-It2 Imager system (UVP, LCC, Upland, Ca).
In vivo orthotopic xenograft models. All animal studies were conducted following NIH experimental animal care principles and protocols approved by the institutional animal care and use committee of the university of tennessee health science. The patient is 5-6 weeks oldNod-Scid-gamma (NSG) female mice were housed in a pathogen-free environment with 12:12 hours of light. The temperature is kept between 20 and 26 ℃, and the relative humidity is kept between 30 and 70 percent. Mu.l of 2.5X 10 in HBSS5Individual MDA-MB-231 cells were surgically inoculated into the left and right inguinal mammary fat pads of NSG mice as described by Pfeffer et al, "Comprehensive analysis of microRNA (miRNA) targets in Breast cells," j. biol. chem.,2013,288, 27480-one 27493, which is hereby incorporated by reference. Mice were examined weekly for tumor appearance until the mean tumor size reached 100mm3. The mice were then randomly divided into 5 groups (n-14 in vehicle control group and n-8 in drug treated group) and drug treatment was started. Control group was orally administered vehicle (PEG 300: water ratio 1:1), drug treated group was orally administered 5mg/kg of compound 17ya, 10mg/kg of compound 17ya, 12.5mg/kg of compound 17ya five times a week, by intraperitoneal injection of 12.5mg/kg paclitaxel every other day, respectively. Primary tumor size was monitored twice weekly using digital calipers and mouse body weight was recorded during treatment. Using the formula volume ═ width2X length)/2 to calculate tumor volume. After 18 days of treatment, the tumor size in the vehicle group reached 1000mm3At the time, tumors and major organs were imaged and collected in 10% phosphate formalin buffer for histological analysis.
Compound 17ya reduced proliferation of different breast cancer cells and interfered with microtubule assembly and the organization of the mitotic spindle. Compound 17ya preceded a set of average ICs50Tested in a melanoma cancer cell line at 4nM, the MTS assay is now used to assess whether compound 17ya can inhibit the growth of breast cancer cells. The results show that compound 17ya has antiproliferative effect on breast cancer cell lines, IC of HER2 positive breast cancer cells50The value was 14nM, while the IC50 value for TNBC cells was 8 nM. The microtubule stabilizing agents colchicine and the tubulin stabilizing agent paclitaxel were added to compare the efficacy of colchicine, paclitaxel and compound 17ya on TNBC cell growth. (for MDA-MB-231, see FIG. 58A; for MDA-MB-486, see FIG. 58B). All three tubulin inhibitors are effective in inhibiting the proliferation of TNBC, whereinIC of Compound 17ya50The values were 8.2-9.6 nM. The results of the colony formation assay showed that compound 17ya attenuated the proliferative capacity of TNBC cells in a dose-dependent manner. (for MDA-MB-231, see FIG. 59A; for MDA-MB-486, see FIG. 59B). Paclitaxel showed the most significant effect, with a relative percentage coverage of 27.5% of colonies relative to colchicine (100%) at 8nM, compound 17ya (55%) being more effective than colchicine. In MDA-MB-468 cells, a reduction in colony formation was observed in colchicine (51%), paclitaxel (7.4%) and compound 17ya (37.7%) at a dose of 8nM, indicating that all three tubulin inhibitors inhibited colony formation of TNBC cells.
Immunofluorescent staining can be used to visualize the microtubule network, in contrast to colchicine and paclitaxel. TNBC cells of the negative control group showed intact microtubule fibers and organization of microtubules as shown in fig. 60. Treatment with paclitaxel produced multipolar spindles with highly condensed chromosomes due to the increase of tubulin polymerization in TNBC cells. As with colchicine treatment, cells treated with compound 17ya shrank and the cell shape changed from spindle to round and irregular, confirming that compound 17ya targets tubulin and interferes with tubulin polymerization.
Example 4
Compound 17ya inhibited TNBC cell migration and invasion. This example focuses on the effect of compound 17ya on TNBC cell migration and invasion after 24 or 48 hours of treatment. Compared to the control group (mobility 100%), compound 17ya inhibited the ability of TNBC cells to migrate through the membrane pores in the presence of 16nM concentration, with MDA-MB-231 cells having an average mobility of 40% and MDA-MB-468 cells having an average mobility of 34%, as shown in fig. 61. Compound 17ya reduced the ability of TNBC cells to invade the Matrigel-coated membrane, with the mean invasion rates of MDA-MB-231 and MDA-MB-468 cells being 55% and 36%, respectively, when the invasion rate of the control group was set at 100%. The results are shown in FIG. 62. The scratch assay was performed using paclitaxel and colchicine as positive controls. For MDA-MB-231, in FIG. 63A, for MDA-MB-486, in FIG. 63B, at 16nM dose, compound 17ya, colchicine and paclitaxel showed effective inhibition of cell migration. After 24 hours, the mean mobilities of DMSO, colchicine, paclitaxel, and compound 17 ya-treated MDA-MB-231 cells were 100%, 67.3%, 13.3%, and 44.9%, respectively. Similarly, MDA-MB-231 cells were shown to have a 15.8%, 14.5% and 17.9% decrease in mobility after 48 hours of treatment with colchicine, paclitaxel and compound 17ya, respectively. This finding led to the conclusion that compound 17ya significantly inhibited cell migration.
Example 5
Compound 17ya blocked TNBC cells and induced apoptosis during G2/M. Microtubule dynamics play an important role in cell division. Its destruction may lead to mitotic arrest of metaphase-growing cells and ultimately to cell death. In this example, it was determined that compound 17ya can affect cell cycle arrest. Flow cytometry analysis was performed on cells treated with 100nM colchicine, 100nM paclitaxel and different concentrations of compound 17ya for 24 hours. Different compounds show different effects on cell cycle progression in different cell lines. Treatment with compound 17ya induced accumulation of MDA-MB-231 cells at G2 and M phases and reduced the cell population at G1 and S phases in a dose-dependent manner. As shown in FIG. 64A, colchicine and paclitaxel used as positive controls also arrested MDA-MB-231 cells at G2/M. As shown in FIG. 64B, compound 17ya induced G2 phase arrest and reduced the cell population in G1 phase in MDA-MB-468 cells with little effect on the percentage of cells in S phase. A small increase in M phase cells was observed. Colchicine arrested MDA-MB-468 cells at G2, and paclitaxel arrested cells at G2 and M, as shown in FIG. 64B. The concentration of compound 17ya resulted in massive accumulation of cells at G2/M phase, 20nM in MDA-MB-231 cells and 50nM in MDA-MB-468 cells, with a maximum accumulation of 100 nM. Thus, compound 17ya induced G2/M phase arrest in TNBC cells, resulting in growth inhibition.
The pro-apoptotic effect of compound 17ya on TNBC cells was investigated. The induction of TNBC apoptosis by compound 17ya was studied by annexin V-FITC-PI double staining. Treatment of MDA-MB-231 and MDA-MB-468 cells 24 minicells with increasing concentrations of Compound 17yaThen (c) is performed. Compound 17ya quantitatively promoted apoptotic cell death in a dose-dependent manner as annexin-V+/PI-Cell, annexin-V+/PI+Cell and annexin-V-/PI+The appearance of the cells is shown in the representative histograms of FIGS. 65A-B. Compound 17ya induced TNBC apoptosis with the same potency as colchicine, but higher than paclitaxel. The results showed that 24, 48 and 72 hours of MDA-MB-231 (FIG. 66A) and MDA-MB-468 (FIG. 66B) cells treated with 100nM of compound 17ya underwent apoptosis in a time-dependent manner.
Caspases and PARP play important roles in the initiation and execution of programmed cell death. By western blot analysis, we determined the role of compound 17ya in whether apoptotic cell death was triggered by modulation of the caspase-3/PARP pathway, expression of cleaved caspase-3, and cleaved PARP in compound 17 ya-treated TNBC cells by western blot analysis. The results show that after 24 hours of compound 17ya treatment, the expression of cleaved caspase-3 and cleaved PARP increased in a dose-dependent manner, although they were both expressed less than MDA-MB-231 (FIG. 67A) and MDA-MB-468 (FIG. 67B) cells in the paclitaxel-treated group. Colchicine is also able to induce upregulation of cleaved caspase-3 and cleaved PARP in MDA-MB-468 cells after 24 hours of treatment. Compound 17ya increased cleaved caspase-3 and cleaved PARP in a time-dependent manner as shown in figure 68. To confirm the effect of compound 17ya on cleaved caspase-3 and cleaved PARP expression at the protein level, caspase 3/7 activity was assessed in MDA-MB-231 and MDA-MB-468 cells using the caspase Glo 3/7 assay system. The results are shown in FIG. 69. Colchicine and paclitaxel were used as positive controls. The caspase 3/7 activity of compound 17ya, colchicine and paclitaxel was increased by up to 4-fold compared to cells in the control group, which is consistent with enhanced induction of apoptosis by TNBC cells.
Example 5
Compound 17ya inhibited TNBC tumor growth in vivo. Compound 17ya affected the in vivo growth of human cancer cell lines by anticancer activity studies in an orthotopic TNBC mouse model. As paclitaxel is one of the chemotherapeutic agents widely used in clinical TNBC therapy; it is included as a comparison. NSG mice bearing MDA-MB-231 xenografts were treated with vehicle, 5mg/kg compound 17ya, 10mg/kg compound 17ya, 12.5mg/kg compound 17ya, and 12.5mg/kg paclitaxel for 18 days. The percentage of tumor size increase was significantly reduced in the 10mg/kg and 12.5mg/kg compound 17ya and paclitaxel treated groups, while the 5mg/kg oral administration showed relatively poor tumor growth inhibition, as shown in figure 70, compared to the vehicle treated group. During the treatment period, no weight loss was observed for compound 17ya treated group, indicating lack of toxicity. Treatment with 12.5mg/kg paclitaxel significantly reduced mouse body weight, indicating the cumulative toxicity of paclitaxel during the treatment, as shown in figure 71. Compound 17ya, 5mg/kg, reduced the mean tumor volume and tumor weight by 38.66% and 26.83%, respectively, compared to vehicle-treated controls. Compound 17ya at 10mg/kg reduced the average tumor volume and weight by 55.73% and 56.10%, respectively, while the dose of 12.5mg/kg reduced the average tumor volume and weight by 61.32% and 62.6%, respectively. The results showed that compound 17ya inhibited TNBC tumor growth in a dose-dependent manner, as shown in fig. 72 and 73. The mean final tumor weights of the group treated with 12.5mg/kg compound 17ya were comparable to paclitaxel (0.46g versus 0.38 g). The efficacy of compound 17ya and paclitaxel on tumors was evident on the tumor images, and treatment showed a significant reduction in tumor volume compared to the vehicle group.
Example 6
Compound 17ya induced tumor necrosis, anti-angiogenesis and apoptosis in vivo. Tumors were excised with H & E staining and the expression of the cell proliferation marker Ki67, the prognostic angiogenesis marker CD31, the apoptosis marker cleaved PARP and cleaved caspase 3 was determined by IHC staining. Both H & E and IHC are imaged near the tumor margins due to internal hypoxia, resulting in natural necrosis inside the tumor. Both compound 17ya and paclitaxel treatment increased the number of atrophic necrotic tumor cells, as indicated by nuclear atrophy. As the dose of compound 17ya was increased from 5mg/kg to 12.5mg/kg, necrotic cells increased. As shown in figure 74, an increase in the percentage of necrotic area of the entire tumor was observed in the group treated with compound 17ya compared to the vehicle-treated counterpart. The area of tumor necrosis in the compound 17ya (12.5mg/kg) treated group was 49.5%, which is comparable to the percentage of tumor necrosis induced by paclitaxel (41.5%), indicating that the compound 17ya is more effective in inducing tumor necrosis than paclitaxel. IHC analysis showed that compound 17ya treatment significantly reduced the number of Ki67 positive cells (fig. 75) and CD31 positive cells (fig. 76) in tumor tissue, and that compound 17ya (12.5mg/kg) treated tumors were reduced by 71% and 87%, respectively, compared to the vehicle control group tumors, indicating that compound 17ya inhibited TNBC cell proliferation and disrupted tumor vasculature in vivo. The results show that cells expressing cleaved PARP (fig. 77) and cleaved caspase-3 (fig. 78) increased significantly in a dose-dependent manner, confirming the increased apoptosis due to treatment with compound 17 ya. Tumor growth inhibition, tumor vasculature destruction and induction of apoptotic cell death following paclitaxel treatment were evident from IHC histological results and the anticancer activity of paclitaxel was similar to compound 17 ya. In summary, the results show that compound 17ya exhibits similar anti-cancer activity to paclitaxel, which significantly inhibits tumor growth at in vivo levels.
Example 7
In a mouse model of lung metastasis, compound 17ya inhibited TNBC spontaneous metastasis and cancer. The inhibition of spontaneous lung metastasis in mice by the vehicle, compound 17ya at 5mg/kg, 10mg/kg and 12.5mg/kg and paclitaxel 12.5mg/kg was tested experimentally. In the vehicle group, lung metastases in the lung lobes were increased (four mice had large metastases, 10 mice had more than five lung metastases). Compound 17ya inhibited spontaneous metastasis of TNBC cells, with a small number of metastases in the 5mg/kg treatment group (six mice had little metastasis and two mice had no metastasis), one or two metastases in the 10mg/kg treatment group (four mice had little metastasis and four mice had no metastasis), metastasis or no metastasis in the 12.5mg/kg treatment group (one mouse had one lung metastasis and seven had no metastasis), and no metastasis in the 12.5mg/kg paclitaxel (all eight mice had no metastasis), indicating that compound has an important effect in inhibiting TNBC metastasis.
Since compound 17ya reduced the number and size of TNBC metastases in the orthotopic mouse model, an experimental lung metastasis model was used to evaluate the anti-metastatic effect of this compound. Due to the weakness of the mice after tail vein inoculation, 10mg/kg paclitaxel and 10mg/kg compound 17ya were selected as the doses for this study. Mice were euthanized 22 days after treatment, and lungs, liver, kidneys and spleen were collected, fixed and examined by anti-mitochondrial IHC and H & E staining. The lungs in the vehicle group completely metastasized (as indicated by brown dots), while the lungs in the compound 17ya and paclitaxel treated groups showed significant inhibition of lung metastasis by TNBC. Results were similar for liver and spleen tissues. Fever metastasis was detected in the kidneys of vehicle mice, while the kidneys of compound 17ya and paclitaxel treated groups were clear, indicating that compound 17ya inhibits metastasis of TNBC. The body weight and physical activity of the mice in the compound 17 ya-treated group were normal, while the body weight and physical activity of the mice in the paclitaxel-treated group were slightly decreased, indicating toxicity of paclitaxel during the long-term treatment. H & E staining showed that multiple metastases of varying sizes were observed in lung, liver, kidney and spleen of vehicle mice, whereas metastases were sparse and smaller in compound 17ya and paclitaxel treated mice. Pulmonary results indicate that compound 17ya has comparable efficacy on paclitaxel in inhibiting TNBC cell metastasis without significant toxicity to mice.
All of the features described herein (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the following claims.